6,937 results on '"Aminoquinolines"'
Search Results
2. G3BP1 binds to guanine quadruplexes in mRNAs to modulate their stabilities.
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He, Xiaomei, Yuan, Jun, and Wang, Yinsheng
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3 Untranslated Regions ,Aminoquinolines ,Base Sequence ,Cloning ,Molecular ,Computational Biology ,DNA Helicases ,Datasets as Topic ,Escherichia coli ,G-Quadruplexes ,Gene Expression ,Genes ,Reporter ,Genetic Vectors ,HEK293 Cells ,HeLa Cells ,Humans ,Ligands ,Luciferases ,Picolinic Acids ,Poly-ADP-Ribose Binding Proteins ,Protein Binding ,RNA Helicases ,RNA Recognition Motif Proteins ,RNA Stability ,Recombinant Proteins - Abstract
RNA guanine quadruplexes (rG4) assume important roles in post-transcriptional regulations of gene expression, which are often modulated by rG4-binding proteins. Hence, understanding the biological functions of rG4s requires the identification and functional characterizations of rG4-recognition proteins. By employing a bioinformatic approach based on the analysis of overlap between peaks obtained from rG4-seq analysis and those detected in >230 eCLIP-seq datasets for RNA-binding proteins generated from the ENCODE project, we identified a large number of candidate rG4-binding proteins. We showed that one of these proteins, G3BP1, is able to bind directly to rG4 structures with high affinity and selectivity, where the binding entails its C-terminal RGG domain and is further enhanced by its RRM domain. Additionally, our seCLIP-Seq data revealed that pyridostatin, a small-molecule rG4 ligand, could displace G3BP1 from mRNA in cells, with the most pronounced effects being observed for the 3-untranslated regions (3-UTR) of mRNAs. Moreover, luciferase reporter assay results showed that G3BP1 positively regulates mRNA stability through its binding with rG4 structures. Together, we identified a number of candidate rG4-binding proteins and validated that G3BP1 can bind directly with rG4 structures and regulate the stabilities of mRNAs.
- Published
- 2021
3. Regulation of P2X1 receptors by modulators of the cAMP effectors PKA and EPAC.
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Griffin, Caoimhín, Large, Roddy, Hollywood, Mark, Thornbury, Keith, Sergeant, Gerard, and Fong, Zhihui
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EPAC ,P2X1 ,cAMP ,Adenosine Triphosphate ,Aminoquinolines ,Cyclic AMP ,Cyclic AMP-Dependent Protein Kinases ,Gene Expression Regulation ,Guanine Nucleotide Exchange Factors ,HEK293 Cells ,Humans ,Kidney ,Pyrimidines ,Receptors ,Purinergic P2X1 ,Receptors ,Purinergic P2X2 ,rac1 GTP-Binding Protein - Abstract
P2X1 receptors are adenosine triphosphate (ATP)-gated cation channels that are functionally important for male fertility, bladder contraction, and platelet aggregation. The activity of P2X1 receptors is modulated by lipids and intracellular messengers such as cAMP, which can stimulate protein kinase A (PKA). Exchange protein activated by cAMP (EPAC) is another cAMP effector; however, its effect on P2X1 receptors has not yet been determined. Here, we demonstrate that P2X1 currents, recorded from human embryonic kidney (HEK) cells transiently transfected with P2X1 cDNA, were inhibited by the highly selective EPAC activator 007-AM. In contrast, EPAC activation enhanced P2X2 current amplitude. The PKA activator 6-MB-cAMP did not affect P2X1 currents, but inhibited P2X2 currents. The inhibitory effects of EPAC on P2X1 were prevented by triple mutation of residues 21 to 23 on the amino terminus of P2X1 subunits to the equivalent amino acids on P2X2 receptors. Double mutation of residues 21 and 22 and single mutation of residue 23 also protected P2X1 receptors from inhibition by EPAC activation. Finally, the inhibitory effects of EPAC on P2X1 were also prevented by NSC23766, an inhibitor of Rac1, a member of the Rho family of small GTPases. These data suggest that EPAC is an important regulator of P2X1 and P2X2 receptors.
- Published
- 2021
4. Non-surgical management of primary invasive melanoma
- Author
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Wang, Elizabeth A, Kao, Jason, Ma, Chelsea, Cheng, Michelle Y, Barton, Virginia R, Petukhova, Tatyana A, Kiuru, Maija, Maverakis, Emanual, and Kirane, Amanda R
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Clinical Research ,Patient Safety ,Aged ,Aminoquinolines ,Antineoplastic Agents ,Humans ,Imiquimod ,Melanoma ,Skin Neoplasms ,Treatment Outcome ,Tretinoin ,Intralesional IL-2 ,interleukin-2 ,non-surgical alternatives ,imiquimod ,tretinoin ,primary invasive melanoma ,TVEC ,Dermatology & Venereal Diseases ,Clinical sciences - Abstract
Surgical excision is standard-of-care for primary invasive melanoma, but best care can be unclear for patients who are surgically high-risk or for whom resection may be excessively morbid. Alternatives to surgical excision have emerged for treatment of metastatic melanoma but have not yet been explored for primary invasive melanoma. Two elderly patients with primary invasive melanoma with many medical co-morbidities who were not surgical candidates were determined to be appropriate candidates for an intralesional IL-2 based regimen. Herein we report their clinical and histological outcome. An intralesional-based regimen (intralesional IL-2, topical imiquimod cream 5%, and tretinoin cream 0.1% under occlusion to the treatment site) was administered over the course of six to seven weeks, followed by two weeks of topical-only therapy. A complete response was seen after eight to nine weeks of treating invasive melanomas that were ≥1.85 mm and 5.5 mm thick. For patients with primary invasive melanoma on high morbidity sites and patients who are poor surgical candidates, a neoadjuvant intralesional IL-2-based approach may be a reasonable alternative. The two cases presented here suggest that alternative intralesional-based treatment modalities may minimize the size of the excision site and can be associated with complete histological clearance of invasive melanoma.
- Published
- 2021
5. Changing Prevalence of Potential Mediators of Aminoquinoline, Antifolate, and Artemisinin Resistance Across Uganda
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Asua, Victor, Conrad, Melissa D, Aydemir, Ozkan, Duvalsaint, Marvin, Legac, Jennifer, Duarte, Elias, Tumwebaze, Patrick, Chin, Deborah M, Cooper, Roland A, Yeka, Adoke, Kamya, Moses R, Dorsey, Grant, Nsobya, Sam L, Bailey, Jeffrey, and Rosenthal, Philip J
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Malaria ,Antimicrobial Resistance ,Rare Diseases ,Infectious Diseases ,Genetics ,Vector-Borne Diseases ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Infection ,Good Health and Well Being ,Aminoquinolines ,Antimalarials ,Artemisinins ,Drug Resistance ,Female ,Folic Acid Antagonists ,Humans ,Malaria ,Falciparum ,Plasmodium falciparum ,Pregnancy ,Prevalence ,Uganda ,drug resistance ,PfCRT ,PfMDR1 ,PfDHFR ,PfDHPS ,PfK13 ,Plasmodium falciparum ,Biological Sciences ,Medical and Health Sciences ,Microbiology - Abstract
BackgroundIn Uganda, artemether-lumefantrine is recommended for malaria treatment and sulfadoxine-pyrimethamine for chemoprevention during pregnancy, but drug resistance may limit efficacies.MethodsGenetic polymorphisms associated with sensitivities to key drugs were characterized in samples collected from 16 sites across Uganda in 2018 and 2019 by ligase detection reaction fluorescent microsphere, molecular inversion probe, dideoxy sequencing, and quantitative polymerase chain reaction assays.ResultsConsidering transporter polymorphisms associated with resistance to aminoquinolines, the prevalence of Plasmodium falciparum chloroquine resistance transporter (PfCRT) 76T decreased, but varied markedly between sites (0-46% in 2018; 0-23% in 2019); additional PfCRT polymorphisms and plasmepsin-2/3 amplifications associated elsewhere with resistance to piperaquine were not seen. For P. falciparum multidrug resistance protein 1, in 2019 the 86Y mutation was absent at all sites, the 1246Y mutation had prevalence ≤20% at 14 of 16 sites, and gene amplification was not seen. Considering mutations associated with high-level sulfadoxine-pyrimethamine resistance, prevalences of P. falciparum dihydrofolate reductase 164L (up to 80%) and dihydropteroate synthase 581G (up to 67%) were high at multiple sites. Considering P. falciparum kelch protein propeller domain mutations associated with artemisinin delayed clearance, prevalence of the 469Y and 675V mutations has increased at multiple sites in northern Uganda (up to 23% and 41%, respectively).ConclusionsWe demonstrate concerning spread of mutations that may limit efficacies of key antimalarial drugs.
- Published
- 2021
6. Associations between Aminoquinoline Resistance Genotypes and Clinical Presentations of Plasmodium falciparum Infection in Uganda
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Cuu, Gloria, Asua, Victor, Tukwasibwe, Stephen, Nsobya, Sam L, Nanteza, Ann, Kimuda, Magambo Phillip, Mpimbaza, Arthur, and Rosenthal, Philip J
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Medical Microbiology ,Biomedical and Clinical Sciences ,Clinical Sciences ,Rare Diseases ,Vector-Borne Diseases ,Infectious Diseases ,Genetics ,Malaria ,Clinical Research ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,Aminoquinolines ,Antimalarials ,Case-Control Studies ,Child ,Child ,Preschool ,Drug Resistance ,Genotype ,Humans ,Infant ,Malaria ,Falciparum ,Multidrug Resistance-Associated Proteins ,Plasmodium falciparum ,Protozoan Proteins ,Uganda ,malaria ,drug resistance ,aminoquinoline ,genotype ,drug resistance mechanisms ,Microbiology ,Pharmacology and Pharmaceutical Sciences ,Medical microbiology ,Pharmacology and pharmaceutical sciences - Abstract
Mutations that mediate resistance of Plasmodium falciparum to aminoquinoline antimalarials are selected by prior drug use and may alter parasite fitness, but associations with clinical presentations are uncertain. We evaluated genotypes in samples from a case-control study of determinants of severe malaria in Ugandan children 4 months to 10 years of age. We studied 274 cases with severe malaria matched by age and geography to 275 uncomplicated malaria controls and 179 asymptomatic parasitemic controls. The overall prevalence of mutations of interest (considering mixed results as mutant) was 67.0% for PfCRT K76T, 8.5% for PfMDR1 N86Y, 71.5% for PfMDR1 Y184F, and 14.7% for PfMDR1 D1246Y. Compared to asymptomatic controls, the odds of mutant PfCRT 76T were lower for uncomplicated (odds ratio, 0.42 [95% confidence interval, 0.24 to 0.72]; P
- Published
- 2020
7. Pharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy.
- Author
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Ma, Zhao, Li, Jin, Lin, Kai, Ramachandran, Mythili, Zhang, Dalin, Showalter, Megan, De Souza, Cristabelle, Lindstrom, Aaron, Solano, Lucas N, Jia, Bei, Urayama, Shiro, Duan, Yuyou, Fiehn, Oliver, Lin, Tzu-Yin, Li, Minyong, and Li, Yuanpei
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Cell Line ,Tumor ,Lysosomes ,Animals ,Humans ,Rats ,Rats ,Sprague-Dawley ,Neoplasms ,Aminoquinolines ,Antineoplastic Agents ,Drug Delivery Systems ,Drug Compounding ,Cell Proliferation ,Autophagy ,Nanomedicine ,Nanoparticles ,Cell Line ,Tumor ,Sprague-Dawley - Abstract
Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy.
- Published
- 2020
8. First Contact: 7‑Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate
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Cinelli, Maris A, Reidl, Cory T, Li, Huiying, Chreifi, Georges, Poulos, Thomas L, and Silverman, Richard B
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Aminoquinolines ,Animals ,Aspartic Acid ,Blood-Brain Barrier ,Catalytic Domain ,Crystallography ,X-Ray ,Enzyme Assays ,Enzyme Inhibitors ,Humans ,Isoenzymes ,Microsomes ,Liver ,Molecular Structure ,Mutagenesis ,Site-Directed ,Mutation ,Nitric Oxide Synthase Type I ,Permeability ,Protein Binding ,Rats ,Structure-Activity Relationship ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry - Abstract
Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS, and only modest selectivity for nNOS over related enzymes. In this study, we synthesized new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS. Compounds with a meta-relationship between the aminoquinoline and a positively charged tail moiety were potent and had up to nearly 900-fold selectivity for human nNOS over human eNOS. X-ray crystallography indicates that the amino groups of some compounds occupy a water-filled pocket surrounding an nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first aminoquinolines to interact with this residue.
- Published
- 2020
9. Metal-Binding Pharmacophore Library Yields the Discovery of a Glyoxalase 1 Inhibitor
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Perez, Christian, Barkley-Levenson, Amanda M, Dick, Benjamin L, Glatt, Peter F, Martinez, Yadira, Siegel, Dionicio, Momper, Jeremiah D, Palmer, Abraham A, and Cohen, Seth M
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Mental Health ,Brain Disorders ,Depression ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Mental health ,Aminoquinolines ,Animals ,Antidepressive Agents ,Brain ,Drug Discovery ,Enzyme Inhibitors ,Female ,Humans ,Lactoylglutathione Lyase ,Male ,Mice ,Molecular Structure ,Pyruvaldehyde ,Small Molecule Libraries ,Structure-Activity Relationship ,Sulfonamides ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry - Abstract
Anxiety and depression are common, highly comorbid psychiatric diseases that account for a large proportion of worldwide medical disability. Glyoxalase 1 (GLO1) has been identified as a possible target for the treatment of anxiety and depression. GLO1 is a Zn2+-dependent enzyme that isomerizes a hemithioacetal, formed from glutathione and methylglyoxal, to a lactic acid thioester. To develop active inhibitors of GLO1, fragment-based drug discovery was used to identify fragments that could serve as core scaffolds for lead development. After screening a focused library of metal-binding pharmacophores, 8-(methylsulfonylamino)quinoline (8-MSQ) was identified as a hit. Through computational modeling and synthetic elaboration, a potent GLO1 inhibitor was developed with a novel sulfonamide core pharmacophore. A lead compound was demonstrated to penetrate the blood-brain barrier, elevate levels of methylglyoxal in the brain, and reduce depression-like behavior in mice. These findings provide the basis for GLO1 inhibitors to treat depression and related psychiatric illnesses.
- Published
- 2019
10. A Novel and Simple Synthesis of Ethers of Hydroxypyridines with Hexafluoropropan-2-ol via Diazotization of Aminopyridines and Aminoquinolines Under Acid-Free Conditions.
- Author
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Filimonov, Victor D., Sanzhiev, Aldar N., Gulyaev, Roman O., Krasnokutskaya, Elena A., and Bondarev, Alexander A.
- Subjects
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AMINOPYRIDINES , *ETHER synthesis , *DIAZOTIZATION , *HYDROXYPYRIDINES - Abstract
Herein, we report the first example of diazotization of aminopyridines and aminoquinolines with t-BuONO in hexafluoropropan-2-ol in the absence of acids or other initiators. For aminopyridines, this reaction is the first general route toward 2-, 3-, and 4-[(1,1,1,3,3,3-hexafluoropropan-2-yl)oxy]pyridines. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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11. Guidelines of care for the management of basal cell carcinoma
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Group, Work, Bichakjian, Christopher, Armstrong, April, Baum, Christian, Bordeaux, Jeremy S, Brown, Marc, Busam, Klaus J, Eisen, Daniel B, Iyengar, Vivek, Lober, Clifford, Margolis, David J, Messina, Jane, Miller, Alexander, Miller, Stanley, Mostow, Eliot, Mowad, Christen, Nehal, Kishwer, Schmitt-Burr, Kristi, Sekulic, Aleksandar, Storrs, Paul, Teng, Joyce, Yu, Siegrid, Huang, Conway, Boyer, Kevin, Begolka, Wendy Smith, Alam, Murad, Reviewers, Invited, Kim, John YS, Kozlow, Jeffrey H, Mittal, Bharat, Moyer, Jeffrey, Olencki, Thomas, and Rodgers, Phillip
- Subjects
Clinical Research ,Cancer ,Administration ,Cutaneous ,Aminoquinolines ,Anilides ,Antineoplastic Agents ,Carcinoma ,Basal Cell ,Dermatologic Surgical Procedures ,Early Detection of Cancer ,Humans ,Imiquimod ,Neoplasm Grading ,Neoplasm Staging ,Neoplasms ,Second Primary ,Photochemotherapy ,Photosensitizing Agents ,Pyridines ,Radiotherapy ,Skin Neoplasms ,United States ,basal cell carcinoma ,biopsy ,curettage ,metastasis ,phototherapy ,radiotherapy ,staging ,surgery ,surveillance ,topical therapy ,Work Group ,Invited Reviewers ,Clinical Sciences ,Dermatology & Venereal Diseases - Abstract
Basal cell carcinoma (BCC) is the most common form of human cancer, with a continually increasing annual incidence in the United States. When diagnosed early, the majority of BCCs are readily treated with office-based therapy, which is highly curative. In these evidence-based guidelines of care, we provide recommendations for the management of patients with BCC, as well as an in-depth review of the best available literature in support of these recommendations. We discuss biopsy techniques for a clinically suspicious lesion and offer recommendations for the histopathologic interpretation of BCC. In the absence of a formal staging system, the best available stratification based on risk for recurrence is reviewed. With regard to treatment, we provide recommendations on treatment modalities along a broad therapeutic spectrum, ranging from topical agents and superficially destructive modalities to surgical techniques and systemic therapy. Finally, we review the available literature and provide recommendations on prevention and the most appropriate follow-up for patients in whom BCC has been diagnosed.
- Published
- 2018
12. Guidelines of care for the management of basal cell carcinoma.
- Author
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Work Group, Invited Reviewers, Kim, John YS, Kozlow, Jeffrey H, Mittal, Bharat, Moyer, Jeffrey, Olencki, Thomas, and Rodgers, Phillip
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Work Group ,Invited Reviewers ,Humans ,Carcinoma ,Basal Cell ,Skin Neoplasms ,Neoplasms ,Second Primary ,Anilides ,Pyridines ,Aminoquinolines ,Antineoplastic Agents ,Photosensitizing Agents ,Neoplasm Staging ,Photochemotherapy ,Radiotherapy ,Administration ,Cutaneous ,United States ,Early Detection of Cancer ,Neoplasm Grading ,Dermatologic Surgical Procedures ,Imiquimod ,basal cell carcinoma ,biopsy ,curettage ,metastasis ,phototherapy ,radiotherapy ,staging ,surgery ,surveillance ,topical therapy ,Dermatology & Venereal Diseases ,Clinical Sciences - Abstract
Basal cell carcinoma (BCC) is the most common form of human cancer, with a continually increasing annual incidence in the United States. When diagnosed early, the majority of BCCs are readily treated with office-based therapy, which is highly curative. In these evidence-based guidelines of care, we provide recommendations for the management of patients with BCC, as well as an in-depth review of the best available literature in support of these recommendations. We discuss biopsy techniques for a clinically suspicious lesion and offer recommendations for the histopathologic interpretation of BCC. In the absence of a formal staging system, the best available stratification based on risk for recurrence is reviewed. With regard to treatment, we provide recommendations on treatment modalities along a broad therapeutic spectrum, ranging from topical agents and superficially destructive modalities to surgical techniques and systemic therapy. Finally, we review the available literature and provide recommendations on prevention and the most appropriate follow-up for patients in whom BCC has been diagnosed.
- Published
- 2018
13. P2X7 receptor antagonism by AZ10606120 significantly depletes glioblastoma cancer stem cells in vitro.
- Author
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Kan LK, Drill M, Jayakrishnan PC, Sequeira RP, Sanfilippo PG, McLean C, Hunn M, Williams DA, O'Brien TJ, Drummond KJ, and Monif M
- Subjects
- Humans, Cell Line, Tumor, Pyridines pharmacology, Apoptosis drug effects, Adamantane analogs & derivatives, Aminoquinolines, Glioblastoma metabolism, Glioblastoma drug therapy, Glioblastoma pathology, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Receptors, Purinergic P2X7 metabolism, Purinergic P2X Receptor Antagonists pharmacology, Temozolomide pharmacology, Brain Neoplasms metabolism, Brain Neoplasms drug therapy, Brain Neoplasms pathology
- Abstract
Glioblastoma is the most aggressive and lethal primary brain malignancy with limited treatment options and poor prognosis. Self-renewing glioblastoma cancer stem cells (GSCs) facilitate tumour progression, resistance to conventional treatment and tumour recurrence. GSCs are resistant to standard treatments. There is a need for novel treatment alternatives that effectively target GSCs. The purinergic P2X receptor 7 (P2X7R) is expressed in glioblastomas and has been implicated in disease pathogenesis. However, the roles of P2X7R have not been comprehensively elucidated in conventional treatment-resistant GSCs. This study characterised P2X7R channel and pore function and investigated the effect of pharmacological P2X7R inhibition in GSCs. Immunofluorescence and live cell fluorescent dye uptake experiments revealed P2X7R expression, and channel and pore function in GSCs. Treatment of GSCs with the P2X7R antagonist, AZ10606120 (AZ), for 72 hours significantly reduced GSC numbers, compared to untreated cells. When compared with the effect of the first-line conventional chemotherapy, temozolomide (TMZ), GSCs treated with AZ had significantly lower cell numbers than TMZ-treated cultures, while TMZ treatment alone did not significantly deplete GSC numbers compared to the control. AZ treatment also induced significant lactate dehydrogenase release by GSCs, indicative of treatment-induced cytotoxic cell death. There were no significant differences in the expression of apoptotic markers, Annexin V and cleaved caspase-3, between AZ-treated cells and the control. Collectively, this study reveals for the first time functional P2X7R channel and pore in GSCs and significant GSC depletion following P2X7R inhibition by AZ. These results indicate that P2X7R inhibition may be a novel therapeutic alternative for glioblastoma, with effectiveness against GSCs resistant to conventional chemotherapy., Competing Interests: Declaration of Competing Interest TJO has received support from the National Health and Medical Research Council (APP1176426), The Medical Research Future Fund, The National Institute of Neurological Disorders and Stroke and Monash University. He has been supported by research grants and consultancies to his institution from Eisai, UCB Pharma, Praxis Precision Medicines, BioGen and Supernus. MM has served on advisory board for Merck and has received speaker honoraria from Merch and Biogen. Her institution receives funding from Merck, Australian National Health Medical Research Council, Brain Foundation, Charles and Sylvia Viertel Foundation, and MS Research Australia., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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14. Small molecule telomerase inhibitors are also potent inhibitors of telomeric C-strand synthesis.
- Author
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Johnson K, Seidel JM, and Cech TR
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- Humans, Picolinic Acids pharmacology, Picolinic Acids chemistry, DNA Replication drug effects, DNA Polymerase I antagonists & inhibitors, DNA Polymerase I metabolism, DNA metabolism, Aminoquinolines, Porphyrins, DNA Primase, Telomerase antagonists & inhibitors, Telomerase metabolism, Telomerase genetics, Telomere metabolism, G-Quadruplexes drug effects, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis
- Abstract
Telomere replication is essential for continued proliferation of human cells, such as stem cells and cancer cells. Telomerase lengthens the telomeric G-strand, while C-strand replication is accomplished by CST-polymerase α-primase (CST-PP). Replication of both strands is inhibited by formation of G-quadruplex (GQ) structures in the G-rich single-stranded DNA. TMPyP4 and pyridostatin (PDS), which stabilize GQ structures in both DNA and RNA, inhibit telomerase in vitro, and in human cells they cause telomere shortening that has been attributed to telomerase inhibition. Here, we show that TMPyP4 and PDS also inhibit C-strand synthesis by stabilizing DNA secondary structures and thereby preventing CST-PP from binding to telomeric DNA. We also show that these small molecules inhibit CST-PP binding to a DNA sequence containing no consecutive guanine residues, which is unlikely to form GQs. Thus, while these "telomerase inhibitors" indeed inhibit telomerase, they are also robust inhibitors of telomeric C-strand synthesis. Furthermore, given their binding to GQ RNA and their limited specificity for GQ structures, they may disrupt many other protein-nucleic acid interactions in human cells., (© 2024 Johnson et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)
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- 2024
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15. The efficacy and potential mechanisms of pyrotinib in targeting EGFR and HER2 in advanced oral squamous cell carcinoma.
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Zhou L, Le K, Chen Q, and Wang H
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- Humans, Animals, Cell Line, Tumor, Female, Mice, Male, Apoptosis drug effects, Acrylamides pharmacology, Acrylamides therapeutic use, Middle Aged, Cell Proliferation drug effects, Mice, Nude, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Movement drug effects, Aminoquinolines, Mouth Neoplasms drug therapy, Mouth Neoplasms pathology, Mouth Neoplasms metabolism, Receptor, ErbB-2 metabolism, ErbB Receptors metabolism, ErbB Receptors antagonists & inhibitors, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell pathology, Carcinoma, Squamous Cell metabolism
- Abstract
Background: Human epidermal growth factor receptor 2 (HER2) plays an important role in the progression of multiple solid tumors and induces resistance to epidermal growth factor receptor (EGFR) target treatment. However, the expression status and the clinical significance of HER2 in oral squamous cell carcinoma (OSCC) is still controversial. Pyrotinib (PYR) is a promising novel EGFR/HER2 dual inhibitor, whose efficacy in OSCC has not been determined., Methods: 57 locally advanced de novo OSCC patients were included in this study to investigate the relationship between the HER2 expression levels and the prognosis by the tissue microarray analysis (TMA). In vitro and in vivo experiments were performed to retrieve the efficacy of PYR in OSCC. The main downstream of HER2 was evaluated by western blotting in OSCC cell lines and xenograft tumors to explore the potential mechanism of PYR., Results: This study revealed the primary tumor of OSCC had higher HER2 expression levels. Patients with HER2 overexpression had poor overall survival (P < 0.014) and poor disease free survival (P < 0.042). In vitro, PYR suppressed the proliferation, colony formation and migration of OSCC cells. It also promoted apoptosis of OSCC cells and induced cell cycle arrest. Furthermore, PYR was able to inhibit the occurrence and development of OSCC effectively in vivo. Western blotting revealed that PYR suppressed OSCC by inhibiting the phosphorylation of HER2, AKT and ERK., Conclusions: This study exhibited the anti-OSCC effects of PYR in vitro and in vivo, and demonstrated PYR inhibited OSCC cells by inducing apoptosis via the HER2/ AKT and ERK pathway. The result of this study also indicated locally advanced OSCC patients might benefit from HER2 assay and EGFR/HER2 dual inhibit treatment., (© 2024. The Author(s).)
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- 2024
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16. Pyrotinib and Trastuzumab Plus Chemotherapy Serve as an Acceptable Neoadjuvant Regimen Exhibiting Good Efficacy and Tolerance in HER2-Positive Breast Cancer Patients.
- Author
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Chen Y, Zhang T, Zhang R, and Cao X
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- Humans, Female, Middle Aged, Adult, Retrospective Studies, Aged, Docetaxel administration & dosage, Docetaxel adverse effects, Docetaxel therapeutic use, Docetaxel pharmacology, Acrylamides administration & dosage, Acrylamides therapeutic use, Acrylamides adverse effects, Aminoquinolines, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Trastuzumab administration & dosage, Trastuzumab therapeutic use, Trastuzumab adverse effects, Trastuzumab pharmacology, Neoadjuvant Therapy methods, Receptor, ErbB-2 metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols adverse effects
- Abstract
Objective: Pyrotinib, a new irreversible dual pan-human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase inhibitor blocking EGFR and HER2, has achieved a promising efficacy for advanced HER2-positive (HER2
+ ) breast cancer. This study intended to further investigate the efficacy and safety of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2+ breast cancer treatment. Methods: Thirty-eight HER2+ breast cancer patients who received neoadjuvant pyrotinib and trastuzumab plus chemotherapy (docetaxel and carboplatin) were retrospectively reviewed. Clinical response by Response Evaluation Criteria in Solid Tumors (RECIST), pathological complete response (pCR), and adverse events data was retrieved. Results: According to the RECIST, the complete response rate was 0.0%, 10.5%, and 15.8% after second-cycle, fourth-cycle, and sixth-cycle therapy, respectively; whereas the objective response rate was 76.3%, 92.1%, and 100.0%, accordingly. The total pCR (tpCR) rate was 52.6%, the pCR rate of the breast was also 52.6%, and the pCR rate of lymph nodes was 86.8%. The tpCR rate was lower in patients with HER2 immunohistochemistry (IHC)++ and amplification by fluorescent in situ hybridization (FISH) than in those with HER2 IHC+++ (14.3% vs. 61.3%, p = 0.024), which was also lower in patients with Ki-67 expression ≥30% than in those with Ki-67 expression <30% (40.0% vs. 76.9%, p = 0.031). The common adverse events included diarrhea (84.2%), anemia (73.7%), nausea and vomiting (63.2%), fatigue (50.0%), hypomagnesemia (44.7%), leukopenia (42.1%), thrombocytopenia (39.5%), elevated transaminase (36.8%), and pruritus (31.6%). Conclusions: Pyrotinib and trastuzumab plus chemotherapy serve as an acceptable neoadjuvant regimen exhibiting good efficacy and tolerance in HER2+ breast cancer patients, while further large-scale validation is warranted.- Published
- 2024
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17. A Planned Trial to Evaluate the Safety and Efficacy of Tafenoquine + Atovaquone/Azithromycin in Hospitalized Patients With Babesiosis.
- Author
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Dow GS and Smith B
- Subjects
- Humans, Fluorenes therapeutic use, Fluorenes adverse effects, Fluorenes administration & dosage, Drug Therapy, Combination, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents adverse effects, Anti-Bacterial Agents administration & dosage, Treatment Outcome, Hospitalization, Aminoquinolines, Atovaquone therapeutic use, Atovaquone adverse effects, Babesiosis drug therapy, Azithromycin therapeutic use, Azithromycin adverse effects, Azithromycin administration & dosage
- Abstract
Competing Interests: Potential conflicts of interest. G. D. is the compensated CEO, president, and board member of 60 Degrees Pharmaceuticals, Inc; a >5% shareholder of the company; and an inventor on US provisional 63/461 060 (“Methods for the treatment and prevention of non-viral tickborne diseases and symptoms thereof”). G. D. has a financial interest in the commercial success of tafenoquine. B. S. is the compensated chief medical officer and <1% equity owner of 60 Degrees Pharmaceuticals, Inc. These statements are made in the interest of full disclosure and not because the authors believe that these statements constitute a conflict of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
- Published
- 2024
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18. Exploring G-quadruplex structure in PRCC-TFE3 fusion oncogene: Plausible use as anti cancer therapy for translocation Renal cell carcinoma (tRCC).
- Author
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Neha N and Das P
- Subjects
- Humans, HEK293 Cells, Circular Dichroism, Aminoquinolines, Neoplasm Proteins, Picolinic Acids, Cell Cycle Proteins, G-Quadruplexes, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell drug therapy, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors chemistry, Kidney Neoplasms genetics, Kidney Neoplasms drug therapy, Kidney Neoplasms metabolism, Kidney Neoplasms pathology, Oncogene Proteins, Fusion genetics, Translocation, Genetic
- Abstract
The TFE3 fusion gene, byproduct of Xp11.2 translocation, is the diagnostic marker for translocation renal cell carcinoma (tRCC). Absence of any clinically recognized therapy for tRCC, pressing a need to create novel and efficient therapeutic approaches. Previous studies shown that stabilization of the G-quadruplex structure in oncogenes suppresses their expression machinery. To combat the oncogenesis caused by fusion genes, our objective is to locate and stabilize the G-quadruplex structure within the PRCC-TFE3 fusion gene. Using the Quadruplex-forming G Rich Sequences (QGRS) mapper and the Non-B DNA motif search tool (nBMST) online server, we found putative G-quadruplex forming sequences (PQS) in the PRCC-TFE3 fusion gene. Circular dichroism demonstrating a parallel G-quadruplex in the targeted sequence. Fluorescence and UV-vis spectroscopy results suggest that pyridostatin binds to this newly discovered G-quadruplex. The PCR stop assay, as well as transcriptional or translational inhibition using real time PCR and Dual luciferase assay, revealed that stable G-quadruplex formation affects biological processes. Confocal microscopy of HEK293T cells transfected with the fusion transcript confirmed G-quadruplexes formation in cell. This investigation may shed light on G-quadruplex's functions in fusion genes and may help in the development of therapies specifically targeted against fusion oncogenes, which would enhance the capability of current tRCC therapy approach., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)
- Published
- 2024
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19. The human malaria- Aotus monkey model: a historical perspective in antimalarial chemotherapy research at the Gorgas Memorial Laboratory-Panama.
- Author
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Obaldía N 3rd
- Subjects
- Animals, Humans, Panama, Aotidae, Plasmodium falciparum drug effects, Malaria drug therapy, Plasmodium vivax drug effects, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Artesunate therapeutic use, Artesunate pharmacology, Artesunate pharmacokinetics, Malaria, Vivax drug therapy, Malaria, Vivax parasitology, History, 20th Century, Aminoquinolines, Antimalarials therapeutic use, Antimalarials pharmacokinetics, Antimalarials pharmacology, Artemisinins therapeutic use, Artemisinins pharmacology, Disease Models, Animal
- Abstract
The human malaria- Aotus monkey model has served the malaria research community since its inception in 1966 at the Gorgas Memorial Laboratory (GML) in Panama. Spanning over five decades, this model has been instrumental in evaluating the in vivo efficacy and pharmacokinetics of a wide array of candidate antimalarial drugs, whether used singly or in combination. The animal model could be infected with drug-resistant and susceptible Plasmodium falciparum and Plasmodium vivax strains that follow a characteristic and reproducible course of infection, remarkably like human untreated and treated infections. Over the years, the model has enabled the evaluation of several synthetic and semisynthetic endoperoxides, for instance, artelinic acid, artesunate, artemether, arteether, and artemisone. These compounds have been evaluated alone and in combination with long-acting partner drugs, commonly referred to as artemisinin-based combination therapies, which are recommended as first-line treatment against uncomplicated malaria. Further, the model has also supported the evaluation of the primaquine analog tafenoquine against blood stages of P. vivax , contributing to its progression to clinical trials and eventual approval. Besides, the P. falciparum / Aotus model at GML has also played a pivotal role in exploring the biology, immunology, and pathogenesis of malaria and in the characterization of drug-resistant P. falciparum and P. vivax strains. This minireview offers a historical overview of the most significant contributions made by the Panamanian owl monkey ( Aotus lemurinus lemurinus ) to malaria chemotherapy research., Competing Interests: The author declares no conflict of interest.
- Published
- 2024
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20. A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome.
- Author
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Badolato R, Alsina L, Azar A, Bertrand Y, Bolyard AA, Dale D, Deyà-Martínez À, Dickerson KE, Ezra N, Hasle H, Kang HJ, Kiani-Alikhan S, Kuijpers TW, Kulagin A, Langguth D, Levin C, Neth O, Olbrich P, Peake J, Rodina Y, Rutten CE, Shcherbina A, Tarrant TK, Vossen MG, Wysocki CA, Belschner A, Bridger GJ, Chen K, Dubuc S, Hu Y, Jiang H, Li S, MacLeod R, Stewart M, Taveras AG, Yan T, and Donadieu J
- Subjects
- Humans, Female, Male, Double-Blind Method, Adult, Middle Aged, Quinolines adverse effects, Quinolines administration & dosage, Quinolines therapeutic use, Adolescent, Young Adult, Child, Lymphocyte Count, Aminoquinolines, Benzimidazoles, Butylamines, Receptors, CXCR4 antagonists & inhibitors, Primary Immunodeficiency Diseases drug therapy, Warts drug therapy, Immunologic Deficiency Syndromes drug therapy
- Abstract
Abstract: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/μL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/μL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/μL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
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21. Targeting specific DNA G-quadruplexes with CRISPR-guided G-quadruplex-binding proteins and ligands.
- Author
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Qin G, Liu Z, Yang J, Liao X, Zhao C, Ren J, and Qu X
- Subjects
- Humans, Ligands, Phosphoproteins metabolism, Phosphoproteins genetics, Picolinic Acids pharmacology, Picolinic Acids chemistry, Cell Proliferation drug effects, Cell Differentiation drug effects, Animals, Cellular Senescence drug effects, Cellular Senescence genetics, CRISPR-Associated Protein 9 metabolism, CRISPR-Associated Protein 9 genetics, Promoter Regions, Genetic, Telomere metabolism, Telomere genetics, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Pyridines pharmacology, Pyridines chemistry, DNA metabolism, DNA genetics, Mice, Clustered Regularly Interspaced Short Palindromic Repeats, HEK293 Cells, Myoblasts metabolism, Myoblasts cytology, Aminoquinolines, G-Quadruplexes, Nucleolin, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, CRISPR-Cas Systems
- Abstract
Despite the demonstrated importance of DNA G-quadruplexes (G4s) in health and disease, technologies to readily manipulate specific G4 folding for functional analysis and therapeutic purposes are lacking. Here we employ G4-stabilizing protein/ligand in conjunction with CRISPR to selectively facilitate single or multiple targeted G4 folding within specific genomic loci. We demonstrate that fusion of nucleolin with a catalytically inactive Cas9 can specifically stabilize G4s in the promoter of oncogene MYC and muscle-associated gene Itga7 as well as telomere G4s, leading to cell proliferation arrest, inhibition of myoblast differentiation and cell senescence, respectively. Furthermore, CRISPR can confer intra-G4 selectivity to G4-binding compounds pyridodicarboxamide and pyridostatin. Compared with traditional G4 ligands, CRISPR-guided biotin-conjugated pyridodicarboxamide enables a more precise investigation into the biological functionality of de novo G4s. Our study provides insights that will enhance understanding of G4 functions and therapeutic interventions., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
- Full Text
- View/download PDF
22. A comprehensive clinical evaluation of HER2-TKIs in patients with previously treated HER2-positive metastatic breast cancer.
- Author
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Ji WJ, Lu X, Wang YG, and Chen LW
- Subjects
- Humans, Female, Lapatinib therapeutic use, Antineoplastic Agents therapeutic use, Quinolines therapeutic use, Quinolines adverse effects, Acrylamides, Aminoquinolines, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Receptor, ErbB-2 metabolism, Protein Kinase Inhibitors therapeutic use
- Abstract
Human epidermal growth factor receptor 2-tyrosine kinase inhibitors (HER2-TKIs) have been extensively utilized for treating HER2-positive metastatic breast cancer (MBC), with numerous clinical trial reports available. We aim to systematically perform a comprehensive clinical evaluation on HER2-TKIs, provide a reference for the clinical rational use of drugs, and serve for the decision-making of the national drug policy. We performed comprehensive clinical evaluation in six dimensions including safety, effectiveness, economy, suitability, accessibility, and innovation through meta-analysis, literature review, drug administration websites, and other relevant medication data to analyze HER2-TKIs in treating HER2-positive MBC. For safety, the risk of ≥ grade 3 adverse events among pyrotinib, lapatinib, and neratinib is not significantly different. Furthermore, pyrotinib and neratinib were found to be higher in the risk of ≥ grade 3 diarrhea than lapatinib, however the risk could be reversed and prevented with loperamide. Regarding effectiveness and economy, pyrotinib was confirmed to have the best efficacy and cost-utility value, neratinib the second, and lapatinib the third. As regards innovation and suitability, pyrotinib showed better than other HER2-TKIs. In addition, pyrotinib received a higher recommendation than other HER2-TKIs in patients with HER2-positive MBC. The accessibility of pyrotinib was found to be the best with better urban, rural, and national affordability and lower annual treatment costs. Pyrotinib is more valuable in clinics with better safety, effectiveness, economy, suitability, accessibility, and innovation in HER2-positive MBC. This study could provide references for the clinical application of HER2-TKIs in treating HER2-positive MBC., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
- Full Text
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23. Identification of a conserved G-quadruplex within the E165R of African swine fever virus (ASFV) as a potential antiviral target.
- Author
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Liu W, He X, Zhu Y, Li Y, Wang Z, Li P, Pan J, Wang J, Chu B, Yang G, Zhang M, He Q, Li Y, Li W, and Zhang C
- Subjects
- Animals, Chlorocebus aethiops, Vero Cells, Swine, African Swine Fever virology, African Swine Fever metabolism, Porphyrins chemistry, Porphyrins pharmacology, Picolinic Acids chemistry, Picolinic Acids pharmacology, Picolinic Acids metabolism, Virus Replication drug effects, Viral Proteins genetics, Viral Proteins metabolism, Viral Proteins chemistry, Aminoquinolines, African Swine Fever Virus genetics, African Swine Fever Virus metabolism, G-Quadruplexes, Antiviral Agents pharmacology, Antiviral Agents chemistry
- Abstract
Identification of a conserved G-quadruplex in E165R of ASFVAfrican swine fever virus (ASFV) is a double-stranded DNA arbovirus with high transmissibility and mortality rates. It has caused immense economic losses to the global pig industry. Currently, no effective vaccines or medications are to combat ASFV infection. G-quadruplex (G4) structures have attracted increasing interest because of their regulatory role in vital biological processes. In this study, we identified a conserved G-rich sequence within the E165R gene of ASFV. Subsequently, using various methods, we verified that this sequence could fold into a parallel G4. In addition, the G4-stabilizers pyridostatin and 5,10,15,20-tetrakis-(N-methyl-4-pyridyl) porphin (TMPyP4) can bind and stabilize this G4 structure, thereby inhibiting E165R gene expression, and the inhibitory effect is associated with G4 formation. Moreover, the G4 ligand pyridostatin substantially impeded ASFV proliferation in Vero cells by reducing gene copy number and viral protein expression. These compelling findings suggest that G4 structures may represent a promising and novel antiviral target against ASFV., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of the article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
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24. Iodine-Promoted Formal [5+1] Annulation of 2-Vinylanilines and Thiurams: A Facile Approach to the Synthesis of 2-Aminoquinolines.
- Author
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Jiao, Jing, Wang, Pengyang, Xiao, Fangtao, and Zhang, Zhipeng
- Subjects
- *
PHARMACEUTICAL chemistry , *TRIFLATE compounds , *IODINE , *HETEROCYCLIC compounds , *COPPER , *ANNULATION , *AMINATION - Abstract
Quinolines, especially 2-aminoquinolines, are highly important heterocycles in medicinal chemistry. 2-Aminoquinolines can be synthesized by stepwise construction of the quinoline ring followed by additional amination; however, this protocol is cumbersome. Here, we describe a [5+1]-cyclization of 2-vinylanilines with tetraalkylthiuram disulfides in the presence of iodine and copper(II) triflate. This reaction directly employs readily available and low-cost thiuram as both a C1 synthon and a nitrogen source, providing a facile approach to one-step syntheses of a variety of 2-aminoquinolines in good to excellent yields. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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25. Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.
- Author
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Chreifi, Georges, Mukherjee, Paramita, Roman, Linda, Martásek, Pavel, Poulos, Thomas, Silverman, Richard, Pensa, Anthony, Cinelli, Maris, and Li, Huiying
- Subjects
Aminoquinolines ,Animals ,Caco-2 Cells ,Cattle ,Cell Membrane Permeability ,Enzyme Assays ,Histidine ,Humans ,Mice ,Nitric Oxide Synthase Type I ,Nitric Oxide Synthase Type II ,Nitric Oxide Synthase Type III ,Rats - Abstract
Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.
- Published
- 2017
26. Hydrophilic, Potent, and Selective 7‑Substituted 2‑Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors
- Author
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Pensa, Anthony V, Cinelli, Maris A, Li, Huiying, Chreifi, Georges, Mukherjee, Paramita, Roman, Linda J, Martásek, Pavel, Poulos, Thomas L, and Silverman, Richard B
- Subjects
Neurosciences ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Aminoquinolines ,Animals ,Caco-2 Cells ,Cattle ,Cell Membrane Permeability ,Enzyme Assays ,Histidine ,Humans ,Mice ,Nitric Oxide Synthase Type I ,Nitric Oxide Synthase Type II ,Nitric Oxide Synthase Type III ,Rats ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry - Abstract
Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.
- Published
- 2017
27. Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2‑Aminoquinoline Inhibitors
- Author
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Cinelli, Maris A, Li, Huiying, Chreifi, Georges, Poulos, Thomas L, and Silverman, Richard B
- Subjects
Emerging Infectious Diseases ,Neurosciences ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Aminoquinolines ,Animals ,Drug Discovery ,Enzyme Inhibitors ,Humans ,Nitric Oxide Synthase Type I ,Nitriles ,Rats ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry - Abstract
Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but the development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold to decrease off-target binding. However, the resulting compounds had decreased permeability, low human nNOS activity, and low selectivity versus human eNOS. In this study, 5-substituted phenyl ether-linked aminoquinolines and derivatives were synthesized and assayed against purified NOS isoforms. 5-Cyano compounds are especially potent and selective rat and human nNOS inhibitors. Activity and selectivity are mediated by the binding of the cyano group to a new auxiliary pocket in nNOS. Potency was enhanced by methylation of the quinoline and by introduction of simple chiral moieties, resulting in a combination of hydrophobic and auxiliary pocket effects that yielded high (∼500-fold) n/e selectivity. Importantly, the Caco-2 assay also revealed improved membrane permeability over previous compounds.
- Published
- 2017
28. Changing Antimalarial Drug Resistance Patterns Identified by Surveillance at Three Sites in Uganda
- Author
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Tumwebaze, Patrick, Tukwasibwe, Stephen, Taylor, Aimee, Conrad, Melissa, Ruhamyankaka, Emmanuel, Asua, Victor, Walakira, Andrew, Nankabirwa, Joaniter, Yeka, Adoke, Staedke, Sarah G, Greenhouse, Bryan, Nsobya, Samuel L, Kamya, Moses R, Dorsey, Grant, and Rosenthal, Philip J
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Clinical Sciences ,Rare Diseases ,Orphan Drug ,Malaria ,Antimicrobial Resistance ,HIV/AIDS ,Infectious Diseases ,Emerging Infectious Diseases ,Vector-Borne Diseases ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Infection ,Good Health and Well Being ,Adolescent ,Aminoquinolines ,Antimalarials ,Artemisinins ,Cross-Sectional Studies ,DNA ,Protozoan ,Drug Resistance ,Ethanolamines ,Female ,Fluorenes ,Folic Acid Antagonists ,Genes ,Protozoan ,Humans ,Lumefantrine ,Malaria ,Falciparum ,Membrane Transport Proteins ,Multidrug Resistance-Associated Proteins ,Mutation ,Plasmodium falciparum ,Polymorphism ,Single Nucleotide ,Protozoan Proteins ,Sequence Analysis ,DNA ,Uganda ,drug resistance ,artemisinin ,chloroquine ,artemether ,lumefantrine ,artesunate ,amodiaquine ,dihydroartemisinin ,piperaquine ,pfcrt ,pfmdr1 ,K13 ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
We assessed Plasmodium falciparum drug resistance markers in parasites collected in 2012, 2013, and 2015 at 3 sites in Uganda. The prevalence and frequency of parasites with mutations in putative transporters previously associated with resistance to aminoquinolines, but increased sensitivity to lumefantrine (pfcrt 76T; pfmdr1 86Y and 1246Y), decreased markedly at all sites. Antifolate resistance mutations were common, with apparent emergence of mutations (pfdhfr 164L; pfdhps 581G) associated with high-level resistance. K13 mutations linked to artemisinin resistance were uncommon and did not increase over time. Changing malaria treatment practices have been accompanied by profound changes in markers of resistance.
- Published
- 2017
29. Targeting Bacterial Nitric Oxide Synthase with Aminoquinoline-Based Inhibitors.
- Author
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Holden, Jeffrey, Lewis, Matthew, Cinelli, Maris, Abdullatif, Ziad, Pensa, Anthony, Silverman, Richard, and Poulos, Thomas
- Subjects
Aminoquinolines ,Bacillus anthracis ,Crystallography ,X-Ray ,Enzyme Inhibitors ,Nitric Oxide Synthase ,Staphylococcus aureus - Abstract
Nitric oxide is produced in Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus by the bacterial isoform of nitric oxide synthase (NOS). Inhibition of bacterial nitric oxide synthase (bNOS) has been identified as a promising antibacterial strategy for targeting methicillin-resistant S. aureus [Holden, J. K., et al. (2015) Chem. Biol. 22, 785-779]. One class of NOS inhibitors that demonstrates antimicrobial efficacy utilizes an aminoquinoline scaffold. Here we report on a variety of aminoquinolines that target the bacterial NOS active site, in part, by binding to a hydrophobic patch that is unique to bNOS. Through mutagenesis and crystallographic studies, our findings demonstrate that aminoquinolines are an excellent scaffold for further aiding in the development of bNOS specific inhibitors.
- Published
- 2016
30. Aminoquinolines afford resistance to cerebral malaria in susceptible mice
- Author
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Jelena Srbljanović, Branko Bobić, Tijana Štajner, Aleksandra Uzelac, Igor Opsenica, Nataša Terzić-Jovanović, Neda Bauman, Bogdan A. Šolaja, and Olgica Djurković-Djaković
- Subjects
Malaria ,Aminoquinolines ,Plasmodium berghei ,C57BL/6 mice ,Hyperparasitaemia ,Microbiology ,QR1-502 - Abstract
Objectives: Malaria treatment is impeded by increasing resistance to conventional antimalarial drugs. Here we explored the activity of ten novel benzothiophene, thiophene and benzene aminoquinolines. Methods: In vitro testing was performed by the lactate dehydrogenase assay in chloroquine (CQ)-sensitive Plasmodium falciparum strain 3D7 and CQ-resistant (CQR) P. falciparum strain Dd2. In vivo activity was evaluated by a modified Thompson test using C57BL/6 mice infected with Plasmodium berghei ANKA strain. Results: Nine of the ten compounds had a lower 50% inhibitory concentration (IC50) than CQ against the CQR strain Dd2. Five of these compounds that were available for in vivo evaluation were shown to be non-toxic. All five compounds administered at a dose of 160 mg/kg/day for 3 days prolonged the survival of treated compared with untreated mice. Untreated control mice died by Day 7 with a mean parasitaemia of 15%. Among treated mice, a dichotomous outcome was observed, with a two-third majority of treated mice dying by Day 17 with a low mean parasitaemia of 5%, whilst one-third survived longer with a mean hyperparasitaemia of 70%; specifically, five of these mice survived a mean of 25 days, whilst two even survived past Day 31. Conclusions: The significant antimalarial potential of this aminoquinoline series is illustrated by its excellent in vitro activity against the CQR P. falciparum strain and significant in vivo activity. Interestingly, compounds ClAQ7, ClAQ9 and ClAQ11 were able to confer resistance to cerebral malaria and afford a switch to hyperparasitaemia to mice prone to the neurological syndrome.
- Published
- 2020
- Full Text
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31. Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase.
- Author
-
Pensa, Anthony, Kang, Soosung, Roman, Linda, Martásek, Pavel, Poulos, Thomas, Silverman, Richard, Cinelli, Maris, and Li, Huiying
- Subjects
Aminoquinolines ,Caco-2 Cells ,Crystallography ,X-Ray ,Enzyme Inhibitors ,Humans ,Models ,Molecular ,Nitric Oxide Synthase ,Nitric Oxide Synthase Type I ,Nitric Oxide Synthase Type II ,Nitric Oxide Synthase Type III ,Phenyl Ethers ,Structure-Activity Relationship - Abstract
Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.
- Published
- 2015
32. Phenyl Ether- and Aniline-Containing 2‑Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase
- Author
-
Cinelli, Maris A, Li, Huiying, Pensa, Anthony V, Kang, Soosung, Roman, Linda J, Martásek, Pavel, Poulos, Thomas L, and Silverman, Richard B
- Subjects
Neurosciences ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Aminoquinolines ,Caco-2 Cells ,Crystallography ,X-Ray ,Enzyme Inhibitors ,Humans ,Models ,Molecular ,Nitric Oxide Synthase ,Nitric Oxide Synthase Type I ,Nitric Oxide Synthase Type II ,Nitric Oxide Synthase Type III ,Phenyl Ethers ,Structure-Activity Relationship ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry - Abstract
Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.
- Published
- 2015
33. Acantholytic pityriasis rubra pilaris associated with topical use of imiquimod 5%: case report and literature review
- Author
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Oriete Gerin Leite, Sandra Tagliolatto, Elemir Macedo de Souza, and Maria Letícia Cintra
- Subjects
Aminoquinolines ,Drug eruptions ,Keratosis, actinic ,Methotrexate ,Pityriasis rubra pilaris ,Dermatology ,RL1-803 - Abstract
Abstract Topical use of immune response modifiers, such as imiquimod, has increased in dermatology. Although its topical use is well tolerated, it may be associated with exacerbations of generalized cutaneous inflammatory diseases, possibly through the systemic circulation of pro-inflammatory cytokines. This report describes a case of development of pityriasis rubra pilaris, a rare erythematous-papulosquamous dermatosis, in a woman aged 60 years during treatment with imiquimod 5% cream for actinic keratosis. It evolved with erythrodermic conditions and palmoplantar keratoderma, presenting progressive clinical resolution after the introduction of methotrexate. The authors emphasize the importance of recognizing possible systemic reactions associated with the topical use of imiquimod.
- Published
- 2020
- Full Text
- View/download PDF
34. Design, Synthesis, Antitumor, and Antiplasmodial Evaluation of New 7-Chloroquinoline-Benzimidazole Hybrids.
- Author
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Krstulović L, Rastija V, Pessanha de Carvalho L, Held J, Rajić Z, Živković Z, Bajić M, and Glavaš-Obrovac L
- Subjects
- Humans, Cell Line, Tumor, Cell Proliferation drug effects, Quinolines chemistry, Quinolines pharmacology, Quinolines chemical synthesis, Molecular Structure, Aminoquinolines, Benzimidazoles chemistry, Benzimidazoles pharmacology, Benzimidazoles chemical synthesis, Antimalarials pharmacology, Antimalarials chemical synthesis, Antimalarials chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Plasmodium falciparum drug effects, Plasmodium falciparum growth & development, Drug Design, Quantitative Structure-Activity Relationship
- Abstract
Newly synthesized 7-chloro-4-aminoquinoline-benzimidazole hybrids were characterized by NMR and elemental analysis. Compounds were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts) and carcinoma (HeLa and CaCo-2), leukemia, and lymphoma (Hut78, THP-1, and HL-60) cell lines. The obtained results, expressed as the concentration at which 50% inhibition of cell growth is achieved (IC
50 value), show that the tested compounds affect cell growth differently depending on the cell line and the applied dose (IC50 ranged from 0.2 to >100 µM). Also, the antiplasmodial activity of these hybrids was evaluated against two P. falciparum strains ( Pf 3D7 and Pf Dd2). The tested compounds showed potent antiplasmodial activity, against both strains, at nanomolar concentrations. Quantitative structure-activity relationship (QSAR) analysis resulted in predictive models for antiplasmodial activity against the 3D7 strain ( R2 = 0.886; Rext 2 = 0.937; F = 41.589) and Dd2 strain ( R2 = 0.859; Rext 2 = 0.878; F = 32.525) of P. falciparum . QSAR models identified the structural features of these favorable effects on antiplasmodial activities., Competing Interests: The authors declare no conflicts of interest.- Published
- 2024
- Full Text
- View/download PDF
35. Trastuzumab-functionalized bionic pyrotinib liposomes for targeted therapy of HER2-positive breast cancer.
- Author
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Du J, Liu X, Sun J, Wu Q, Hu Y, Shi H, Zheng L, Liu Y, Wu C, and Gao Y
- Subjects
- Humans, Female, Animals, Cell Line, Tumor, Mice, Cell Proliferation drug effects, Drug Liberation, Drug Delivery Systems, Molecular Targeted Therapy, Acrylamides, Aminoquinolines, Liposomes chemistry, Trastuzumab administration & dosage, Trastuzumab pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms metabolism, Receptor, ErbB-2 metabolism, Apoptosis drug effects, Xenograft Model Antitumor Assays
- Abstract
In this study, we prepared a bionic nanosystem of trastuzumab-functionalized SK-BR-3 cell membrane hybrid liposome-coated pyrotinib (Ptb-M-Lip-Her) for the treatment of HER2-positive breast cancer. Transmission electron microscopy, dynamic light scattering, polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting were used to verify the successful preparation of Ptb-M-Lip-Her. In vitro drug release experiments proved that Ptb-M-Lip-Her had a sustained release effect. Cell uptake experiments and in vivo imaging experiments proved that Ptb-M-Lip-Her had good targeting ability to homologous tumor cells (SK-BR-3). The results of cell experiments such as MTT, flow cytometry, immunofluorescence staining and in vivo antitumor experiments showed that Ptb-M-Lip-Her could significantly promote apoptosis and inhibit the proliferation of SK-BR-3 cells. These results clearly indicated that Ptb-M-Lip-Her may be a promising biomimetic nanosystem for targeted therapy of HER2-positive breast cancer., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
36. Efficacy of first-line dual oral pyrotinib plus capetabine therapy in HER2-positive metastatic breast cancer: A real-world retrospective study.
- Author
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Dai S, Zhang Y, Tan X, Luo F, and Yan X
- Subjects
- Humans, Female, Middle Aged, Retrospective Studies, Aged, Adult, Administration, Oral, Acrylamides administration & dosage, Acrylamides therapeutic use, Treatment Outcome, Aminoquinolines, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms mortality, Breast Neoplasms metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Receptor, ErbB-2 metabolism
- Abstract
Background: The combination of dual-targeted human epidermal growth factor receptor 2 (HER2) therapy and chemotherapy is the standard first-line regimen for recurrent/metastatic breast cancer (mBC). However, the toxicity of such combination therapy can lead to some patients being unable to tolerate adverse events or bear treatment costs. As a novel irreversible pan-ErbB receptor TKI (pyrotinib), can the dual oral administration of pyrotinib plus capetabine (PyroC) provide first-line survival benefits and serve as a more affordable treatment option?, Methods: This real-world retrospective study included patients diagnosed with HER2-positive mBC who received PyroC as a first-line treatment at West China Hospital between May 2018 and July 2023. The survival data and toxicity profiles were reported in this study., Results: A total of 64 patients received PyroC as first-line therapy. The median progression-free survival (PFS) was 19.6 months (95% CI 15.0-27.2), while overall survival (OS) has not yet been reached. Kaplan-Meier analysis indicated that age (≥60, p = 0.03) and metastasis sites (p = 0.004) were related to poor efficacy of PyroC, while there was no relationship between effectiveness and menstrual status, hormone receptor (HR) status or previous treatment with anti-HER2 therapy. Furthermore, the objective response rate (ORR) and disease control rate (DCR) were 79.7% and 98.4%, respectively. Of the patients, 78.1% reported treatment-related adverse events (TRAEs). The predominant adverse events were diarrhea (n = 46, 71.9%) and hand-foot syndrome (n = 10, 15.6%)., Conclusion: The dual oral administration regimen (PyroC) has a promising ORR or PFS in HER2-positive mBC patients, with an acceptable safety profile and convenience., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF
37. The PreQuine Platform: A novel diagnostic tool for measuring glucose-6-phosphate dehydrogenase (G6PD) activity and hemoglobin concentration.
- Author
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Harper R, Ley B, Kabir MA, Matulis G, von Seidlein L, Alam MS, Adhikari B, Okech BA, Williams AL, Price RN, and von Fricken ME
- Subjects
- Humans, Biosensing Techniques methods, Malaria, Vivax diagnosis, Malaria, Vivax blood, Aminoquinolines, Glucosephosphate Dehydrogenase metabolism, Glucosephosphate Dehydrogenase blood, Glucosephosphate Dehydrogenase Deficiency diagnosis, Glucosephosphate Dehydrogenase Deficiency blood, Hemoglobins analysis, Hemoglobins metabolism
- Abstract
Quantitative diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency is essential for the safe administration of 8-aminoquinoline based radical cure for the treatment of Plasmodium vivax infections. Here, we present the PreQuine Platform (IVDS, USA), a quantitative biosensor that uses a dual-analyte assay for the simultaneous measurement of Hemoglobin (Hgb) levels and G6PD enzyme activity within the same sample. The platform relies on a downloadable mobile application. The device requires 10μl of whole blood and works with a reflectance-based meter. Comparing the G6PD measurement normalized by Hgb of 12 samples from the PreQuine Platform with reference measurements methods (spectrophotometry, Pointe Scientific, USA and hemoglobin meter, HemoCue, Sweden) showed a positive and significant agreement with a slope of 1.0091 and an intercept of -0.0379 under laboratory conditions. Next steps will be to conduct field trials in Bangladesh, Cambodia, and the USA to assess diagnostic performance, user friendliness and acceptance., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RH is the Founder and CEO of In Vitro Diagnostic Solutions, MAK is a scientist currently employed by IVDS, BL, LvS, MSA, BA, BAO, and MEV are receiving project funding for the field trials in the United States, Bangladesh and Cambodia. Both MEV and BL serve as academic editors for PLoS One. This does not alter our adherence to PLoS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
- Published
- 2024
- Full Text
- View/download PDF
38. Cardiomyocytes, cardiac endothelial cells and fibroblasts contribute to anthracycline-induced cardiac injury through RAS-homologous small GTPases RAC1 and CDC42.
- Author
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Kücük P, Abbey L, Schmitt J, Henninger C, and Fritz G
- Subjects
- Animals, Cardiotoxicity, Antibiotics, Antineoplastic toxicity, Mice, Apoptosis drug effects, Male, Humans, Mice, Inbred C57BL, DNA Breaks, Double-Stranded drug effects, Neuropeptides metabolism, DNA Damage drug effects, Cells, Cultured, rac1 GTP-Binding Protein metabolism, rac1 GTP-Binding Protein antagonists & inhibitors, rac1 GTP-Binding Protein genetics, Myocytes, Cardiac drug effects, Myocytes, Cardiac pathology, Myocytes, Cardiac metabolism, Fibroblasts drug effects, Fibroblasts metabolism, Fibroblasts pathology, cdc42 GTP-Binding Protein metabolism, Doxorubicin toxicity, Doxorubicin adverse effects, Endothelial Cells drug effects, Endothelial Cells pathology, Endothelial Cells metabolism, Aminoquinolines, Pyrimidines
- Abstract
The clinical use of the DNA damaging anticancer drug doxorubicin (DOX) is limited by irreversible cardiotoxicity, which depends on the cumulative dose. The RAS-homologous (RHO) small GTPase RAC1 contributes to DOX-induced DNA damage formation and cardiotoxicity. However, the pathophysiological relevance of other RHO GTPases than RAC1 and different cardiac cell types (i.e., cardiomyocytes, non-cardiomyocytes) for DOX-triggered cardiac damage is unclear. Employing diverse in vitro and in vivo models, we comparatively investigated the level of DOX-induced DNA damage in cardiomyocytes versus non-cardiomyocytes (endothelial cells and fibroblasts), in the presence or absence of selected RHO GTPase inhibitors. Non-cardiomyocytes exhibited the highest number of DOX-induced DNA double-strand breaks (DSB), which were efficiently repaired in vitro. By contrast, rather low levels of DSB were formed in cardiomyocytes, which however remained largely unrepaired. Moreover, DOX-induced apoptosis was detected only in non-cardiomyocytes but not in cardiomyocytes. Pharmacological inhibitors of RAC1 and CDC42 most efficiently attenuated DOX-induced DNA damage in all cell types examined in vitro. Consistently, immunohistochemical analyses revealed that the RAC1 inhibitor NSC23766 and the pan-RHO GTPase inhibitor lovastatin reduced the level of DOX-induced residual DNA damage in both cardiomyocytes and non-cardiomyocytes in vivo. Overall, we conclude that endothelial cells, fibroblasts and cardiomyocytes contribute to the pathophysiology of DOX-induced cardiotoxicity, with RAC1- and CDC42-regulated signaling pathways being especially relevant for DOX-stimulated DSB formation and DNA damage response (DDR) activation. Hence, we suggest dual targeting of RAC1/CDC42-dependent mechanisms in multiple cardiac cell types to mitigate DNA damage-dependent cardiac injury evoked by DOX-based anticancer therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Gerhard Fritz reports financial support was provided by German Cancer Aid and the Deutsche Forschungsgemeinschaft (DFG). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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- View/download PDF
39. Elucidating molecular mechanisms and therapeutic synergy: irreversible HER2-TKI plus T-Dxd for enhanced anti-HER2 treatment of gastric cancer.
- Author
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Liu J, Zhu T, Zhao R, Ren W, Zhao F, and Liu J
- Subjects
- Humans, Animals, Mice, Receptor, ErbB-2 metabolism, Cell Line, Tumor, Trastuzumab therapeutic use, Stomach Neoplasms pathology, Camptothecin analogs & derivatives, Immunoconjugates, Acrylamides, Aminoquinolines
- Abstract
Background: HER2-targeted therapies have improved the outcomes of HER2-positive gastric cancer (GC), yet resistance remains a challenge. We sought to explore the effects of reversible and irreversible HER2 tyrosine kinase inhibitors (TKIs) alone or in combination with the HER2-targeting antibody drug conjugate trastuzumab deruxtecan (T-Dxd)., Methods: The effects of HER2-TKIs on HER2 and downstream signaling were evaluated via Western blotting. Proteasomal inhibitors and co-immunoprecipitation assays were performed to explore the role of proteasomal degradation in HER2 expression modulation, and immunofluorescence assays were employed to explore mechanisms of HER2 internalization. The synergistic potential of the irreversible HER2-TKI pyrotinib in combination with T-Dxd was validated using growth and viability assays in anti-HER2-positive GC cell cultures and tumor growth and immunohistochemical staining assays in a mouse xenograft model., Results: Our study revealed that reversible HER2-TKIs elevated HER2 protein levels, whereas irreversible HER2-TKIs decreased them. Pyrotinib triggered HER2 degradation within the proteasome by promoting ubiquitination and dissociation from HSP90. Furthermore, pyrotinib substantially induced HER2 internalization, which led to improved cellular uptake of T-Dxd. The increased T-Dxd uptake was accompanied by greater efficacy in suppressing the growth of GC cells and enhanced anti-tumor effects in an animal model., Conclusion: In summary, our research reveals the molecular mechanisms of irreversible HER2-TKIs in regulating HER2 protein expression by promoting HER2 internalization. These findings advance our comprehension of targeted therapy for GC and provide a promising therapeutic combination strategy with enhanced efficacy against HER2-positive GC., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
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40. Targeting of G-quadruplex DNA with 99m Tc(I)/Re(I) Tricarbonyl Complexes Carrying Pyridostatin Derivatives.
- Author
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Palma E, Içhedef C, Fernandes C, Belchior A, Raposinho P, Gano L, Miranda A, Moreira D, Lourenço P, Cruz C, Pires AS, Botelho MF, and Paulo A
- Subjects
- Mice, Animals, Technetium chemistry, Tissue Distribution, DNA chemistry, Chelating Agents chemistry, Tomography, Emission-Computed, Single-Photon, RNA, Radiopharmaceuticals chemistry, G-Quadruplexes, Neoplasms, Rhenium chemistry, Aminoquinolines, Picolinic Acids
- Abstract
The main goal of this work was to elucidate the potential relevance of (radio)metal chelates of
99m Tc and Re targeting G-quadruplex structures for the design of new tools for cancer theranostics.99m Tc provides the complexes with the ability to perform single-photon-emission computed tomography imaging studies, while the Re complexes should act as anticancer agents upon interaction with specific G4 DNA or RNA structures present in tumor tissues. Towards this goal, we have developed isostructural99m Tc(I) and Re(I) tricarbonyl complexes anchored by a pyrazolyl-diamine (Pz) chelator carrying a pendant pyridostatin (PDS) fragment as the G4-binding motif. The interaction of the PDF-Pz-Re (8) complex with different G4-forming oligonucleotides was studied by circular dichroism, fluorescence spectroscopy and FRET-melting assays. The results showed that the Re complex retained the ability to bind and stabilize G4-structures from different DNA or RNA sequences, namely those present on the SRC proto-oncogene and telomeric RNA (TERRA sequence). PDF-Pz-Re (8) showed low to moderate cytotoxicity in PC3 and MCF-7 cancer cell lines, as typically observed for G4-binders. Biodistribution studies of the congener PDF-Pz-99m Tc (12) in normal mice showed that the complex undergoes a fast blood clearance with a predominant hepatobiliary excretion, pointing also for a high in vitro stability., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)- Published
- 2024
- Full Text
- View/download PDF
41. Third-line pyrotinib, trastuzumab (Zercepac®) and vinorelbine for brain metastases of HER2-positive advanced breast cancer patient.
- Author
-
Wang H, Shao B, and DI L
- Subjects
- Female, Humans, Middle Aged, Aminoquinolines, Receptor, ErbB-2 metabolism, Receptor, ErbB-2 analysis, Acrylamides therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms secondary, Brain Neoplasms drug therapy, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Trastuzumab therapeutic use, Trastuzumab administration & dosage, Vinorelbine administration & dosage, Vinorelbine therapeutic use
- Published
- 2024
- Full Text
- View/download PDF
42. An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase.
- Author
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Zhang Y, Guo J, Liu Y, Qu Y, Li YQ, Mu Y, and Li W
- Subjects
- Humans, Peptide Hydrolases metabolism, Protease Inhibitors chemistry, Molecular Docking Simulation, Cysteine Endopeptidases metabolism, Molecular Dynamics Simulation, Antiviral Agents pharmacology, Antiviral Agents chemistry, SARS-CoV-2 metabolism, COVID-19, Aminoquinolines, Aniline Compounds
- Abstract
The main proteinase (M
pro ) of SARS-CoV-2 plays a critical role in cleaving viral polyproteins into functional proteins required for viral replication and assembly, making it a prime drug target for COVID-19. It is well known that noncompetitive inhibition offers potential therapeutic options for treating COVID-19, which can effectively reduce the likelihood of cross-reactivity with other proteins and increase the selectivity of the drug. Therefore, the discovery of allosteric sites of Mpro has both scientific and practical significance. In this study, we explored the binding characteristics and inhibiting process of Mpro activity by two recently reported allosteric inhibitors, pelitinib and AT7519 which were obtained by the X-ray screening experiments, to probe the allosteric mechanism via molecular dynamic (MD) simulations. We found that pelitinib and AT7519 can stably bind to Mpro far from the active site. The binding affinity is estimated to be -24.37 ± 4.14 and - 26.96 ± 4.05 kcal/mol for pelitinib and AT7519, respectively, which is considerably stable compared with orthosteric drugs. Furthermore, the strong binding caused clear changes in the catalytic site of Mpro , thus decreasing the substrate accessibility. The community network analysis also validated that pelitinib and AT7519 strengthened intra- and inter-domain communication of Mpro dimer, resulting in a rigid Mpro , which could negatively impact substrate binding. In summary, our findings provide the detailed working mechanism for the two experimentally observed allosteric sites of Mpro . These allosteric sites greatly enhance the 'druggability' of Mpro and represent attractive targets for the development of new Mpro inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
43. Inflammation induces dermal Vγ4+ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses
- Author
-
Ramírez-Valle, Francisco, Gray, Elizabeth E, and Cyster, Jason G
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Immunology ,2.1 Biological and endogenous factors ,Skin ,Inflammatory and immune system ,Aminoquinolines ,Animals ,Imiquimod ,Immunologic Memory ,Inflammation ,Interleukin-17 ,Mice ,Receptors ,Antigen ,T-Cell ,gamma-delta ,T-Lymphocytes ,immunological memory ,gamma delta T cells ,inflammation ,γδT cells - Abstract
Gamma delta (γδ) T cells represent a major IL-17 committed T-cell population (γδT17 cells) in the mouse dermis. Following exposure to the inflammatory agent imiquimod (IMQ) the Vγ4(+) subset of γδT cells produce IL-17 in the skin and expand rapidly in draining lymph nodes (LNs). Local IMQ treatment in humans is known to exacerbate psoriasis skin lesion activity at distant sites. Whether expanded γδT17 cells sensitize distant sites to inflammation has been unknown. Here we show that expanded Vγ4(+) γδT17 cells egress from LNs in a fingolimod (FTY720)-sensitive manner and use C-C chemokine receptor type 2 to accumulate in inflamed skin where they augment neutrophil recruitment and inflammation. They also travel to noninflamed skin and peripheral LNs and remain in elevated numbers at these distant sites for at least 3 mo. Sensitized mice show more rapid skin inflammation and greater proliferation and IL-17 production by Vγ4(+) γδT cells upon imiquimod challenge. Transfer experiments confirm that memory-like Vγ4(+) γδT17 cells respond more rapidly. Memory-like Vγ4(+) γδT17 cells are distinguished by greater IL-1R1 expression and more proliferation in response to IL-1β. These findings establish that local skin inflammation leads to faster and stronger secondary responses to the same stimulus through long-term and systemic changes in the composition and properties of the dermal γδT-cell population.
- Published
- 2015
44. Aminoquinolines: Fluorescent sensors to DNA – A minor groove probe. Experimental and in silico studies
- Author
-
de Carvalho Bertozo L., Tutone M., Pastrello B., da Silva-Filho L. C., Culletta G., Almerico A. M., Farias Ximenes V., de Carvalho Bertozo L., Tutone M., Pastrello B., da Silva-Filho L.C., Culletta G., Almerico A.M., and Farias Ximenes V.
- Subjects
Aminoquinolines ,Minor Groove ,DNA ,Molecular Dynamics ,Settore CHIM/08 - Chimica Farmaceutica ,Fluorescence - Abstract
An aminoquinoline (AQ4) was developed and proven to be a new and efficient DNA minor groove fluorescent probe. The specificity for DNA minor groove was attested by comparing it with well-established DNA probes such as Hoechst stain, acridine orange, and ethidium bromide. AQ4 was similar to the Hoechst stain, a classic minor groove probe, and opposite to acridine orange and ethidium bromide, the typical intercalating probes. An advantage of AQ4 to the Hoechst stain was the higher fluorescent signal-to-noise ratio (+DNA/-DNA). The interaction with DNA leads to an exclusive fluorescent band centered at 590 nm. The red-shifted fluorescent band is associated with a new absorption band (490 nm), revealing a ground-state complex formation. The complexation was also evidenced by circular dichroism, anisotropy, and fluorescence lifetime. The complex AQ4-DNA was pH dependent, being favored in an acidic medium. This feature was related to the preferential interaction with a protonated form of AQ4, i.e., AQ4(H+), revealing the role of electrostatic forces, which was corroborated by the strong dependence on the ionic strength of the medium and, particularly, on magnesium ions. The complexes were studied by docking and molecular dynamics and confirmed the stability of AQ4(H+). Additionally, 500 ns simulations were performed by adding salts. The presence of the salts leads to the loss of the binding of AQ4(H+) after 52 ns (NaCl) and 142 ns (MgCl2). Experimental and in silico outcomes showed the advantages of the aminoquinoline over the commercial DNA minor groove stain, the Hoechst dye. Hence, we propose its further application in cell-based assays.
- Published
- 2023
45. Base‐Promoted Synthesis of Polysubstituted 4‐Aminoquinolines from Ynones and 2‐Aminobenzonitriles under Transition‐Metal‐Free Conditions.
- Author
-
Kumar, Ankit, Mishra, Pawan K., Saini, Kapil Mohan, and Verma, Akhilesh K.
- Subjects
- *
ANNULATION , *SIMPLICITY - Abstract
A transition‐metal‐free and base‐promoted one‐pot reaction of ynones with 2‐aminobenzonitriles is described. The reaction was initiated through sequential aza‐Michael addition/intramolecular annulation to afford various multisubstituted 4‐aminoquinolines and 4‐amino‐1,8‐naphthyridines in good to excellent yields. Operational simplicity, high atom‐economy with broad substrate scope makes this protocol more attractive. Also, the gram‐scale synthesis and further transformation of the product were studied. Additionally, 2‐haloarylyones as substrate provide N‐arylquinolones as the sole product via the SNAr mechanism. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
46. β-amino-alcohol tethered 4-aminoquinoline-isatin conjugates: Synthesis and antimalarial evaluation
- Author
-
Nisha, Gut, Jiri, Rosenthal, Philip J, and Kumar, Vipan
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Rare Diseases ,Vector-Borne Diseases ,Alcoholism ,Alcohol Use and Health ,Substance Misuse ,Malaria ,Orphan Drug ,Good Health and Well Being ,Amino Alcohols ,Aminoquinolines ,Antimalarials ,Cell Survival ,Dose-Response Relationship ,Drug ,HCT116 Cells ,Humans ,Isatin ,Molecular Structure ,Parasitic Sensitivity Tests ,Plasmodium falciparum ,Structure-Activity Relationship ,beta-amino alcohol ,4-Aminoquinoline-isatin conjugates ,Antimalarial activity ,Cytotoxicity ,β-amino alcohol ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry ,Pharmacology and pharmaceutical sciences ,Medicinal and biomolecular chemistry ,Organic chemistry - Abstract
A series of β-amino alcohol tethered 4-aminoquinoline-isatin conjugates were synthesized with the aim of probing their antimalarial structure activity relationship. Two of the most active conjugates (11b and 11f) exhibited antimalarial efficacy comparable to that of chloroquine, with IC50 values of 11.8 and 13.5 nM, respectively against chloroquine resistant W2 strain of Plasmodium falciparum and are devoid of any cytotoxicity.
- Published
- 2014
47. Stimulation of Innate Immune Cells by Light-Activated TLR7/8 Agonists
- Author
-
Ryu, Keun Ah, Stutts, Lalisa, Tom, Janine K, Mancini, Rock J, and Esser-Kahn, Aaron P
- Subjects
Immunization ,Vaccine Related ,1.1 Normal biological development and functioning ,Underpinning research ,Inflammatory and immune system ,Aminoquinolines ,Animals ,Bone Marrow Cells ,Cell Line ,Dendritic Cells ,Imiquimod ,Immunity ,Innate ,Light ,Mice ,Models ,Molecular ,Protein Multimerization ,Protein Structure ,Quaternary ,Toll-Like Receptor 7 ,Toll-Like Receptor 8 ,Chemical Sciences ,General Chemistry - Abstract
The innate immune response is controlled, in part, by the synergistic interaction of multiple Toll-like receptors (TLRs). This multi-receptor cooperation is responsible for the potent activity of many vaccines, but few tools have been developed to understand the spatio-temporal elements of TLR synergies. In this Communication, we present photo-controlled agonists of TLR7/8. By strategically protecting the active agonist moiety based on an agonist-bound crystal structure, TLR activity is suppressed and then regained upon exposure to light. We confirmed NF-κB production upon light exposure in a model macrophage cell line. Primary cell activity was confirmed by examining cytokine and cell surface marker production in bone-marrow-derived dendritic cells. Finally, we used light to activate dendritic cell sub-populations within a larger population.
- Published
- 2014
48. Simplified 2-aminoquinoline-based scaffold for potent and selective neuronal nitric oxide synthase inhibition.
- Author
-
Cinelli, Maris, Chreifi, Georges, Martásek, Pavel, Roman, Linda, Poulos, Thomas, Silverman, Richard, and Li, Huiying
- Subjects
Aminoquinolines ,Catalytic Domain ,Enzyme Inhibitors ,Magnetic Resonance Spectroscopy ,Mass Spectrometry ,Models ,Molecular ,Nitric Oxide Synthase Type I - Abstract
Since high levels of nitric oxide (NO) are implicated in neurodegenerative disorders, inhibition of the neuronal isoform of nitric oxide synthase (nNOS) and reduction of NO levels are therapeutically desirable. Nonetheless, many nNOS inhibitors mimic l-arginine and are poorly bioavailable. 2-Aminoquinoline-based scaffolds were designed with the hope that they could (a) mimic aminopyridines as potent, isoform-selective arginine isosteres and (b) possess chemical properties more conducive to oral bioavailability and CNS penetration. A series of these compounds was synthesized and assayed against purified nNOS enzymes, endothelial NOS (eNOS), and inducible NOS (iNOS). Several compounds built on a 7-substituted 2-aminoquinoline core are potent and isoform-selective; X-ray crystallography indicates that aminoquinolines exert inhibitory effects by mimicking substrate interactions with the conserved active site glutamate residue. The most potent and selective compounds, 7 and 15, were tested in a Caco-2 assay and showed good permeability and low efflux, suggesting high potential for oral bioavailability.
- Published
- 2014
49. Synthesis and in Vitro and in Vivo Pharmacological Evaluation of New 4‑Aminoquinoline-Based Compounds
- Author
-
Tukulula, Matshawandile, Njoroge, Mathew, Abay, Efrem T, Mugumbate, Grace C, Wiesner, Lubbe, Taylor, Dale, Gibhard, Liezl, Norman, Jennifer, Swart, Kenneth J, Gut, Jiri, Rosenthal, Philip J, Barteau, Samuel, Streckfuss, Judith, Kameni-Tcheudji, Jacques, and Chibale, Kelly
- Subjects
Malaria ,Rare Diseases ,Vector-Borne Diseases ,Infection ,Good Health and Well Being ,Aminoquinolines ,antiplasmodial activity ,pharmacokinetics ,plasma protein binding ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences - Abstract
A new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitro. Pharmacokinetic studies on 3d and 3e in mice showed that they had moderate half-life (4-6 h) and low oral bioavailability. The front runner compound 3d exhibited moderate inhibition of the malaria parasite on P. berghei infected mice following oral administration (5 mg/kg), achieving reduction of parasitemia population by 47% on day 7.
- Published
- 2013
50. Intracranial Efficacy of Pyrotinib and Capecitabine Combination Therapy in HER2-Positive Breast Cancer with Brain Metastases.
- Author
-
Wang C, Xiang J, Zhang Q, Li J, Liu Y, and Liu J
- Subjects
- Humans, Female, Capecitabine, Quality of Life, Receptor, ErbB-2 metabolism, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms pathology, Brain Neoplasms drug therapy, Acrylamides, Aminoquinolines
- Abstract
Aim: Approximately 50% of patients diagnosed with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (BC) are estimated to develop brain metastases (BMs). This study was aimed to assess the intracranial efficacy and survival benefits of pyrotinib and capecitabine combination therapy in the treatment of BMs in patients with HER2-positive BC., Methods: A total of 56 HER2-positive BC patients with BMs were treated with 400 mg pyrotinib once daily along with 1000 mg/m
2 capecitabine twice daily for 14 days in 21-day cycles. The patients were allocated into three cohorts: (1) Cohort A composed of patients with newly diagnosed BMs without prior local radiotherapy, (2) Cohort B included patients with stable post-local radiotherapy, and (3) Cohort C composed of patients with progression following local radiotherapy. The primary endpoint was the intracranial objective response rate (CNS-ORR), while secondary endpoints included intracranial disease control rate (CNS-DCR), progression-free survival (PFS), overall survival (OS), safety, as well as QoL., Results: The observed CNS-ORR CNS-ORR of 72.73% (95% CI 51.85-86.85%) in cohort A, 55% (95% CI 34.21-74.18%) in cohort B, and 42.86% (95% CI 21.38-67.41%) in cohort C. The mPFS was 11 months, 8.4 months, and 5.2 months in cohorts A, B, and C, respectively. Diarrhea, accounting for 23.21% of all the patients, was the most common grade 3/4 adverse event related with treatments (6/22 [27.3%] in cohort A, 4/20 [20.0%] in cohort B, and 3/14 [21.4%] in cohort C). However, there were no deaths related with treatments observed. Importantly, the QoL was efficiently maintained throughout the treatment duration., Conclusion: Pyrotinib and capecitabine combination therapy proved significant effectiveness as well as tolerability in treating HER2-positive BC with BMs, yielding satisfactory results, especially in radiotherapy-naive population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wang et al.)- Published
- 2024
- Full Text
- View/download PDF
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