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A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of β-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA in this study. The compounds significantly reduced haeme crystallization, with IC50 values < 10 µM. The values were comparable to chloroquine's, with an IC50 of 1.50 ± 0.01 µM. The compounds 4c and 4e prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds 4b, 4c, and 4e on another important human parasite, Leishmania mexicana, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC50 < 10 µM. Concerning the possible mechanism of action of these compounds on Lesihmania mexicana, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber's rules, and except for 2 and 4i, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo. [ABSTRACT FROM AUTHOR]

A series of benzofuro‐fused 7‐deazapurine (6H‐furo[2,3‐e]pyrimido[4,5‐b]indole) 2'‐deoxyribo‐ and ribonucleosides was designed and synthesized. The synthesis of key compound 10‐chloro‐6H‐furo[2,3‐e]pyrimido[4,5‐b]indole was based on the Negishi cross‐coupling of iodobenzofurane with zincated 4,6‐dichloropyrimidine followed by azidation and photochemical cyclization. Glycosylation of the heterocycle with either Hoffer's chlorodeoxyribose or protected ribose followed by cross‐coupling or substitution reactions at position 10 gave the desired two sets of final nucleosides that showed moderate to weak cytostatic activity and interesting fluorescence properties. [ABSTRACT FROM AUTHOR]

P2X7 sites are emerging targets for molecular imaging research, notably in the context of neurodegeneration and inflammatory conditions. Therefore, we prepared a precursor for (radio)iodination of the P2X7 ligand VPGIS191. We then developed a radioiodination method with 123I for SPECT with a radiochemical yield of 71 ± 13% and 125I for autoradiography with a radiochemical yield of 85 ± 6% Autoradiography of [125I]VPGIS191 in mouse brain cryostat sections demonstrated approximately 36 nM binding affinity and Bmax of approximately 400 pmol/gram tissue for P2X7 binding sites. VPGIS191 (cis) had a two-fold lower affinity compared to its geometric trans-isomer TZ6019. [ABSTRACT FROM AUTHOR]

Cervical mucus (CM) is a viscous fluid that is produced by the cervical glands and functions as a uterine cervix plug. Its viscosity decreases during ovulation, providing a window for non-invasive sampling. This study focuses on proteomic characterization of CM to evaluate its potential as a non-invasively acquired source of biomarkers and in understanding of molecular (patho)physiology of the female genital tract. The first objective of this work was to optimize experimental workflow for CM processing and the second was to assess differences in the proteomic composition of CM during natural ovulatory cycles obtained from intrauterine insemination (IUI) cycles and in vitro fertilization (IVF) cycles with controlled ovarian hyperstimulation. Proteomic analysis of CM samples revealed 4370 proteins involved in processes including neutrophil degranulation, cellular stress responses, and hemostasis. Differential expression analysis revealed 199 proteins enriched in IUI samples and 422 enriched in IVF. The proteins enriched in IUI were involved in phosphatidic acid synthesis, responses to external stimulus, and neutrophil degranulation, while those enriched in IVF samples were linked to neutrophil degranulation, formation of a cornified envelope and hemostasis. Subsequent analyses clarified the protein composition of the CM and how it is altered by hormonal stimulation of the uterus. [ABSTRACT FROM AUTHOR]

After cardiovascular diseases, cancer, a non-communicable pathology, has been considered the second cause of death each year globally and as the most important barrier to increasing life expectancy in the 21st century. Advances of great relevance have been made in its prevention and treatment, however, there is still a long way to go to achieve an eff ective treatment for each type of cancer. This paper describes approaches to reposition and synthesis of hybrid molecules with potential antineoplastic activity. To obtain the key intermediate aldehyde, the Dess-Martin oxidation methodology was used, which was coupled with the corresponding ketones using LDA. The fi nal hybrid compounds were obtained as a racemic mixture. The in vitro antiproliferative activity of the fi nal compounds was evaluated against eight cell lines derived from human solid tumors, and four non-cancerous cell lines. The compound 11d turned out to be the most eff ective and with the highest safety index. The results suggested that these compounds could block the cell cycle and induce apoptosis and death in CCRF-CEM cells in a dose-dependent manner in vitro. [ABSTRACT FROM AUTHOR]

A series of 78 synthetic 7-chloro-(4-thioalkylquinoline) derivatives were investigated for cytotoxic activity against eight human cancer as well as 4 non-tumor cell lines. The results showed, with some exceptions, that sulfanyl 5–40 and sulfinyl 41–62 derivatives exhibited lower cytotoxicity for cancer cell lines than those of well-described sulfonyl N-oxide derivatives 63–82. As for compound 81, the most pronounced selectivity (compared against BJ and MRC-5 cells) was observed for human cancer cells from HCT116 (human colorectal cancer with wild-type p53) and HCT116p53−/− (human colorectal cancer with deleted p53), as well as leukemia cell lines (CCRF-CEM, CEM-DNR, K562, and K562-TAX), lung (A549), and osteosarcoma cells (U2OS). A good selectivity was also detected for compounds 73 and 74 for leukemic and colorectal (with and without p53 deletion) cancer cells (compared to MRC-5). At higher concentrations (5 × IC50) against the CCRF-CEM cancer cell line, we observe the accumulation of the cells in the G0/G1 cell phase, inhibition of DNA and RNA synthesis, and induction of apoptosis. In addition, X-ray data for compound 15 is being reported. These results provide useful scientific data for the development of 4-thioalkylquinoline derivatives as a new class of anticancer candidates. [ABSTRACT FROM AUTHOR]

Aryl hydrocarbon receptor (AHR) plays pivotal roles in intestinal physiology and pathophysiology. Intestinal AHR is activated by numerous dietary, endogenous, and microbial ligands. Whereas the effects of individual compounds on AHR are mostly known, the effects of real physiological mixtures occurring in the intestine have not been studied. Using reporter gene assays and RT-PCR, we evaluated the combinatorial effects (3520 combinations) of 11 microbial catabolites of tryptophan (MICTs) on AHR. We robustly (n = 30) determined the potencies and relative efficacies of single MICTs. Synergistic effects of MICT binary mixtures were observed between low- or medium-efficacy agonists, in particular for combinations of indole-3-propionate and indole-3-lactate. Combinations comprising highly efficacious agonists such as indole-3-pyruvate displayed rather antagonist effects, caused by saturation of the assay response. These synergistic effects were confirmed by RT-PCR as CYP1A1 mRNA expression. We also tested mimic multicomponent and binary mixtures of MICTs, prepared based on the metabolomic analyses of human feces and colonoscopy aspirates, respectively. In this case, AHR responsiveness did not correlate with type of diet or health status, and the indole concentrations in the mixtures were determinative of gross AHR activity. Future systematic research on the synergistic activation of AHR by microbial metabolites and other ligands is needed. [ABSTRACT FROM AUTHOR]

The coexistence of leishmaniasis, Chagas disease, and neoplasia in endemic areas has been extensively documented. The use of common drugs in the treatment of these pathologies invites us to search for new molecules with these characteristics. In this research, we report 16 synthetic chalcone derivatives that were investigated for leishmanicidal and trypanocidal activities as well as for antiproliferative potential on eight human cancers and two nontumor cell lines. The final compounds 8–23 were obtained using the classical base-catalyzed Claisen–Schmidt condensation. The most potent compounds as parasiticidal were found to be 22 and 23, while compounds 18 and 22 showed the best antiproliferative activity and therapeutic index against CCRF-CEM, K562, A549, and U2OS cancer cell lines and non-toxic VERO, BMDM, MRC-5, and BJ cells. In the case of K562 and the corresponding drug-resistant K562-TAX cell lines, the antiproliferative activity has shown a more significant difference for compound 19 having 10.3 times higher activity against the K562-TAX than K562 cell line. Flow cytometry analysis using K562 and A549 cell lines cultured with compounds 18 and 22 confirmed the induction of apoptosis in treated cells after 24 h. Based on the structural analysis, these chalcones represent new compounds potentially useful for Leishmania, Trypanosoma cruzi, and some cancer treatments. [ABSTRACT FROM AUTHOR]

A key objective in immuno-oncology is to reactivate the dormant immune system and increase tumour immunogenicity. Adenosine is an omnipresent purine that is formed in response to stress stimuli in order to restore physiological balance, mainly via anti-inflammatory, tissue-protective, and anti-nociceptive mechanisms. Adenosine overproduction occurs in all stages of tumorigenesis, from the initial inflammation/local tissue damage to the precancerous niche and the developed tumour, making the adenosinergic pathway an attractive but challenging therapeutic target. Many current efforts in immuno-oncology are focused on restoring immunosurveillance, largely by blocking adenosine-producing enzymes in the tumour microenvironment (TME) and adenosine receptors on immune cells either alone or combined with chemotherapy and/or immunotherapy. However, the effects of adenosinergic immunotherapy are not restricted to immune cells; other cells in the TME including cancer and stromal cells are also affected. Here we summarise recent advancements in the understanding of the tumour adenosinergic system and highlight the impact of current and prospective immunomodulatory therapies on other cell types within the TME, focusing on adenosine receptors in tumour cells. In addition, we evaluate the structure- and context-related limitations of targeting this pathway and highlight avenues that could possibly be exploited in future adenosinergic therapies. [ABSTRACT FROM AUTHOR]

A series of triterpenoid pyrones was synthesized and subsequently modified to introduce phthalimide or phthalate moieties into the triterpenoid skeleton. These compounds underwent in vitro cytotoxicity screening, revealing that a subset of six compounds exhibited potent activity, with IC 50 values in the low micromolar range. Further biological evaluations, including Annexin V and propidium iodide staining experiment revealed, that all compounds induce selective apoptosis in cancer cells. Measurements of mitochondrial potential, cell cycle analysis, and the expression of pro- and anti-apoptotic proteins confirmed, that apoptosis was mediated via the mitochondrial pathway. These findings were further supported by cell cycle modulation and DNA/RNA synthesis studies, which indicated a significant increase in cell accumulation in the G0/G1 phase and a marked reduction in S-phase cells, alongside a substantial inhibition of DNA synthesis. The activation of caspase-3 and the cleavage of PARP, coupled with a decrease in the expression of Bcl-2 and Bcl-XL proteins, underscored the induction of apoptosis through the mitochondrial pathway. Given their high activity and pronounced effect on mitochondria function, trifluoromethyl pyrones 1f and 2f , and dihydrophthalimide 2h have been selected for further development. [Display omitted] • A set of novel triterpenoid pyrones, phthalimides and phthalates was synthesized. • Six compounds with high in vitro cytotoxicity in CCRF-CEM cells was identified. • All compounds induce apoptosis via the mitochondrial intrinsic pathway. • Pyrones 1f , 2f , and dihydrophthalimide 2h were selected for further development. [ABSTRACT FROM AUTHOR]

The synthesis and anticancer activity evaluation of new quinazoline alkaloids rutaecarpine and evodiamine semisynthetic derivatives and their molecular hybrids with lupinine moiety is described. Newly synthesized compounds were elucidated based on elemental analyses and spectral data (1H and 13C NMR). Anticancer cytotoxicity was studied toward some cell lines of lung cancer, T-lymphoblastic leukemia, colon cancer, myeloid leukemia, and osteosarcoma. Among the tested compounds, the highest activity with a specific sensitivity profile toward the Leukemia cell lines CCRF-CEM and K-562 was demonstrated by the starting compound evodiamine. Structural modifications of the studied quinazoline alkaloids did not lead to the improvement of anticancer activity. [ABSTRACT FROM AUTHOR]

The combination of cytotoxic amino‐BODIPY dye and 2‐phenyl‐3‐hydroxy‐4(1H)‐quinolinone (3‐HQ) derivatives into one molecule gave rise to selective activity against lymphoblastic or myeloid leukemia and the simultaneous disappearance of the cytotoxicity against normal cells. Both species′ conjugation can be realized via a disulfide linker cleavable in the presence of glutathione characteristic for cancer cells. The cleavage liberating the free amino‐BODIPY dye and 3‐HQ derivative can be monitored by ratiometric fluorescence or by the OFF‐ON effect of the amino‐BODIPY dye. A similar cytotoxic activity is observed when the amino‐BODIPY dye and 3‐HQ derivative are connected through a non‐cleavable maleimide linker. The work reports the synthesis of several conjugates, the study of their cleavage inside cells, and cytotoxic screening. [ABSTRACT FROM AUTHOR]

The interleukin‐2‐inducible kinase (ITK) and Bruton tyrosine kinase (BTK) are two crucial Tec family kinase members with important roles in the development of hematopoietic malignancies, autoimmune disorders and other diseases in humans. Thus, ITK and BTK are key targets for drug development. Spirooxindoles are important scaffolds for the synthesis of small molecules with broad and potent biological activities. In this study, we performed a structure‐activity relationship study of a new series of 5′‐(benzo[d][1,3]dioxol‐5‐yl)spiro[piperidine‐4,3′‐pyrrolo[2,3–b]pyridin]‐2′(1′H)‐one linked with N‐acyl and C‐5 aryl‐substituted scaffolds in a panel of ITK and BTK cancer cell lines. Four compounds 11, 12, 14, and 15 showed high antiproliferative activity against ITK and BTK cell lines. Compounds 11 and 12 with a C‐5 benzodioxole group and gem‐dialkyl group attached to carbonyl on piperidine were highly effective in ITK‐high Jurkat and CEM cell lines, and compound 14, a biotin analogue, was identified as a good inhibitor of BTK‐high RAMOS cells. Compound 15 with cyclopropyl group attached to carbonyl on piperidine also showed good activity in ITK and BTK cell lines. [ABSTRACT FROM AUTHOR]

[Display omitted] • Triazole-Based Estradiol dimers inhibit tubulin assembly in vitro. • Triazole-Based Estradiol dimers reversibly disrupt microtubule structures in U2OS cells. • Triazole-Based Estradiol dimers show cytotoxic activities on cancer cell lines, arrest cells in the G2/M phase of the cell cycle and attenuate DNA/RNA synthesis. • Structural changes in the bridge are essential for the activity of estradiol dimers at the cytoskeletal level. • Simple linkers seem more suitable than more complex ones, bulky groups (benzyl pendants), are reducing the activity. Microtubule dynamic is exceptionally sensitive to modulation by small-molecule ligands. Our previous work presented the preparation of microtubule-targeting estradiol dimer (ED) with anticancer activity. In the present study, we explore the effect of selected linkers on the biological activity of the dimer. The linkers were designed as five-atom chains with carbon, nitrogen or oxygen in their centre. In addition, the central nitrogen was modified by a benzyl group with hydroxy or methoxy substituents and one derivative possessed an extended linker length. Thirteen new dimers were subjected to cytotoxicity assay and cell cycle profiling. Dimers containing linker with benzyl moiety substituted with one or more methoxy groups and longer branched ones were found inactive, whereas other structures had comparable efficacy as the original ED (e.g. D1 with IC 50 = 1.53 µM). Cell cycle analysis and immunofluorescence proved the interference of dimers with microtubule assembly and mitosis. The proposed in silico model and calculated binding free energy by the MM-PBSA method were closely correlated with in vitro tubulin assembly assay. [ABSTRACT FROM AUTHOR]

In this work, a large set of betulinic acid derivatives modified with various aromatic substituents at the position C-3 were prepared via Suzuki-Myiaura cross-coupling. All compounds were tested for their in vitro cytotoxic activity in 8 cancer and 2 healthy cell lines. Derivatives 6h , 6i , and 6o had the lowest IC 50 in the CCRF-CEM cell line (0.69–4.0 μM) and had high selectivity. In addition, 6h and 6i also showed significant activity in daunorubicin-resistant CEM and taxol-resistant K562 cell lines; therefore, they were selected for the evaluation of the mechanism of action. First, the effect of 6h , 6i , and 6o on cell death induction was studied. To our surprise, we have not detected almost any apoptotic cells, even following a long-time exposure of CCRF-CEM cells to the compounds. On the other hand, a dramatic cell number decrease was observed, proportional to the time of the compound's exposure. Based on this data it was concluded that the effect of compounds is cytostatic rather than cytotoxic, which was further confirmed by subsequent studies of the impact of 6h , 6i , and 6o on the cell cycle. Detailed cell cycle analysis revealed a block in the G1 phase accompanied by reduced expression of phosphorylated forms of the RB protein as well as cyclin A protein. Evaluation of the pharmacological properties of the most promising compounds revealed their high stability in the presence of phosphate buffer, human plasma, and microsomes and limited permeability determined using permeability through artificial membrane (PAMPA) and cell permeability assay: Caco-2 and MDCK-MDR1 cell lines. Compounds 6h , 6i , and 6o were selected for further drug development; their cytostatic effect may be advantageous in this process since we expect fewer non-specific interactions and toxicity than in highly cytotoxic compounds. In addition, the activity of 6h and 6i against resistant CEM-DNR and K562-TAX leukemic cell lines makes them promising as a possible future alternative to currently used therapies. [Display omitted] • Arylated lupane derivatives were prepared and their cytotoxicity tested. • Pharmacological parameters and selectivity were measured. • Most active compounds were cytostatic against leukemic cells including resistant. • Compounds 6h , 6i , 6o were selected for further drug development. [ABSTRACT FROM AUTHOR]

A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid, moronic acid, ursonic acid, heterobetulonic acid, and allobetulone). Cytotoxicity of all compounds was tested in eight cancer and two non-cancer cell lines. Evaluation of the structure-activity relationships revealed that the triterpenoid core determined whether the final molecule is active or not, while the heterocycle is able to increase the activity and modulate the specificity. Five compounds (1b , 1c , 2b , 2c , and 8) were found to be preferentially and highly cytotoxic (IC 50 ≈ 1 μM) against leukemic cancer cell lines (CCRF-CEM, K562, CEM-DNR, or K562-TAX). Surprisingly, compounds 1c , 2b , and 2c are 10-fold more active in multidrug-resistant leukemia cells (CEM-DNR and K562-TAX) than in their non-resistant analogs (CCRF-CEM and K562). Pharmacological parameters were measured for the most promising candidates and two types of prodrugs were synthesized: 1) Sugar-containing conjugates, most of which had improved cell penetration and retained high cytotoxicity in the CCRF-CEM cell line, unfortunately, they lost the selectivity against resistant cells. 2) Medoxomil derivatives, among which compounds 26 – 28 gained activities of IC 50 0.026–0.043 μM against K562 cells. Compounds 1b , 8 , 21 , 22 , 23 , and 24 were selected for the evaluation of the mechanism of action based on their highest cytotoxicity against CCRF–CEM cell line. Several experiments showed that the majority of them cause apoptosis via the mitochondrial pathway. Compounds 1b , 8 , and 21 inhibit growth and disintegrate spheroid cultures of HCT116 and HeLa cells, which would be important for the treatment of solid tumors. In summary, compounds 1b , 1c , 2b , 2c , 24 , and 26 – 28 are highly and selectively cytotoxic against cancer cell lines and were selected for future in vivo tests and further development of anticancer drugs. [Display omitted] • Triterpenoid pyridines and pyrazines were prepared and their cytotoxicity tested. • Pharmacological parameters and selectivity were optimized by prodrug synthesis. • Most active compounds cause apoptosis via the intrinsic pathway. • Compounds 1b , 1c , 2b , 2c , 24 , and 26 – 28 were selected for further development. [ABSTRACT FROM AUTHOR]

A series of 1-aryl-4-(phthalimidoalkyl) piperazines and 1-aryl-4-(naphthalimidoalkyl) piperazines were retrieved from a proprietary library based on their high structural similarity to haloperidol, an antipsychotic with antiparasitic activity, and assessed as potential antileishmanial scaffolds. Selected compounds were tested for antileishmanial activity against promastigotes of Leishmania major and Leishmania mexicana in dose-response assays. Two of the 1-aryl-4-(naphthalimidoalkyl) piperazines (compounds 10 and 11) were active against promastigotes of both Leishmania species without being toxic to human fibroblasts. Their activity was found to correlate with the length of their alkyl chains. Further analyses showed that compound 11 was also active against intracellular amastigotes of both Leishmania species. In promastigotes of both Leishmania species, compound 11 induced collapse of the mitochondrial electrochemical potential and increased the intracellular Ca2+ concentration. Therefore, it may serve as a promising lead compound for the development of novel antiparasitic drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

A set of new substituted dienes were synthesized from betulinic acid by its oxidation to 30-oxobetulinic acid followed by the Wittig reaction. Cytotoxicity of all compounds was tested in vitro in eight cancer cell lines and two noncancer fibroblasts. Almost all dienes were more cytotoxic than betulinic acid. Compounds 4.22 , 4.30 , 4.33 , 4.39 had IC 50 below 5 μmol/L; 4.22 and 4.39 were selected for studies of the mechanism of action. Cell cycle analysis revealed an increase in the number of apoptotic cells at 5 × IC 50 concentration, where activation of irreversible changes leading to cell death can be expected. Both 4.22 and 4.39 led to the accumulation of cells in the G0/G1 phase with partial inhibition of DNA/RNA synthesis at 1 × IC 50 and almost complete inhibition at 5 × IC 50. Interestingly, compound 4.39 at 5 × IC 50 caused the accumulation of cells in the S phase. Higher concentrations of tested drugs probably inhibit more off-targets than lower concentrations. Mechanisms disrupting cellular metabolism can induce the accumulation of cells in the S phase. Both compounds 4.22 and 4.39 trigger selective apoptosis in cancer cells via intrinsic pathway, which we have demonstrated by changes in the expression of the crucial apoptosis-related protein. Pharmacological parameters of derivative 4.22 were superior to 4.39 , therefore 4.22 was the finally selected candidate for the development of anticancer drug. [Display omitted] • Forty new triterpenoids were prepared from 30-oxobetulinic acid by Wittig reaction • Four compounds had high selective cytotoxicity to cancer cells • Compounds 4.22 and 4.39 were selected for further development • Both compounds cause selective apoptosis in cancer cells via the intrinsic pathway • Diene 4.22 has appropriate pharmacological parameters and will be further developed [ABSTRACT FROM AUTHOR]