8 results on '"Mark J. Kurth"'
Search Results
2. 1-BENZYLSPIRO[PIPERIDINE-4,1'-PYRIDO[3,4-b]indole] 'co-potentiators' for minimal function CFTR mutants
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Puay-Wah Phuan, Alan S. Verkman, Jie S. Zhu, Jung-Ho Son, Ka Yi Tsui, Peter M. Haggie, Soren Lipman, Mark J. Kurth, Amy Cheung, and Dean J. Tantillo
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Models, Molecular ,Indoles ,Cystic Fibrosis ,Mutant ,Cystic Fibrosis Transmembrane Conductance Regulator ,Quinolones ,Aminophenols ,01 natural sciences ,chemistry.chemical_compound ,Piperidines ,Models ,Drug Discovery ,CFTR ,Chloride Channel Agonists ,Lung ,0303 health sciences ,biology ,Chemistry ,G%22">c.3700A>G ,General Medicine ,Pharmacology and Pharmaceutical Sciences ,Small molecule ,Cystic fibrosis transmembrane conductance regulator ,Potentiator ,Piperidine ,Stereochemistry ,Medicinal & Biomolecular Chemistry ,Modulator ,Article ,Cell Line ,03 medical and health sciences ,Structure-Activity Relationship ,Medicinal and Biomolecular Chemistry ,Rare Diseases ,Potency ,Animals ,Humans ,030304 developmental biology ,Pharmacology ,Indole test ,010405 organic chemistry ,Organic Chemistry ,Molecular ,N1303K-CFTR ,0104 chemical sciences ,Rats ,Mutation ,biology.protein ,+G%22">c.3700A > G ,Function (biology) - Abstract
We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6′-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC50 ∼600 nM representing an ∼17-fold improvement over the original compound identified in a small molecule screen.
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- 2021
3. Davis-Beirut Reaction: Diverse Chemistries of Highly Reactive Nitroso Intermediates in Heterocycle Synthesis
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Makhluf J. Haddadin, Jie S. Zhu, and Mark J. Kurth
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Indazoles ,Imine ,Reactive intermediate ,Chemical ,010402 general chemistry ,01 natural sciences ,Article ,chemistry.chemical_compound ,Nucleophile ,Models ,Amines ,010405 organic chemistry ,Chemistry ,Regioselectivity ,General Medicine ,Nitroso ,General Chemistry ,Combinatorial chemistry ,0104 chemical sciences ,Models, Chemical ,Cyclization ,Electrophile ,Chemical Sciences ,Click chemistry ,Davis–Beirut reaction ,Nitroso Compounds - Abstract
Indazoles are an important class of nitrogen heterocycles because of their excellent performance in biologically relevant applications, such as in chemical biology and medicinal chemistry. In these applications, convenient synthesis using commercially available and diverse building blocks is highly desirable. Within this broad class, 2H-indazoles are relatively underexploited when compared to 1H-indazole, perhaps because of regioselectivity issues associated with the synthesis of 2H-indazoles. This Account describes our unfolding of the synthetic utility of the Davis–Beirut reaction (DBR) for the construction of 2H-indazoles and their derivatives; parallel unfoldings of mechanistic models for these interrelated N–N bond forming reactions are also summarized. The Davis–Beirut reaction is a robust method that exploits the diverse chemistries of a key nitroso imine or nitroso benzaldehyde intermediate generated in situ under redox neutral conditions. The resulting N–N bond-forming heterocyclization between nucleophilic and electrophilic nitrogens can be leveraged for the synthesis of multiple classes of indazoles and their derivatives, such as simple or fused indazolones, thiazolo-indazoles, 3-alkoxy-2H-indazoles, 2H-indazole N-oxides, and 2H-indazoles with various substitutions on the ring system or the nitrogens. These diverse products can all be synthesized under alkaline conditions and the various strategies for accessing these heterocycles are discussed. Alternatively, we have also developed methods involving mild photochemical conditions for the nitrobenzyl → aci-nitro → nitroso imine sequence. Solvent consideration is especially important for modulating the chemistry of the reactive intermediates in these reactions; the presence of water is critically important in some cases, but water’s beneficial effect has a ceiling because of the alternative reaction pathways it enables. Fused 2H-indazoles readily undergo ring opening reactions to give indazolones when treated with nucleophiles or electrophiles. Furthermore, palladium-catalyzed cross coupling, the Sonagashira reaction, EDC amide coupling, 1,3-dipolar cycloadditions with nitrile oxides, copper-catalyzed alkyne–azide cycloadditions (click reaction), as well as copper-free click reactions, can all be used late-stage to modify 2H-indazoles and indazolones. The continued development and applications of the Davis–Beirut reaction has provided many insights for taming the reactivity of highly reactive nitro and nitroso groups, which still has a plethora of underexplored chemistries and challenges. For example, there is currently a limited number of nonfused 2H-indazole examples containing an aryl substitution at nitrogen. This is caused by relatively slow N–N bond formation between N-aryl imine and nitroso reactants, which allows water to add to the key nitroso imine intermediate causing imine bond cleavage to be a competitive reaction pathway rather than proceeding through the desired N–N bond-forming heterocyclization.
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- 2019
4. Novel 2-(5-Imino-5H-isoquinolones[3,4-b]quinoxalin-7-ylmethyl)-benzonitrile (DIQ3) and Other Related Derivatives Targeting Colon Cancer Cells: Syntheses and in Vitro Models
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Alissar Monzer, Farah Ballout, Jie S. Zhu, Mark J. Kurth, Hala Gali-Muhtasib, Nayri Jabotian, and Makhluf J. Haddadin
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Drug ,Colorectal cancer ,General Chemical Engineering ,media_common.quotation_subject ,medicine.medical_treatment ,010402 general chemistry ,01 natural sciences ,Article ,lcsh:Chemistry ,medicine ,Cytotoxic T cell ,2.1 Biological and endogenous factors ,Aetiology ,media_common ,Cancer ,Chemotherapy ,010405 organic chemistry ,Chemistry ,General Chemistry ,Materials Engineering ,Chemical Engineering ,medicine.disease ,Stem Cell Research ,In vitro ,3. Good health ,0104 chemical sciences ,Quinone ,Colo-Rectal Cancer ,lcsh:QD1-999 ,5.1 Pharmaceuticals ,Cancer research ,Stem cell ,Development of treatments and therapeutic interventions ,Digestive Diseases - Abstract
Chemotherapy has been shown to be effective in reducing the progression and development of cancer in metastatic patients. However, drug selectivity is still a major issue for most chemotherapeutics. In this study, we synthesized four novel heterocyclic compounds having similarity in structure with quinone systems whereby nitrogen atoms replace the oxygen atoms. The anticancer activity of these compounds (DIQ3-6) was tested against HCT116 human colon cancer cells. We showed that all four heterocycles caused significant reduction in colon cancer cell viability at doses as low as 4 μM, a concentration that was not cytotoxic to normal human FHs74Int intestinal cell lines. Interestingly, these heterocycles inhibited colon sphere formation in 3D cultures at first generation (G1), mainly because of inhibition of proliferation as evidenced by Ki67 staining. Thus, DIQ3 causes sufficient eradication of the self-renewal ability of the highly resistant cancer stem cells. This study represents the first documentation of the activity of these novel heterocyclic compounds, particularly compound DIQ3, and their potential therapeutic use in targeting colon cancer self-renewal capacity. Our findings provide the basis for proposing these nontoxic and stable compounds for additional testing against cancer.
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- 2019
5. N-N Bond Formation between Primary Amines and Nitrosos: Direct Synthesis of 2-Substituted Indazolones with Mechanistic Insights
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Clarabella J. Li, Jung-Ho Son, Jie S. Zhu, Niklas Kraemer, Marina E. Shatskikh, Dean J. Tantillo, Makhluf J. Haddadin, and Mark J. Kurth
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Indazoles ,Alcohol ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Catalysis ,chemistry.chemical_compound ,Reactivity (chemistry) ,Physical and Theoretical Chemistry ,Amines ,Retrosynthetic analysis ,Alkyl ,Benzyl Alcohols ,chemistry.chemical_classification ,Primary (chemistry) ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Oxidation reduction ,Bond formation ,Combinatorial chemistry ,0104 chemical sciences ,Cyclization ,Chemical Sciences ,Oxidation-Reduction ,Nitroso Compounds - Abstract
A concise, one-step route to indazolones from primary alkyl amines and o-nitrobenzyl alcohols is reported. The key step in this readily scalable indazolone forming process involves base-mediated in situ o-nitrobenzyl alcohol → o-nitrosobenzaldehyde conversion. Although this functional group interconversion is known to be useful for 2 H-indazole synthesis, its reactivity was modulated for indazolone formation.
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- 2018
6. Proinflammatory secreted phospholipase A2 type IIA (sPLA-IIA) induces integrin activation through direct binding to a newly identified binding site (site 2) in integrins αvβ3, α4β1, and α5β1
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Min Zhao, Yoko K. Takada, Kit S. Lam, Mark J. Kurth, Kan Zhu, Chitose K. Fujita, Yoshikazu Takada, and Masaaki Fujita
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Models, Molecular ,Integrin ,Plasma protein binding ,Integrin alpha4beta1 ,Biochemistry ,Medical and Health Sciences ,Collagen receptor ,Models ,Receptors ,Enzyme Inhibitors ,Integrin alphaVbeta3 ,biology ,Biological Sciences ,Recombinant Proteins ,Cell biology ,Molecular Docking Simulation ,Integrin alpha M ,5.1 Pharmaceuticals ,Adhesion ,Integrin, beta 6 ,Development of treatments and therapeutic interventions ,Integrin Activation ,Signal Transduction ,Protein Binding ,Biochemistry & Molecular Biology ,1.1 Normal biological development and functioning ,Immunology ,Allosteric regulation ,Molecular Sequence Data ,CHO Cells ,Group II Phospholipases A2 ,Fractalkine ,Cricetulus ,Allosteric Regulation ,Underpinning research ,Escherichia coli ,Animals ,Humans ,Receptors, Vitronectin ,Vitronectin ,Amino Acid Sequence ,Binding site ,Secreted Phospholipase A2 Type IIA ,Molecular Biology ,Inflammation ,Binding Sites ,Docking Simulation ,Molecular ,Cell Biology ,Molecular biology ,Gene Expression Regulation ,Chemical Sciences ,biology.protein ,K562 Cells ,Peptides ,Sequence Alignment - Abstract
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Integrins are activated by signaling from inside the cell (inside-out signaling) through global conformational changes of integrins. We recently discovered that fractalkine activates integrins in the absence of CX3CR1 through the direct binding of fractalkine to a ligand-binding site in the integrin headpiece (site 2) that is distinct from the classical RGD-binding site (site 1). We propose that fractalkine binding to the newly identified site 2 induces activation of site 1 though conformational changes (in an allosteric mechanism). We reasoned that site 2-mediated activation of integrins is not limited to fractalkine. Human secreted phospholipase A2 type IIA (sPLA2-IIA), a proinflammatory protein, binds to integrins αvβ3 and α4β1 (site 1), and this interaction initiates a signaling pathway that leads to cell proliferation and inflammation. Human sPLA2-IIA does not bind to M-type receptor very well. Here we describe that sPLA2-IIA directly activated purified soluble integrin αvβ3 and transmembrane αvβ3 on the cell surface. This activation did not require catalytic activity or M-type receptor. Docking simulation predicted that sPLA2-IIA binds to site 2 in the closed-headpiece of αvβ3. A peptide from site 2 of integrin β1 specifically bound to sPLA2-IIA and suppressed sPLA2-IIA-induced integrin activation. This suggests that sPLA2-IIA activates αvβ3 through binding to site 2. sPLA2-IIA also activated integrins α4β1 and α5β1 in a site 2-mediated manner. We recently identified small compounds that bind to sPLA2-IIA and suppress integrin-sPLA2-IIA interaction (e.g. compound 21 (Cmpd21)). Cmpd21 effectively suppressed sPLA2-IIA-induced integrin activation. These results define a novel mechanism of proinflammatory action of sPLA2-IIA through integrin activation.
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- 2015
7. ΔF508-CFTR correctors: synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles
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Long Ye, Bao Hu, Mark J. Kurth, Alan S. Verkman, Puay Wah Phuan, Faris El-Badri, Dean J. Tantillo, and Brandi M. Hudson
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Correctors ,Molecular model ,Cystic Fibrosis ,Stereochemistry ,Medicinal & Biomolecular Chemistry ,Clinical Biochemistry ,Molecular Conformation ,Pharmaceutical Science ,Cystic Fibrosis Transmembrane Conductance Regulator ,Plasma protein binding ,Biochemistry ,Article ,Transmembrane regulator ,chemistry.chemical_compound ,Structure-Activity Relationship ,Congenital ,Medicinal and Biomolecular Chemistry ,Rare Diseases ,Thiadiazoles ,Drug Discovery ,Structure–activity relationship ,Humans ,Thiazole ,Molecular Biology ,Oxazoles ,Lung ,Oxadiazoles ,biology ,Organic Chemistry ,Imidazoles ,Water ,Pharmacology and Pharmaceutical Sciences ,Small molecule ,Transmembrane protein ,Cystic fibrosis transmembrane conductance regulator ,Thiazoles ,Kinetics ,chemistry ,biology.protein ,Molecular Medicine ,Thermodynamics ,Protein Binding ,C-linked bisazoles - Abstract
© 2014 Elsevier Ltd. The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective ΔF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1. Interestingly, bisazole ΔF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule's ability to access this molecular geometry.
- Published
- 2014
8. Inhibition of myeloperoxidase: evaluation of 2H-indazoles and 1H-indazolones
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Makhluf J. Haddadin, Mark J. Kurth, Jason P. Eiserich, Aaron Roth, Sean Ott, Wayne E. Conrad, Teresa A. Palazzo, Dean J. Tantillo, Kelli M. Farber, and Carroll E. Cross
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Toxicophore ,Taurine ,Indazoles ,Medicinal & Biomolecular Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Structure–activity relationship ,Biochemistry ,Article ,Davis-Beirut reaction ,chemistry.chemical_compound ,Structure-Activity Relationship ,Medicinal and Biomolecular Chemistry ,Catalytic Domain ,Drug Discovery ,Humans ,Binding site ,Molecular Biology ,Peroxidase ,Innate immune system ,Binding Sites ,Davis–Beirut reaction ,Myeloperoxidase ,biology ,Chemistry ,Chloramines ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Structure-activity relationship ,Computational docking ,Molecular Docking Simulation ,Docking (molecular) ,2H-Indazole ,biology.protein ,Molecular Medicine ,Protein Binding - Abstract
© 2014 Elsevier Ltd. All rights reserved. Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC50values
- Published
- 2014
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