title: Novel 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents.
abstract: Liver fibrosis is a critical wound healing response to chronic liver injury such as hepatitis C virus (HCV) infection. If persistent, liver fibrosis can lead to cirrhosis and hepatocellular carcinoma (HCC). The development of new therapies for preventing liver fibrosis and its progression to cancer associated with HCV infection remains a critical challenge. Identification of novel anti-fibrotic compounds will provide opportunities for innovative therapeutic intervention of HCV-mediated liver fibrosis. We designed and synthesized a focused set of 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents. Liver fibrosis assays demonstrated that the compounds 3a and 3c show inhibitory activity towards human hepatic stellate cells (LX2) activation at 10μM. The HCV NS3 and NS5A proteins in HCV subgenome-expressing cells were also significantly reduced in cells treated with 3a and 3c, suggesting the possible inhibitory role of the compounds in HCV translation/replication activities. We have also examined the reactivity of these compounds with medicinally-relevant metal compounds such as platinum and gold. The reactivity of these complexes with metals and during Mass Spectrometry suggests that CS bond cleavage is relatively facile.
authors.affiliation: Pharmaceutical Sciences Department, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, United States.
authors.forename: Renukadevi
authors.initials: R
authors.lastname: Patil
authors.affiliation: Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, United States.
authors.forename: Anandita
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Chemistry, College of Science and Health, DePaul University, Chicago, IL 60614, United States.
authors.forename: Phoebus
authors.initials: P
authors.lastname: Sun Cao
authors.affiliation: X-ray Crystallography Facility, Department of Chemistry, North Carolina State University, Raleigh, NC 27695, United States.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Sommer
authors.affiliation: Department of Chemistry, College of Science and Health, DePaul University, Chicago, IL 60614, United States. Electronic address: kgrice1@depaul.edu.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Grice
authors.affiliation: Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, United States. Electronic address: gulam.waris@rosalindfranklin.edu.
authors.forename: Gulam
authors.initials: G
authors.lastname: Waris
authors.affiliation: Pharmaceutical Sciences Department, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, United States. Electronic address: shivaputra.patil@rosalindfranklin.edu.
authors.forename: Shivaputra
authors.initials: S
authors.lastname: Patil
mesh_terms: D016174:Hepacivirus / Q000378:metabolism; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000517:prevention & control*; D011743:Pyrimidines / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D011743:Pyrimidines; D017361:Viral Nonstructural Proteins
keywords: Chromenopyridines; Hepatitis C; Liver fibrosis; Metal-drug interactions; Multi-component reactions