530 results on '"Mark J. Kurth"'
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2. 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, Nayri Jabotian, Farah Ballout, Jie S. Zhu, Mark J. Kurth, Makhluf J. Haddadin, and Hala Gali-Muhtasib
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Chemistry ,QD1-999 - Published
- 2019
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3. Heterocycles as a Peptidomimetic Scaffold: Solid-Phase Synthesis Strategies
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Aizhan Abdildinova, Mark J. Kurth, and Young-Dae Gong
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solid-phase synthesis ,peptidomimetics ,peptidomimetic synthesis ,protein secondary structure mimetics ,solid-phase peptide synthesis strategies ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Peptidomimetics are a privileged class of pharmacophores that exhibit improved physicochemical and biological properties. Solid-phase synthesis is a powerful tool for gaining rapid access to libraries of molecules from small molecules to biopolymers and also is widely used for the synthesis of peptidomimetics. Small molecules including heterocycles serve as a core for hundreds of drugs, including peptidomimetic molecules. This review covers solid-phase synthesis strategies for peptidomimetics molecules based on heterocycles.
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- 2021
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4. Supplementary Figures 1-4, Methods from Halogenated Benzimidazole Carboxamides Target Integrin α4β1 on T-Cell and B-Cell Lymphomas
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Mark J. Kurth, Kit S. Lam, Sally J. DeNardo, Felice C. Lightstone, Danielle M. Solano, Mirela Andrei, Edmond Y. Lau, Arutselvan Natarajan, and Richard D. Carpenter
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Supplementary Figures 1-4, Methods from Halogenated Benzimidazole Carboxamides Target Integrin α4β1 on T-Cell and B-Cell Lymphomas
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- 2023
5. Data from Halogenated Benzimidazole Carboxamides Target Integrin α4β1 on T-Cell and B-Cell Lymphomas
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Mark J. Kurth, Kit S. Lam, Sally J. DeNardo, Felice C. Lightstone, Danielle M. Solano, Mirela Andrei, Edmond Y. Lau, Arutselvan Natarajan, and Richard D. Carpenter
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Integrin α4β1 is an attractive but poorly understood target for selective diagnosis and treatment of T-cell and B-cell lymphomas. This report focuses on the rapid microwave preparation, structure-activity relationships, and biological evaluation of medicinally pertinent benzimidazole heterocycles as integrin α4β1 antagonists. We documented tumor uptake of derivatives labeled with 125I in xenograft murine models of B-cell lymphoma. Molecular homology models of integrin α4β1 predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. The high-affinity halogenated ligands identified offer attractive tools for medicinal and biological use, including fluoro and iodo derivatives with potential radiodiagnostic (18F) or radiotherapeutic (131I) applications, or chloro and bromo analogues that could provide structural insights into integrin-ligand interactions through photoaffinity, cross-linking/mass spectroscopy, and X-ray crystallographic studies. Cancer Res; 70(13); 5448–56. ©2010 AACR.
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- 2023
6. Solid‐Phase Synthesis of Peptidomimetics with Peptide Backbone Modifications
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Aizhan Abdildinova, Young-Dae Gong, and Mark J. Kurth
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Solid-phase synthesis ,Peptide backbone ,Chemistry ,Peptidomimetic ,Organic Chemistry ,Combinatorial chemistry - Published
- 2021
7. The etiology of primary biliary cirrhosis: connecting xenobiotics to anti-mitochondrial antibodies by AB initio quantum chemistry: S A Long, University of California at Davis, Davis, CA; Chao Quan, Judy Van de Water, Michael H Nantz, Mark J Kurth, University of California, Davis, CA; Daniel Barsky, Michael E Colvin, Lawrence Livermore National Labs, Livermore, CA; Kit S Lam, University of California, Davis, CA; Ross L Coppel, Monash University, Melbourne Australia; Aftab Ansari, Emory University, Atlanta, GA; M E Gershwin, University of California, Davis, CA
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- 2001
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8. Autoimmunity affecting the biliary tract fuels the immunosurveillance of cholangiocarcinoma
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Franck Letourneur, Jérémy Augustin, Mark J. Kurth, Julie Le Naour, Sylvie Lachkar, Pamela Caudana, Eliane Piaggio, Youra Kim, Sarah Levesque, Jie S. Zhu, Guido Kroemer, Jonathan Pol, Bouchra Lekbaby, Andrea Checcoli, Patrick S.C. Leung, Allan Sauvat, Shashi Gujar, Agathe Delaune, Chantal Housset, Pierre de la Grange, Paule Opolon, Laura Fouassier, Noémie Robil, Laurence Zitvogel, Patrick Soussan, Juliette Paillet, Céleste Plantureux, Jimena Tosello Boari, M. Eric Gershwin, Isabelle Martins, Maria Chiara Maiuri, Cédric Coulouarn, Gautier Stoll, Norma Bloy, Gwennhael Autret, Juliette Hamroune, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Gustave Roussy (IGR), Institut Curie [Paris], Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), GenoSplice [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of California [Los Angeles] (UCLA), University of California, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dalhousie University [Halifax], Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CRLCC Eugène Marquis (CRLCC), Université Paris-Saclay, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karolinska University Hospital [Stockholm], Association pour la lutte contre les maladies inflammatoires du foie et des voies biliaires, Dalhousie Medical Research Foundation, Agence National de la Recherche, ERA-Net for Research on Rare Diseases, Association pour la recherche sur le cancer, Cancéropôle Ile-de-France, Chancellerie des universités de Paris, Fondation pour la Recherche Médicale, Elior, European Research Area Network on Cardiovascular Diseases, Gustave Roussy Odyssea, European Union Horizon 2020, Canadian Cancer Society, Project Oncobiome, Fondation Carrefour, GDW20171100085, High-end Foreign Expert Program in China, Institut National du Cancer, Inserm, Institut Universitaire de France, LeDucq Foundation, LabEx, Recherche Hospitalo-Universitaire Torino Lumière, Seerave Foundation, Canadian Institutes of Health Research, Site de Recherche intégrée sur le Cancer Stratified Oncology Cell DNA Repair and Tumor Immune Elimination, Cancer Research and Personalized Medicine, Multi-Organism Institute (ITMO) Aviesan Cancer, Association Française d'Hépatologie, Site de Recherche intégrée sur le Cancer Cancer Research and Personalized Medicine, Ligue contre le Cancer, École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of California (UC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
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CD4-Positive T-Lymphocytes ,Cholangitis ,Autoimmunity ,CD8-Positive T-Lymphocytes ,Inbred C57BL ,medicine.disease_cause ,Medical and Health Sciences ,Malignant transformation ,Cholangiocarcinoma ,Mice ,0302 clinical medicine ,Immunologic ,Neoplasms ,2.1 Biological and endogenous factors ,Immunology and Allergy ,Medicine ,Aetiology ,Cancer ,0303 health sciences ,Tumor ,Liver Disease ,Forkhead Transcription Factors ,3. Good health ,Immunosurveillance ,medicine.anatomical_structure ,Liver ,Biliary tract ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,cardiovascular system ,Cytokines ,Female ,Biotechnology ,Liver Cancer ,Monitoring ,T cell ,Chronic Liver Disease and Cirrhosis ,Immunology ,Context (language use) ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Autoimmune Disease ,digestive system ,Cell Line ,Primary sclerosing cholangitis ,Experimental ,03 medical and health sciences ,Rare Diseases ,Monitoring, Immunologic ,Cell Line, Tumor ,parasitic diseases ,Animals ,cardiovascular diseases ,Digestive Diseases - (Gallbladder) ,030304 developmental biology ,business.industry ,Neoplasms, Experimental ,medicine.disease ,digestive system diseases ,Mice, Inbred C57BL ,Bile Duct Neoplasms ,Cancer research ,Digestive Diseases ,business - Abstract
International audience; Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.
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- 2021
9. E. coli and the etiology of human PBC: Antimitochondrial antibodies and spreading determinants
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Patrick S.C. Leung, Pietro Invernizzi, Natalia S. Nemeria, William M. Ridgway, M. Eric Gershwin, Yao Yang, Guo-Xiang Yang, Mark J. Kurth, Frank Jordan, Jinjung Choi, Ross L. Coppel, Ying Chen, Ti-Hong Shao, Weici Zhang, Aftab A. Ansari, Yang, Y, Choi, J, Chen, Y, Invernizzi, P, Yang, G, Zhang, W, Shao, T, Jordan, F, Nemeria, N, Coppel, R, Ridgway, W, Kurth, M, Ansari, A, Leung, P, and Gershwin, M
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Lipoylation ,Molecular Conformation ,Cross Reactions ,PBC ,medicine.disease_cause ,Dihydrolipoyllysine-Residue Acetyltransferase ,Autoantigens ,Epitope ,law.invention ,Mitochondrial Proteins ,chemistry.chemical_compound ,Epitopes ,Plasmid ,law ,medicine ,Escherichia coli ,Humans ,Escherichia coli Infections ,Autoantibodies ,Hepatology ,biology ,Thioctic Acid ,Liver Cirrhosis, Biliary ,Autoantibody ,Pyruvate dehydrogenase complex ,Molecular biology ,Mitochondria ,Lipoic acid ,Hepatitis, Autoimmune ,chemistry ,Case-Control Studies ,Recombinant DNA ,biology.protein ,Antibody - Abstract
Background and Aims: The increased frequency of urinary tract infections in patients with primary biliary cholangitis (PBC) and the cross-reactivity between the lipoyl domains (LD) of human pyruvate dehydrogenase complex (hPDC-E2) and Escherichia coli PDC-E2 (ePDC-E2) have long suggested a role of E. coli in causality of PBC. This issue, however, has remained speculative. We hypothesized that by generating specific constructs of human and E. coli PDC-E2, we would be able to assess the specificity of autoantibody responses and define whether exposure to E. coli in susceptible hosts is the basis for the antimitochondrial antibody (AMA) response. Approach and Results: Importantly, the reactivity of hPDC-E2 LD (hPDC-E2LD) affinity-purified antibodies against hPDC-E2LD could only be removed by prior absorption with hPDC-E2LD and not ePDC-E2, suggesting the presence of unique human PDC-E2 epitopes distinct from E. coli PDC-E2. To identify the autoepitope(s) present in hPDC-E2LD, a more detailed study using a variety of PDC-E2 constructs was tested, including the effect of lipoic acid (LA) on ePDC-E2 conformation and AMA recognition. Individual recombinant ePDCE2 LD domains LD1, LD2 and LD3 did not react with either AMA or antibodies to LA (anti-LA), but in contrast, anti-LA was readily reactive against purified recombinant LD1, LD2, and LD3 expressed in tandem (LP); such reactivity increased when LP was precultured with LA. Moreover, when the three LD (LD1, LD2, LD3) domains were expressed in tandem in pET28a or when LD1 was expressed in another plasmid pGEX, they were lipoylated and reactive to PBC sera. Conclusions: In conclusion, our data are consistent with an exposure to E. coli that elicits specific antibody to ePDC-E2 resulting in determinant spreading and the classic autoantibody to hPDC-E2LD. We argue this is the first step to development of human PBC.
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- 2021
10. Synthesis and evaluation of tetrahydropyrazolopyridine inhibitors of anion exchange protein SLC26A4 (pendrin)
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Mark J. Kurth, Peter M. Haggie, Marina E. Shatskikh, Julia Y. Lu, Jung-Ho Son, Alan S. Verkman, Amber A. Rivera, Joseph-Anthony Tan, Jie S. Zhu, and Puay-Wah Phuan
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Pyridines ,Chronic rhinosinusitis ,Antiporter ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,01 natural sciences ,Biochemistry ,Cystic fibrosis ,Mice ,Regioselectivity ,Drug Discovery ,Lung ,Inbred F344 ,Anion transporter ,Molecular Structure ,biology ,Ion exchange ,Chemistry ,Pharmacology and Pharmaceutical Sciences ,Transmembrane protein ,Sulfate Transporters ,5.1 Pharmaceuticals ,Respiratory ,Molecular Medicine ,Development of treatments and therapeutic interventions ,Medicinal & Biomolecular Chemistry ,Article ,Small Molecule Libraries ,Structure-Activity Relationship ,Medicinal and Biomolecular Chemistry ,Downregulation and upregulation ,SLC26A4 ,otorhinolaryngologic diseases ,medicine ,Animals ,Pendrin ,Hydrazine (antidepressant) ,Molecular Biology ,010405 organic chemistry ,Organic Chemistry ,medicine.disease ,Rats, Inbred F344 ,Rats ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Pyrazole ,biology.protein ,Pyrazoles - Abstract
Pendrin is a transmembrane chloride/anion antiporter that is strongly upregulated in the airways in rhinoviral infection, asthma, cystic fibrosis and chronic rhinosinusitis. Based on its role in the regulation of airway surface liquid depth, pendrin inhibitors have potential indications for treatment of inflammatory airways diseases. Here, a completely regioselective route to tetrahydro-pyrazolopyridine pendrin inhibitors based on 1,3-diketone and substituted hydrazine condensation was been developed. Structure-activity relationships at the tetra hydropyridyl nitrogen were investigated using a focused library, establishing the privileged nature of N-phenyl ureas and improving inhibitor potency by greater than 2-fold.
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- 2019
11. Davis–Beirut Reaction: A Photochemical Brønsted Acid Catalyzed Route to N-Aryl 2H-Indazoles
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Makhluf J. Haddadin, Ka Yi Tsui, Niklas Kraemer, Jie S. Zhu, Clarabella J. Li, Mark J. Kurth, Dean J. Tantillo, and Julio M. Larach
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chemistry.chemical_classification ,Aryl ,Organic Chemistry ,Imine ,Nitroso ,Photochemistry ,Biochemistry ,Catalysis ,chemistry.chemical_compound ,chemistry ,Nitro ,Physical and Theoretical Chemistry ,Brønsted–Lowry acid–base theory ,Davis–Beirut reaction ,Alkyl - Abstract
The Davis-Beirut reaction provides access to 2H-indazoles from aromatic nitro compounds. However, N-aryl targets have been traditionally challenging to access due to competitive alternate reaction pathways. Previously, the key nitroso imine intermediate was generated under alkaline conditions, but as reported here, the photochemistry of o-nitrobenzyl alcohols empowered Bronsted acid catalyzed conditions for accessing N-aryl targets. Anilines and alkyl amines give different outcomes under optimized conditions; the proposed mechanism was studied using quantum chemical calculations.
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- 2019
12. Photochemical Preparation of 1,2-Dihydro-3H-indazol-3-ones in Aqueous Solvent at Room Temperature
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Clarabella J. Li, Niklas Kraemer, Mark J. Kurth, Jie S. Zhu, and Makhluf J. Haddadin
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Indazoles ,Aqueous solution ,010405 organic chemistry ,Extramural ,Organic Chemistry ,Reactive intermediate ,Temperature ,Water ,chemistry.chemical_element ,Photochemical Processes ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Nitrogen ,Catalysis ,Article ,0104 chemical sciences ,Solvent ,Medicinal and Biomolecular Chemistry ,chemistry ,Solvents ,Water chemistry - Abstract
o-Nitrosobenzaldehyde is a reactive intermediate useful in the synthesis of nitrogen heterocycles. Previous strategies for using o-nitrosobenzaldehyde involve its isolation via chromatography and/or formation under harsh conditions. Herein, this intermediate was photochemically generated in situ from o-nitrobenzyl alcohols in a mild, efficient manner for the construction of 1,2-dihydro-3 H-indazol-3-ones using an aqueous solvent at room temperature. This convenient reaction offers several advantages over reported methods. The commercially available photoreactor employed 3 × 18 W bulbs outputting broad emission above 365 nm.
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- 2018
13. 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
14. Combination potentiator (‘co-potentiator’) therapy for CF caused by CFTR mutants, including N1303K, that are poorly responsive to single potentiators
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Peter M. Haggie, Walter E. Finkbeiner, Joseph-Anthony Tan, Alan S. Verkman, Dennis W. Nielson, Jung-Ho Son, Luis J. V. Galietta, Mark J. Kurth, Lorna Zlock, Puay-Wah Phuan, Ilaria Musante, Clarabella J. Li, Phuan, Puay-Wah, Son, Jung-Ho, Tan, Joseph-Anthony, Li, Clarabella, Musante, Ilaria, Zlock, Lorna, Nielson, Dennis W., Finkbeiner, Walter E., Kurth, Mark J., Galietta, Luis J., Haggie, Peter M., and Verkman, Alan S.
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0301 basic medicine ,Cystic Fibrosis ,High-throughput screen ,Respiratory System ,Mutant ,Cystic Fibrosis Transmembrane Conductance Regulator ,Quinolones ,Pharmacology ,Aminophenols ,medicine.disease_cause ,Cystic fibrosis ,Congenital ,0302 clinical medicine ,CFTR ,Lung ,Sulfonamides ,Mutation ,Cultured ,Drug Synergism ,respiratory system ,Small molecule ,Potentiator ,Cystic fibrosi ,N1303K ,Ion Channel Gating ,Pulmonary and Respiratory Medicine ,Agonist ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.drug_class ,Cells ,Clinical Sciences ,Article ,Cell Line ,Structure-Activity Relationship ,03 medical and health sciences ,Rare Diseases ,medicine ,Animals ,Humans ,Structure–activity relationship ,business.industry ,medicine.disease ,030104 developmental biology ,030228 respiratory system ,Cell culture ,Pediatrics, Perinatology and Child Health ,Mutant Proteins ,business - Abstract
Background Current modulator therapies for some cystic fibrosis-causing CFTR mutants, including N1303K, have limited efficacy. We provide evidence here to support combination potentiator (co-potentiator) therapy for mutant CFTRs that are poorly responsive to single potentiators. Methods Functional synergy screens done on N1303K and W1282X CFTR, in which small molecules were tested with VX-770, identified arylsulfonamide-pyrrolopyridine, phenoxy-benzimidazole and flavone co-potentiators. Results A previously identified arylsulfonamide-pyrrolopyridine co-potentiator (ASP-11) added with VX-770 increased N1303K-CFTR current 7-fold more than VX-770 alone. ASP-11 increased by ~65% of the current of G551D-CFTR compared to VX-770, was additive with VX-770 on F508del-CFTR, and activated wild-type CFTR in the absence of a cAMP agonist. ASP-11 efficacy with VX-770 was demonstrated in primary CF human airway cell cultures having N1303K, W1282X and G551D CFTR mutations. Structure-activity studies on 11 synthesized ASP-11 analogs produced compounds with EC 50 down to 0.5 μM. Conclusions These studies support combination potentiator therapy for CF caused by some CFTR mutations that are not effectively treated by single potentiators.
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- 2018
15. Ethyl 1-benzyl-1,2,3,3a,4,10b-hexahydropyrrolo[2′,3′:3,4]pyrrolo[1,2-a]benzimidazole-2-carboxylate
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Liping Meng, James C. Fettinger, and Mark J. Kurth
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Crystallography ,QD901-999 - Abstract
The title molecule, C22H23N3O2, was obtained via an intramolecular cycloaddition of an azomethine ylide and an alkene tethered by a benzimidazole unit. The benzoimidazole unit is essentially planar, with an r.m.s. deviation of 0.0087 Å from the nine constituent atoms. It has a cis fusion of the two pyrrolidine rings as well as a cis ester appendage. The two pyrrolidine rings rings have envelope conformations. The crystal packing is stabilized by aromatic π–π stacking of parallel benzimidazole ring systems, with a centroid-to-centroid distance of 3.518 (6) Å. Weak intermolecular C—H...O contacts may also play a role in the stability of the packing.
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- 2011
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16. Heterocycles as a Peptidomimetic Scaffold: Solid-Phase Synthesis Strategies
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Mark J. Kurth, Young-Dae Gong, and Aizhan Abdildinova
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Scaffold ,solid-phase synthesis ,Peptidomimetic ,Pharmaceutical Science ,Review ,010402 general chemistry ,01 natural sciences ,Pharmacy and materia medica ,Solid-phase synthesis ,Biological property ,Drug Discovery ,Rapid access ,010405 organic chemistry ,Chemistry ,Pharmacology and Pharmaceutical Sciences ,protein secondary structure mimetics ,Combinatorial chemistry ,Small molecule ,0104 chemical sciences ,RS1-441 ,solid-phase peptide synthesis strategies ,peptidomimetic synthesis ,peptidomimetics ,Medicine ,Molecular Medicine ,Pharmacophore - Abstract
Peptidomimetics are a privileged class of pharmacophores that exhibit improved physicochemical and biological properties. Solid-phase synthesis is a powerful tool for gaining rapid access to libraries of molecules from small molecules to biopolymers and also is widely used for the synthesis of peptidomimetics. Small molecules including heterocycles serve as a core for hundreds of drugs, including peptidomimetic molecules. This review covers solid-phase synthesis strategies for peptidomimetics molecules based on heterocycles.
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- 2021
17. A Redox Isomerization Strategy for Accessing Modular Azobenzene Photoswitches with Near Quantitative Bidirectional Photoconversion
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Jie S. Zhu, Jeremy R. Tuck, Robert J. Tombari, Mark J. Kurth, Julio M. Larach, Stanley R. Bode, Phillip W. Gingrich, Whitney C. Duim, Jung-Ho Son, Makhluf J. Haddadin, Dean J. Tantillo, Hunter T. Warren, James C. Fettinger, and David E. Olson
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Models, Molecular ,Molecular Conformation ,010402 general chemistry ,Hydrazide ,01 natural sciences ,Biochemistry ,Redox ,Article ,chemistry.chemical_compound ,Isomerism ,Models ,Dimethyl Sulfoxide ,Physical and Theoretical Chemistry ,010405 organic chemistry ,business.industry ,Organic Chemistry ,Molecular ,Oxidation reduction ,Modular design ,Photochemical Processes ,Combinatorial chemistry ,0104 chemical sciences ,chemistry ,Azobenzene ,Chemical Sciences ,Click chemistry ,Pharmacophore ,business ,Isomerization ,Azo Compounds ,Oxidation-Reduction - Abstract
Photoswitches capable of accessing two geometric states are highly desirable, especially if their design is modular and incorporates a pharmacophore tethering site. We describe a redox isomerization strategy for synthesizing p-formylazobenzenes from p-nitrobenzyl alcohol. The resulting azo-aldehydes can be readily converted to photoswitchable compounds with excellent photophysical properties using simple hydrazide click chemistry. As a proof of principle, we synthesized a photoswitchable surfactant enabling the photocontrol of an emulsion with exceptionally high spatiotemporal precision.
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- 2019
18. 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.
- Published
- 2019
19. Davis-Beirut Reaction: A Photochemical Brønsted Acid Catalyzed Route to
- Author
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Niklas, Kraemer, Clarabella J, Li, Jie S, Zhu, Julio M, Larach, Ka Yi, Tsui, Dean J, Tantillo, Makhluf J, Haddadin, and Mark J, Kurth
- Subjects
Indazoles ,Imines ,Amines ,Nitro Compounds ,Benzyl Alcohols ,Catalysis ,Article - Abstract
The Davis−Beirut reaction provides access to2H-indazoles from aromatic nitro compounds. However, N-aryl targets have been traditionally challenging to access due to competitive alternate reaction pathways. Previously, the key nitroso imine intermediate was generated under alkaline conditions, but as reported here, the photochemistry of o-nitrobenzyl alcohols empowered Brønsted acid catalyzed conditions for accessing N-aryl targets. Anilines and alkyl amines give different outcomes under optimized conditions; the proposed mechanism was studied using quantum chemical calculations.
- Published
- 2019
20. Accessing Multiple Classes of 2H-Indazoles: Mechanistic Implications for the Cadogan and Davis-Beirut Reactions
- Author
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Dean J. Tantillo, Ka Yi Tsui, Jung-Ho Son, Jie S. Zhu, Makhluf J. Haddadin, Clarabella J. Li, Niklas Kraemer, and Mark J. Kurth
- Subjects
Indazoles ,Molecular Structure ,Chemistry ,Nitrene ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,Catalysis ,Article ,0104 chemical sciences ,Colloid and Surface Chemistry ,Mechanism (philosophy) ,Cyclization ,Deoxygenation - Abstract
The Cadogan cyclization is a robust but harsh method for the synthesis of 2 H-indazoles, a valuable class of nitrogen heterocycles. Although nitrene generation by exhaustive deoxygenation is widely accepted as the operating mechanism in the reductive cyclization of nitroaromatics, non-nitrene pathways have only been theorized previously. Here, 2 H-indazole N-oxides were synthesized through an interrupted Cadogan/Davis-Beirut reaction and are presented as direct evidence of competent oxygenated intermediates; mechanistic implications for both reactions are discussed. Isolation and characterization of these N-oxides enabled a formal Cadogan cyclization at room temperature for 2 H-indazole synthesis.
- Published
- 2019
21. Davis–Beirut reaction inspired nitroso Diels–Alder reaction
- Author
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Jie S. Zhu, Jung-Ho Son, Mark J. Kurth, Amy Cheung, and Makhluf J. Haddadin
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inorganic chemicals ,010405 organic chemistry ,Chemistry ,organic chemicals ,fungi ,Organic Chemistry ,Nitroso ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Medicinal chemistry ,Article ,0104 chemical sciences ,Para position ,chemistry.chemical_compound ,Deprotonation ,Drug Discovery ,Nitro ,Moiety ,Davis–Beirut reaction ,Diels–Alder reaction - Abstract
A Davis–Beirut reaction inspired nitroso Diels–Alder protocol is reported. The starting material for the procedure is a nitrophenyl moiety with the para position appropriately substituted with a 2°-amine (see 5) or 2°-alcohol (see 6). Deprotonation at the benzylic position followed by concomitant oxidation of the benzylic position and reduction of the nitro moiety delivers a nitrosophenyl intermediate, which subsequently undergoes a nitroso Diels–Alder reaction. This one-pot procedure delivers aryldihydro-1,2-oxazines in moderate yields.
- Published
- 2021
22. One-Pot Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolines and Isoquinolino[3,4-b]quinoxalines via Tandem Cyclization Strategies
- Author
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Alex L. Bagdasarian, Teresa A. Palazzo, James C. Fettinger, Makhluf J. Haddadin, Huy Nguyen, and Mark J. Kurth
- Subjects
Molecular Structure ,Tandem ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,One-pot synthesis ,Isoquinolines ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Article ,Catalysis ,0104 chemical sciences ,Medicinal and Biomolecular Chemistry ,Cyclization ,Quinoxalines ,Benzimidazoles - Abstract
Two operationally simple one-pot protocols have been developed for the synthesis of amino-functionalized benzo[4,5]imidazo[2,1–a]isoquinolines and isoquinolino[3,4–b]quinoxalines. Optimization data and substrate scope for these atom-economical transformations, which engage commercially available o-phenylenediamines and o-cyanobenzalde-hydes, are discussed.
- Published
- 2016
23. The Solid-Phase Part of Supported Small-Molecule Synthesis
- Author
-
Mark J. Kurth
- Subjects
Chemistry ,QD1-999 - Abstract
The synthesis of small molecules on solid phase must not only address the vagaries of C–C-bond formation and functional-group manipulation, but must also take into account solid-support issues such as 'point of attachment', 'resin compatibility', 'reagent accesibility', and 'product liberation'. Hence, the resin plays a vital role in the solid-phase venture and the polymer advantages can be summarized as reactions can be driven to completion by addition of excess solution-phase reagents, reaction products are 'isolated' by filtration and washing, and multiple-step synthesis terminating with a 'selective' liberation step can deliver essentially pure product. These issues, as well as a number of strategies for the preparation and functionalization of resin supports, are discussed.
- Published
- 1996
24. Abstract 4797: A novel Diiminoquinone targets colorectal cancer stem cells
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Jie S. Zhu, Nayri Jabotian, Mark J. Kurth, Alissar Monzer, Makhlouf Haddadin, Wassim Abou Kheir, and Hala Gali-Muhtasib
- Subjects
Cancer Research ,Cardiotoxicity ,Chemotherapy ,education.field_of_study ,business.industry ,Colorectal cancer ,medicine.medical_treatment ,Population ,Cancer ,Drug resistance ,medicine.disease ,Oncology ,Cancer stem cell ,medicine ,Cancer research ,Stem cell ,business ,education - Abstract
5-Fluorouracil (5-Fu) remains the standard chemotherapy for metastatic colorectal cancer, but drug resistance and unpredictable cardiotoxicity limit its effectiveness. The high recurrence rates and common resistance are thought to be due to a population of self-renewing cancer stem cells (CSCs). In this study, we synthesized four novel heterocyclic compounds that are similar in structure with quinones and tested their anticancer activity against HCT116 human colon cancer cells in 2D monolayer and 3D sphere cultures. In 2D, all compounds caused significant inhibition of colon cancer cell viability at concentrations non-cytotoxic to normal human FHs74Int intestinal cell lines. In 3D cultures, these heterocycles eradicated the self-renewal ability of the highly resistant cancer stem cells and inhibited colon sphere formation in first generation (G1), as well as subsequent generations. This study represents the first documentation of the activity of these novel heterocyclic compounds, particularly compound 6a, abbreviated as DIQ-3, which we propose to be an effective treatment strategy to prevent colon cancer recurrence by targeting colorectal CSCs. Our findings provide the basis for suggesting these non-toxic and stable compounds for additional testing against cancer. Citation Format: Alissar Monzer, Nayri Jabotian, Jie S. Zhu, Mark J. Kurth, Wassim Abou Kheir, Makhlouf Haddadin, Hala Gali-Muhtasib. A novel Diiminoquinone targets colorectal cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4797.
- Published
- 2019
25. Dibenzonaphthyridinones: Heterocycle-to-Heterocycle Synthetic Strategies and Photophysical Studies
- Author
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Mark J. Kurth, Elsy El Khoury, Dean J. Tantillo, Teresa A. Palazzo, Digambara Patra, Mackenzie G. Appleton, Makhluf J. Haddadin, and Joung S. Yang
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Molecular Structure ,Chemistry ,Organic Chemistry ,Solvatochromism ,Chemical ,Isoxazoles ,Time-dependent density functional theory ,Biochemistry ,Fluorescence ,Article ,Models, Chemical ,Models ,Computational chemistry ,Chemical Sciences ,Benzene derivatives ,Benzene Derivatives ,Combinatorial Chemistry Techniques ,Molecule ,Naphthyridines ,Physical and Theoretical Chemistry ,Linear correlation ,Excitation - Abstract
A heterocycle-to-heterocycle strategy is presented for the preparation of highly fluorescent and solvatochromic dibenzonaphthyridinones (DBNs) via methodology that leads to the formation of a tertiary, spiro-fused carbon center. A linear correlation between the results of photophysical experiments and time dependent density functional theory calculations was observed for the λ(max) of excitation for DBNs with varying electronic character.
- Published
- 2015
26. N-N Bond Formation between Primary Amines and Nitrosos: Direct Synthesis of 2-Substituted Indazolones with Mechanistic Insights
- Author
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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
- Subjects
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.
- Published
- 2018
27. Davis–Beirut Reaction: Alkoxide versus Hydroxide Addition to the Key o-Nitrosoimine Intermediate
- Author
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Andrew P. Teuthorn, Julia Y. Lu, Matthew R. Duong, Jung-Ho Son, Makhluf J. Haddadin, Jie S. Zhu, and Mark J. Kurth
- Subjects
Nucleophilic addition ,Indazoles ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Design elements and principles ,Substrate (chemistry) ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,0104 chemical sciences ,chemistry.chemical_compound ,Alkoxide ,Polymer chemistry ,Hydroxides ,Hydroxide ,Amine gas treating ,Imines ,Physical and Theoretical Chemistry ,Amines ,Selectivity ,Davis–Beirut reaction - Abstract
Reaction options, alkoxide vs hydroxide vs amine addition to the key intermediate (o-nitrosoimine) generated in the Davis–Beirut reaction of an o-nitrobenzyl-amine substrate, are reported to explain the nucleophilic addition selectivity of this one-pot indazole-forming process. The hydroxide addition/deprotection pathway as well as the fate of the resulting o-nitrosobenzaldehyde were both uncovered with several o-nitrobenzylamine substrates, and design elements required for an efficient double Davis–Beirut reaction, inspired by new mechanistic insights, were defined.
- Published
- 2018
28. Correction to 'Diverting Reactive Intermediates Toward Unusual Chemistry: Unexpected Anthranil Products from Davis-Beirut Reaction'
- Author
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Andrew P. Teuthorn, Jung-Ho Son, Makhluf J. Haddadin, Mark J. Kurth, Jie S. Zhu, and Dean J. Tantillo
- Subjects
Anthranil ,chemistry.chemical_compound ,chemistry ,Organic Chemistry ,Reactive intermediate ,Organic chemistry ,Davis–Beirut reaction ,Article - Abstract
The discovery of a new variation on the Davis–Beirut reaction is described in which an atypical heterocyclic framework (the anthranil or benzo[c]isoxazole framework) is formed as the result of diversion of a key reactive intermediate away from its usual reactivity – a potentially general approach to reaction design and development. Experimental and computational support for the proposed mechanism and origins of altered reactivity are described.
- Published
- 2017
29. Expedient one-pot synthesis of indolo[3,2-c]isoquinolines via a base-promoted N-alkylation/tandem cyclization
- Author
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Huy Nguyen, Makhluf J. Haddadin, Mark J. Kurth, and James C. Fettinger
- Subjects
chemistry.chemical_classification ,Annulation ,domino process ,Tandem ,Base (chemistry) ,Chemistry ,one-pot ,tandem cyclization ,Organic Chemistry ,One-pot synthesis ,Substrate (chemistry) ,Alkylation ,Biochemistry ,Combinatorial chemistry ,Medicinal and Biomolecular Chemistry ,Indolo[3 ,2-c]isoquinoline ,Drug Discovery ,photoluminescence ,Domino process - Abstract
A transition metal-free, one-pot protocol has been developed for the synthesis of 11H-indolo[3,2-c]isoquinolin-5-amines via the atom economical annulation of ethyl (2-cyanophenyl)carbamates and 2-cyanobenzyl bromides. This method proceeds via sequential N-alkylation and base-promoted cyclization. Optimization data, substrate scope, mechanistic insights, and photoluminescence properties are discussed.
- Published
- 2015
30. Reassigning the Structures of Natural Products Using NMR Chemical Shifts Computed with Quantum Mechanics: A Laboratory Exercise
- Author
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Justin B. Siegel, R. Alan Gamage, Tiana T. Truong, Teresa A. Palazzo, Jason G. Harrison, Michael W. Lodewyk, Emma T. Mack, Shirley M. T. Wong, Mark J. Kurth, and Dean J. Tantillo
- Subjects
Quantum chemical ,Physics ,Computer based learning ,Science instruction ,Theoretical computer science ,010405 organic chemistry ,4. Education ,Chemical shift ,05 social sciences ,Measure (physics) ,Educational technology ,050301 education ,General Chemistry ,01 natural sciences ,Engineering physics ,0104 chemical sciences ,Education ,Concept learning ,ComputingMilieux_COMPUTERSANDEDUCATION ,Student learning ,0503 education - Abstract
An applied computational chemistry laboratory exercise is described in which students use modern quantum chemical calculations of chemical shifts to assign the structure of a recently isolated natural product. A pre/post assessment was used to measure student learning gains and verify that students demonstrated proficiency of key learning objectives.
- Published
- 2014
31. Diverting Reactive Intermediates Toward Unusual Chemistry: Unexpected Anthranil Products from Davis-Beirut Reaction
- Author
-
Dean J. Tantillo, Jung-Ho Son, Makhluf J. Haddadin, Mark J. Kurth, Jie S. Zhu, and Andrew P. Teuthorn
- Subjects
Molecular Structure ,010405 organic chemistry ,Extramural ,Stereochemistry ,Reactive intermediate ,Organic Chemistry ,Isoxazoles ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Anthranil ,chemistry.chemical_compound ,Medicinal and Biomolecular Chemistry ,chemistry ,Quantum Theory ,Reactivity (chemistry) ,Isoxazole ,Davis–Beirut reaction - Abstract
The discovery of a new variation on the Davis–Beirut reaction is described in which an atypical heterocyclic framework (the anthranil or benzo[c]isoxazole framework) is formed as the result of diversion of a key reactive intermediate away from its expected reactivity—a potentially general approach to reaction design and development. Experimental and computational support for the proposed mechanism and origins of altered reactivity are described.
- Published
- 2017
32. High-Potency Phenylquinoxalinone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activators
- Author
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Colton K. Ku, Jung-Ho Son, Andrew P. Teuthorn, Alan S. Verkman, Onur Cil, Jie S. Zhu, Mark J. Kurth, Puay Wah Phuan, and Sujin Lee
- Subjects
0301 basic medicine ,Cystic Fibrosis ,Medicinal & Biomolecular Chemistry ,Cystic Fibrosis Transmembrane Conductance Regulator ,Article ,Cell Line ,03 medical and health sciences ,Medicinal and Biomolecular Chemistry ,Mice ,Rare Diseases ,Microsomes ,Quinoxalines ,Drug Discovery ,Moiety ,Potency ,Animals ,Humans ,Lung ,EC50 ,biology ,Chemistry ,Activator (genetics) ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Metabolic stability ,Cystic fibrosis transmembrane conductance regulator ,030104 developmental biology ,Orphan Drug ,Biochemistry ,Liver ,Acute Disease ,biology.protein ,Microsomes, Liver ,Molecular Medicine ,Digestive Diseases ,Constipation - Abstract
We previously identified phenylquinoxalinone CFTRact-J027 (4) as a cystic fibrosis transmembrane conductance regulator (CFTR) activator with an EC50 of ∼200 nM and demonstrated its therapeutic efficacy in mouse models of constipation. Here, structure v–activity studies were done on 36 synthesized phenylquinoxalinone analogs to identify compounds with improved potency and altered metabolic stability. Synthesis of the phenylquinoxalinone core was generally accomplished by condensation of 1,2-phenylenediamines with substituted phenyloxoacetates. Structure–activity studies established, among other features, the privileged nature of a properly positioned nitro moiety on the 3-aryl group. Synthesized analogs showed improved CFTR activation potency compared to 4 with EC50 down to 21 nM and with greater metabolic stability. CFTR activators have potential therapeutic indications in constipation, dry eye, cholestatic liver diseases, and inflammatory lung disorders.
- Published
- 2017
33. The Fingerprint of Antimitochondrial Antibodies and the Etiology of Primary Biliary Cholangitis
- Author
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Madhu Badamagunta, Weici Zhang, Jinjun Wang, Pietro Invernizzi, Jinjung Choi, Patrick S.C. Leung, Guo-Xiang Yang, Aftab A. Ansari, Kathryn G. Guggenheim, Zongwen Shuai, John C. Voss, Mark J. Kurth, M. Eric Gershwin, Thomas P. Kenny, Ross L. Coppel, Shuai, Z, Wang, J, Badamagunta, M, Choi, J, Yang, G, Zhang, W, Kenny, T, Guggenheim, K, Kurth, M, Ansari, A, Voss, J, Coppel, R, Invernizzi, P, Leung, P, and Gershwin, M
- Subjects
0301 basic medicine ,Cholangitis ,inner lipoyl domain ,intein mediated ligation ,Clinical Sciences ,Immunology ,Antibody Affinity ,Peptide ,Enzyme-Linked Immunosorbent Assay ,Medical Biochemistry and Metabolomics ,medicine.disease_cause ,Autoimmune Disease ,Article ,primary biliary cholangiti ,Autoimmunity ,Xenobiotics ,Inteins ,03 medical and health sciences ,chemistry.chemical_compound ,Rare Diseases ,E2 subunit of the pyruvate dehydrogenase ,MED/12 - GASTROENTEROLOGIA ,medicine ,Humans ,Pyruvate Dehydrogenase (Lipoamide) ,xenobiotics ,Autoantibodies ,2-octynoic acid ,chemistry.chemical_classification ,Hepatology ,biology ,Gastroenterology & Hepatology ,Autoantibody ,Electron Spin Resonance Spectroscopy ,electron paramagnetic resonance spectroscopy ,hemic and immune systems ,Isotype ,Mitochondria ,Lipoic acid ,030104 developmental biology ,chemistry ,Biochemistry ,Antimitochondrial antibodie ,Case-Control Studies ,biology.protein ,Protein Fragment ,Antibody ,Intein - Abstract
The identification of environmental factors that lead to loss of tolerance has been coined the holy grail of autoimmunity. Our work has focused on the reactivity of antimitochondrial autoantibodies (AMA) to chemical xenobiotics and has hypothesized that a modified peptide within PDC-E2, the major mitochondrial autoantigen, will have been immunologically recognized at the time of loss of tolerance. Herein, we successfully applied intein technology to construct a PDC-E2 protein fragment containing amino acid residues 177-314 of PDC-E2 by joining a recombinant peptide spanning residues 177-252 (PDC-228) with a 62-residue synthetic peptide from 253 to 314 (PP), which encompasses PDC-E2 inner lipoyl domain (ILD). We named this intein-constructed fragment PPL. Importantly, PPL, as well as lipoic acid conjugated PPL (LA-PPL) and xenobiotic 2-octynoic acid conjugated PPL (2OA-PPL), are recognized by AMA. Of great importance, AMA has specificity for the 2OA-modified PDC-E2 ILD peptide backbone distinct from antibodies that react with native lipoylated PDC-E2 peptide. Interestingly, this unique AMA subfraction is of the immunoglobulin M isotype and more dominant in early-stage primary biliary cholangitis (PBC), suggesting that exposure to 2OA-PPL-like compounds occurs early in the generation of AMA. To understand the structural basis of this differential recognition, we analyzed PPL, LA-PPL, and 2OA-PPL using electron paramagnetic resonance spectroscopy, with confirmations by enzyme-linked immunosorbent assay, immunoblotting, and affinity antibody analysis. We demonstrate that the conformation of PDC-E2 ILD is altered when conjugated with 2OA, compared to conjugation with lipoic acid. Conclusion: A molecular understanding of the conformation of xenobiotic-modified PDC-E2 is critical for understanding xenobiotic modification and loss of tolerance in PBC with widespread implications for a role of environmental chemicals in the induction of autoimmunity. (Hepatology 2017;65:1670-1682).
- Published
- 2017
34. Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation
- Author
-
Andrew P. Teuthorn, Alan S. Verkman, Mark Donowitz, Loretta Ferrera, Mark J. Kurth, Luis J. V. Galietta, Ruxian Lin, Nicholas C. Zachos, Onur Cil, Jung-Ho Son, Jie S. Zhu, Puay Wah Phuan, Colton K. Ku, Niloufar Akhavan Tabib, Cil, Onur, Phuan, Puay-Wah, Son, Jung-Ho, Zhu, Jie S., Ku, Colton K., Tabib, Niloufar Akhavan, Teuthorn, Andrew P., Ferrera, Loretta, Zachos, Nicholas C., Lin, Ruxian, Galietta, Luis J. V., Donowitz, Mark, Kurth, Mark J., and Verkman, Alan S.
- Subjects
0301 basic medicine ,Patch-Clamp Techniques ,Constipation ,Cystic Fibrosis ,Acute constipation ,Patch-Clamp Technique ,Cystic Fibrosis Transmembrane Conductance Regulator ,chemistry.chemical_compound ,Mice ,Lubiprostone ,Lung ,General Clinical Medicine ,Linaclotide ,biology ,General Medicine ,Fluid transport ,Cystic fibrosis transmembrane conductance regulator ,Body Fluids ,medicine.anatomical_structure ,Jejunum ,Liver ,5.1 Pharmaceuticals ,Acute Disease ,Peptide ,Chloride channel ,Microsomes, Liver ,Female ,Development of treatments and therapeutic interventions ,medicine.symptom ,medicine.drug ,Human ,medicine.medical_specialty ,Quinoxaline ,Duodenum ,Clinical Sciences ,Scopolamine ,Article ,Cell Line ,Gastric Acid ,03 medical and health sciences ,Structure-Activity Relationship ,Rare Diseases ,Body Fluid ,Microsomes ,Quinoxalines ,Internal medicine ,Physiology (medical) ,medicine ,Animals ,Humans ,business.industry ,Animal ,Biochemistry (medical) ,Public Health, Environmental and Occupational Health ,Small intestine ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,chemistry ,Disease Models ,Chronic Disease ,biology.protein ,Rat ,Digestive Diseases ,Peptides ,business - Abstract
Constipation is a common condition for which current treatments can have limited efficacy. By high-throughput screening, we recently identified a phenylquinoxalinone activator of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel that stimulated intestinal fluid secretion and normalized stool output in a mouse model of opioid-induced constipation. Here, we report phenylquinoxalinone structure-activity analysis, mechanism of action, animal efficacy data in acute and chronic models of constipation, and functional data in exvivo primary cultured human enterocytes. Structure-activity analysis was done on 175 phenylquinoxalinone analogs, including 15 synthesized compounds. The most potent compound, CFTRact-J027, activated CFTR with EC50 ∼ 200nM, with patch-clamp analysis showing a linear CFTR current-voltage relationship with direct CFTR activation. CFTRact-J027 corrected reduced stool output and hydration in a mouse model of acute constipation produced by scopolamine and in a chronically constipated mouse strain (C3H/HeJ). Direct comparison with the approved prosecretory drugs lubiprostone and linaclotide showed substantially greater intestinal fluid secretion with CFTRact-J027, as well as greater efficacy in a constipation model. As evidence to support efficacy in human constipation, CFTRact-J027 increased transepithelial fluid transport in enteroids generated from normal human small intestine. Also, CFTRact-J027 was rapidly metabolized invitro in human hepatic microsomes, suggesting minimal systemic exposure upon oral administration. These data establish structure-activity and mechanistic data for phenylquinoxalinone CFTR activators, and support their potential efficacy in human constipation.
- Published
- 2017
35. Heterocycle-to-Heterocycle Route to Quinoline-4-amines: Reductive Heterocyclization of 3-(2-Nitrophenyl)isoxazoles
- Author
-
Keith C. Coffman, Alex L. Bagdasarian, Makhluf J. Haddadin, James C. Fettinger, Mark J. Kurth, and Vy Duong
- Subjects
chemistry.chemical_compound ,chemistry ,Organic Chemistry ,Quinoline ,Physical and Theoretical Chemistry ,Combinatorial chemistry ,Cycloaddition - Abstract
A variety of quinoline-4-amines were synthesized from substituted 3-(2-nitrophenyl)isoxazoles utilizing Zn0 or Fe0 dust and HOAc via a reductive heterocyclization process. The starting isoxazoles were synthesized from readily available starting materials. A brief survey of functional groups tolerated in this reductive heterocyclization was performed and several 10-amino-3,4-dihydrobenzo[b][1,6]naphthyridin-1(2H)-one and 9-amino-3,4-dihydroacridin-1(2H)-one examples were synthesized.
- Published
- 2014
36. Synthesis–Spectroscopy Roadmap Problems: Discovering Organic Chemistry
- Author
-
Mark J. Kurth and Laurie L. Kurth
- Subjects
Science instruction ,Instructional strategy ,Chemistry education ,Chemistry ,Teaching method ,Organic chemistry ,General Chemistry ,Spectroscopy ,Discovery learning ,Education - Abstract
Organic chemistry problems that interrelate and integrate synthesis with spectroscopy are presented. These synthesis–spectroscopy roadmap (SSR) problems uniquely engage second-year undergraduate organic chemistry students in the personal discovery of organic chemistry. SSR problems counter the memorize-or-bust strategy that many students tend to employ in the study of organic chemistry with an instructional strategy that fosters “seeing” connections, “hearing” what a problem has to say, and “feeling” the exhilaration that comes with discovery.
- Published
- 2014
37. Constrained Bithiazoles: Small Molecule Correctors of Defective ΔF508–CFTR Protein Trafficking
- Author
-
Choong L. Yoo, Baoxue Yang, Brandi M. Hudson, Mark J. Kurth, Gui J. Yu, Huy Nguyen, Dean J. Tantillo, Alan S. Verkman, Michael W. Lodewyk, Puay Wah Phuan, Deanna Montgomery, Alex L. Bagdasarian, and Keith C. Coffman
- Subjects
Mutant ,Thyroid Gland ,Cystic Fibrosis Transmembrane Conductance Regulator ,Plasma protein binding ,Article ,Cyclooctanes ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,Animals ,Humans ,Cycloheptanes ,ΔF508 ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Epithelial Cells ,Small molecule ,In vitro ,Cystic fibrosis transmembrane conductance regulator ,Rats ,Cell biology ,Ring size ,Protein Transport ,Thiazoles ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Molecular Medicine ,Protein trafficking - Abstract
Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the ΔF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using ΔF508-CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7- versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7- and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.
- Published
- 2014
38. Mechanism-based corrector combination restores ΔF508-CFTR folding and function
- Author
-
Miklós Bagdány, Mark J. Kurth, Johanna F. Dekkers, Haijin Xu, Guido Veit, Tsukasa Okiyoneda, Gergely L. Lukacs, Ariel Roldan, Alan S. Verkman, Ágnes Simon, Jeffrey M. Beekman, Naoto Soya, and Tamás Hegedus
- Subjects
Protein Folding ,Glycosylation ,Cystic Fibrosis ,Aminopyridines ,Cystic Fibrosis Transmembrane Conductance Regulator ,Bronchi ,Biology ,Endoplasmic Reticulum ,medicine.disease_cause ,Cystic fibrosis ,Article ,chemistry.chemical_compound ,Cricetinae ,medicine ,Animals ,Humans ,Benzodioxoles ,ΔF508 ,Molecular Biology ,Mutation ,Binding Sites ,Nucleotides ,Cell Membrane ,Lumacaftor ,Epithelial Cells ,Cell Biology ,medicine.disease ,Recombinant Proteins ,Cystic fibrosis transmembrane conductance regulator ,Protein Structure, Tertiary ,Cell biology ,Biochemistry ,chemistry ,Cyclic nucleotide-binding domain ,biology.protein ,Protein folding ,Chemical chaperone - Abstract
The most common cystic fibrosis mutation, ΔF508 in nucleotide binding domain 1 (NBD1), impairs cystic fibrosis transmembrane conductance regulator (CFTR)-coupled domain folding, plasma membrane expression, function and stability. VX-809, a promising investigational corrector of ΔF508-CFTR misprocessing, has limited clinical benefit and an incompletely understood mechanism, hampering drug development. Given the effect of second-site suppressor mutations, robust ΔF508-CFTR correction most likely requires stabilization of NBD1 energetics and the interface between membrane-spanning domains (MSDs) and NBD1, which are both established primary conformational defects. Here we elucidate the molecular targets of available correctors: class I stabilizes the NBD1-MSD1 and NBD1-MSD2 interfaces, and class II targets NBD2. Only chemical chaperones, surrogates of class III correctors, stabilize human ΔF508-NBD1. Although VX-809 can correct missense mutations primarily destabilizing the NBD1-MSD1/2 interface, functional plasma membrane expression of ΔF508-CFTR also requires compounds that counteract the NBD1 and NBD2 stability defects in cystic fibrosis bronchial epithelial cells and intestinal organoids. Thus, the combination of structure-guided correctors represents an effective approach for cystic fibrosis therapy.
- Published
- 2013
39. Absolute Configuration and Biological Properties of Enantiomers of CFTR Inhibitor BPO-27
- Author
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Sailaja Battula, Chenjuan Yao, Mark J. Kurth, James C. Fettinger, Alan S. Verkman, Lukmanee Tradtrantip, David S. Snyder, and Puay Wah Phuan
- Subjects
Kidney Disease ,Stereochemistry ,Pharmacology ,Biochemistry ,Chloride ,cystic fibrosis ,Medicinal and Biomolecular Chemistry ,Rare Diseases ,Drug Discovery ,medicine ,crystallography ,Lung ,IC50 ,polycystic kidney disease ,biology ,Chemistry ,secretory diarrhea ,Organic Chemistry ,Absolute configuration ,Pharmacology and Pharmaceutical Sciences ,Metabolism ,Cystic fibrosis transmembrane conductance regulator ,Chloride channel ,Supercritical fluid chromatography ,biology.protein ,Enantiomer ,medicine.drug - Abstract
We previously reported benzopyrimido-pyrrolo-oxazinedione (BPO) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in a model of polycystic kidney disease. Here, we separated the enantiomers of lead compound BPO-27, (1), which contains a single chiral center, and determined their absolute configuration, activity and metabolic stability. Following separation by chiral supercritical fluid chromatography, the R enantiomer, as determined by x-ray crystallography, inhibited CFTR chloride conductance with IC50 ~ 4 nM, while S enantiomer was inactive. In vitro metabolic stability in hepatic microsomes showed both enantiomers as stable, with
- Published
- 2013
40. Antimitochondrial antibody heterogeneity and the xenobiotic etiology of primary biliary cirrhosis
- Author
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Thomas P. Kenny, Richy C Y Chen, Jeffrey D. Butler, Kathryn G. Guggenheim, Patrick S.C. Leung, Ross L. Coppel, Christopher L. Bowlus, Min-Hua Tao, Shang-An Shu, Jinjun Wang, Aftab A Ansari, Guo-Xiang Yang, Phornnop Naiyanetr, Marshall M. Kaplan, Ana Lleo, Mark J. Kurth, and M. Eric Gershwin
- Subjects
Hepatology ,biology ,Serum albumin ,Pyruvate dehydrogenase complex ,medicine.disease ,Isotype ,chemistry.chemical_compound ,Lipoic acid ,Primary biliary cirrhosis ,chemistry ,Immunoglobulin M ,Immunology ,biology.protein ,medicine ,Antibody ,Xenobiotic - Abstract
Antimitochondrial antibodies (AMAs) directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2) are detected in 95% of patients with primary biliary cirrhosis (PBC) and are present before the onset of clinical disease. The recent demonstration that AMAs recognize xenobiotic modified PDC-E2 with higher titers than native PDC-E2 raises the possibility that the earliest events involved in loss of tolerance are related to xenobiotic modification. We hypothesized that reactivity to such xenobiotics would be predominantly immunoglobulin M (IgM) and using sera from a large cohort of PBC patients and controls (n = 516), we examined in detail sera reactivity against either 6,8-bis(acetylthio) octanoic acid (SAc)-conjugated bovine serum albumin (BSA), recombinant PDC-E2 (rPDC-E2) or BSA alone. Further, we also defined the relative specificity to the SAc moiety using inhibition enzyme-linked immunosorbent assay (ELISA); SAc conjugate and rPDC-E2-specific affinity-purified antibodies were also examined for antigen specificity, isotype, and crossreactivity. Reactivity to SAc conjugates is predominantly IgM; such reactivity reflects a footprint of previous xenobiotic exposure. Indeed, this observation is supported by both direct binding, crossreactivity, and inhibition studies. In both early and late-stage PBC, the predominant Ig isotype to SAc is IgM, with titers higher with advanced stage disease. We also note that there was a higher level of IgM reactivity to SAc than to rPDC-E2 in early-stage versus late-stage PBC. Interestingly, this finding is particularly significant in light of the structural similarity between SAc and the reduced form of lipoic acid, a step which is similar to the normal physiological oxidation of lipoic acid. Conclusion: Specific modifications of the disulfide bond within the lipoic-acid-conjugated PDC-E2 moiety, i.e., by an electrophilic agent renders PDC-E2 immunogenic in a genetically susceptible host. (HEPATOLOGY 2013)
- Published
- 2013
41. Identification of inhibitors against interaction between pro-inflammatory sPLA2-IIA protein and integrin αvβ3
- Author
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Handeep Kaur, Mark J. Kurth, Yoko K. Takada, Masaaki Fujita, Yoshikazu Takada, Tiffany J. Dickerson, John M. Knapp, Ruiwu Liu, Kit S. Lam, Long Ye, and Neil E. Schore
- Subjects
Clinical Biochemistry ,Integrin ,Pharmaceutical Science ,Inflammation ,Group II Phospholipases A2 ,Biochemistry ,Article ,Collagen receptor ,Structure-Activity Relationship ,Phospholipase A2 ,Peptide Library ,Drug Discovery ,medicine ,Amino Acid Sequence ,Molecular Biology ,Binding Sites ,biology ,Cell growth ,Chemistry ,Organic Chemistry ,Integrin alphaVbeta3 ,Molecular biology ,Protein Structure, Tertiary ,Molecular Docking Simulation ,Thiazoles ,Integrin alpha M ,Cancer research ,biology.protein ,Molecular Medicine ,Integrin, beta 6 ,medicine.symptom ,Signal transduction ,Peptides ,Protein Binding - Abstract
Increased concentrations of secreted phospholipase A2 type IIA (sPLA2-IIA), have been found in the synovial fluid of patients with rheumatoid arthritis. It has been shown that sPLA2-IIA specifically binds to integrin αvβ3, and initiates a signaling pathway that leads to cell proliferation and inflammation. Therefore, the interaction between integrin and sPLA2-IIA could be a potential therapeutic target for the treatment of proliferation or inflammation-related diseases. Two one-bead-one-compound peptide libraries were co nstructed and screened, and seven target hits were identified. Herein we report the identification, synthesis, and biological testing of two pyrazolylthiazole-tethered peptide hits and their analogs. Biological assays showed that these compounds were able to suppress the sPLA2-IIA-integrin interaction and sPLA2-IIA-induced migration of monocytic cells and that the blockade of the sPLA2-IIA-integrin binding was specific to sPLA2-IIA and not to the integrin.
- Published
- 2013
42. Microwave-Assisted Synthesis of 3-Nitroindoles from N-Aryl Enamines via Intramolecular Arene–Alkene Coupling
- Author
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Huy Nguyen and Mark J. Kurth
- Subjects
Indoles ,chemistry.chemical_element ,Alkenes ,Photochemistry ,Biochemistry ,Catalysis ,Article ,Coupling reaction ,chemistry.chemical_compound ,Molecule ,Amines ,Physical and Theoretical Chemistry ,Microwaves ,chemistry.chemical_classification ,Molecular Structure ,Alkene ,Aryl ,Organic Chemistry ,Regioselectivity ,Nitro Compounds ,chemistry ,Cyclization ,Intramolecular force ,Palladium - Abstract
A variety of N-aryl β-nitroenamines were effectively transformed into 3-nitroindoles in good yields and with complete regioselectivity via a rapid microwave (μW) assisted intramolecular arene-alkene coupling reaction. This report further demonstrates the versatility of this method by constructing 3-carboalkoxy- and 3-cyanoindoles. Optimization data, substrate scope, and applications are discussed.
- Published
- 2012
43. ChemInform Abstract: One-Pot Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolines and Isoquinolino[3,4-b]quinoxalines via Tandem Cyclization Strategies
- Author
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Mark J. Kurth, Huy Nguyen, Alex L. Bagdasarian, Makhluf J. Haddadin, Teresa A. Palazzo, and James C. Fettinger
- Subjects
Tandem ,Chemistry ,One-pot synthesis ,General Medicine ,Combinatorial chemistry - Abstract
Two operationally simple one-pot protocols have been developed for the synthesis of amino-functionalized benzo[4,5]imidazo[2,1-a]isoquinolines and isoquinolino[3,4-b]quinoxalines. Optimization data and substrate scope for these atom-economical transformations, which engage commercially available o-phenylenediamines and o-cyanobenzaldehydes, are discussed.
- Published
- 2016
44. ChemInform Abstract: Dibenzonaphthyridinones: Heterocycle-to-Heterocycle Synthetic Strategies and Photophysical Studies
- Author
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Elsy El Khoury, Joung S. Yang, Mackenzie G. Appleton, Dean J. Tantillo, Digambara Patra, Makhluf J. Haddadin, Teresa A. Palazzo, and Mark J. Kurth
- Subjects
Character (mathematics) ,Chemistry ,Chemical physics ,Solvatochromism ,chemistry.chemical_element ,General Medicine ,Time-dependent density functional theory ,Linear correlation ,Fluorescence ,Carbon ,Excitation - Abstract
A heterocycle-to-heterocycle strategy is presented for the preparation of highly fluorescent and solvatochromic dibenzonaphthyridinones (DBNs) via methodology that leads to the formation of a tertiary, spiro-fused carbon center. A linear correlation between the results of photophysical experiments and time dependent density functional theory calculations was observed for the λmax of excitation for DBNs with varying electronic character.
- Published
- 2016
45. ChemInform Abstract: Expedient One-Pot Synthesis of Indolo[3,2-c]isoquinolines via a Base-Promoted N-Alkylation/Tandem Cyclization
- Author
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Makhluf J. Haddadin, Huy Nguyen, Mark J. Kurth, and James C. Fettinger
- Subjects
chemistry.chemical_classification ,Base (chemistry) ,Tandem ,Chemistry ,One-pot synthesis ,Organic chemistry ,General Medicine ,Alkylation - Abstract
Transition metal-free and operationally simple one-pot protocol for the synthesis of the title compounds is developed starting from readily available ethyl (2-cyanophenyl)carbamates and 2-cyanobenzyl bromides.
- Published
- 2016
46. Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis?
- Author
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Mark J. Kurth, Kit S. Lam, Patrick S.C. Leung, Ross L. Coppel, and M. Eric Gershwin
- Subjects
Quantitative Structure-Activity Relationship ,Autoimmunity ,Pyruvate Dehydrogenase Complex ,Mitochondrion ,Biology ,medicine.disease_cause ,digestive system ,Article ,Xenobiotics ,Mice ,chemistry.chemical_compound ,Primary biliary cirrhosis ,medicine ,Animals ,Humans ,Molecular Biology ,Acetaminophen ,Autoantibodies ,Thioctic Acid ,Liver Cirrhosis, Biliary ,digestive, oral, and skin physiology ,Autoantibody ,medicine.disease ,Pyruvate dehydrogenase complex ,digestive system diseases ,Mitochondria ,Lipoic acid ,chemistry ,Immunology ,Molecular Medicine ,medicine.drug - Abstract
The serologic hallmark of primary biliary cirrhosis (PBC) is the presence of antimitochondrial autoantibodies (AMAs) directed against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). The PBC-related autoepitope of PDC-E2 contains lipoic acid, and previous work has demonstrated that mimics of lipoic acid following immunization of mice lead to a PBC-like disease. Furthermore, approximately one-third of patients who have ingested excessive amounts of acetaminophen (paracetamol) develop AMA of the same specificity as patients with PBC. Quantitative structure-activity relationship (QSAR) data indicates that acetaminophen metabolites are particularly immunoreactive with AMA, and we submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate a loss of tolerance and lead to the development of PBC.
- Published
- 2012
47. Click-based synthesis of triazolobithiazole ΔF508-CFTR correctors for cystic fibrosis
- Author
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Michael B. Donald, Puay Wah Phuan, Mark J. Kurth, Hannah Shay, Kevin X. Rodriguez, and Alan S. Verkman
- Subjects
Cystic Fibrosis ,Stereochemistry ,Medicinal & Biomolecular Chemistry ,Clinical Biochemistry ,Cystic Fibrosis Transmembrane Conductance Regulator ,Pharmaceutical Science ,Biochemistry ,Cystic fibrosis ,Article ,Dose-Response Relationship ,Congenital ,Medicinal and Biomolecular Chemistry ,Structure-Activity Relationship ,Rare Diseases ,Drug Discovery ,medicine ,Structure–activity relationship ,Lung ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Triazoles ,medicine.disease ,Cycloaddition ,Cystic fibrosis transmembrane conductance regulator ,Thiazoles ,Orphan Drug ,Triazolobithiazole ,CF corrector ,Copper catalyzed ,biology.protein ,Molecular Medicine ,Drug ,CuAAC ,δf508 cftr - Abstract
Copper catalyzed azide-alkyne cycloaddition (CuAAC) chemistry is reported for the construction of previously unknown 5-(1 H -1,2,3-triazol-1-yl)-4,5′-bithiazoles from 2-bromo-1-(thiazol-5-yl)ethanones. These novel triazolobithiazoles are shown to have cystic fibrosis (CF) corrector activity and, compared to the benchmark bithiazole CF corrector corr- 4a , improved log P values (4.5 vs 5.96).
- Published
- 2012
48. The Davis-Beirut Reaction: A Novel Entry into 2H-indazoles and Indazolones. Recent Biological Activity of Indazoles
- Author
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Makhluf J. Haddadin, Mark J. Kurth, and Wayne E. Conrad
- Subjects
Pharmacology ,Indazoles ,Extramural ,Chemistry ,Stereochemistry ,Antineoplastic Agents ,Biological activity ,General Medicine ,Isomerism ,Cardiovascular Diseases ,Fertilization ,Drug Discovery ,Animals ,Humans ,Nitric Oxide Synthase ,Davis–Beirut reaction ,Cell Proliferation - Abstract
A novel, easy method for the syntheses of richly diversified 2H-indazoles and indazolones, called the Davis-Beirut reaction, and other recent 2H-indazole synthetic routes are briefly reviewed. An update on the biological activity of indazoles is also surveyed.
- Published
- 2012
49. Structure–Activity Relationships of Cyanoquinolines with Corrector–Potentiator Activity in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Protein
- Author
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Michael W. Lodewyk, Mark J. Kurth, Alex B. Wood, John M. Knapp, Alan S. Verkman, Puay Wah Phuan, and Dean J. Tantillo
- Subjects
Models, Molecular ,biology ,Chemistry ,Molecular Conformation ,Cystic Fibrosis Transmembrane Conductance Regulator ,Epithelial Cells ,Potentiator ,Rats, Inbred F344 ,Article ,Molecular conformation ,Cystic fibrosis transmembrane conductance regulator ,Rats ,Structure-Activity Relationship ,Biochemistry ,Nitriles ,Drug Discovery ,Quinolines ,biology.protein ,Animals ,Humans ,Molecular Medicine ,Structure–activity relationship ,ΔF508 ,Cells, Cultured - Abstract
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ΔF508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified, cyanoquinolines with both corrector (“Co”; normalizing ΔF508-CFTR targeting) and potentiator (“Po”; normalizing ΔF508-CFTR channel gating) activities. Here, we synthesized and characterized twenty-four targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector-only and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search ⇒ force-field lowest energy assessment ⇒ geometry optimization] suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and aryl amide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo’s should adopt two distinct π-stacking conformations to elicit corrector and potentiator activities.
- Published
- 2012
50. Functional Fluorescently Labeled Bithiazole ΔF508-CFTR Corrector Imaged in Whole Body Slices in Mice
- Author
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Chenjuan Yao, Nico Derichs, Stephanie Taylor, Mark J. Kurth, Christopher R. Drake, Puay Wah Phuan, Julie L. Sutcliffe, Holly R. Davison, Ella F. Jones, and Alan S. Verkman
- Subjects
Boron Compounds ,Biodistribution ,Fluorescence-lifetime imaging microscopy ,Fluorophore ,Cystic Fibrosis ,Stereochemistry ,Whole body imaging ,Biomedical Engineering ,Cystic Fibrosis Transmembrane Conductance Regulator ,Pharmaceutical Science ,Bioengineering ,Article ,Mice ,chemistry.chemical_compound ,Animals ,Whole Body Imaging ,Fluorescent Dyes ,Pharmacology ,biology ,Chemistry ,Organic Chemistry ,Fluorescence ,Cystic fibrosis transmembrane conductance regulator ,Thiazoles ,Mutation ,Biophysics ,biology.protein ,BODIPY ,Biotechnology ,Conjugate - Abstract
We previously reported the identification and structure-activity analysis of bithiazole-based correctors of defective cellular processing of the cystic fibrosis-causing CFTR mutant, ΔF508-CFTR. Here, we report the synthesis and uptake of a functional, fluorescently labeled bithiazole corrector. Following synthesis and functional analysis of four bithiazole-fluorophore conjugates, we found that 5, a bithazole-based BODIPY conjugate, had low micromolar potency for correction of defective δF508-CFTR cellular misprocessing, with comparable efficacy to benchmark corrector corr-4a. Intravenous administration of 5 to mice established its stability in extrahepatic tissues for tens of minutes. By fluorescence imaging of whole-body frozen slices, fluorescent corrector 5 was visualized strongly in gastrointestinal organs, with less in lung and liver. Our results provide proof-of-concept for mapping the biodistribution of a ΔF508-CFTR corrector by fluorophore labeling and fluorescence imaging of whole-body slices.
- Published
- 2011
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