ABSTRACT
Natural α-noscapine, a known antitussive drug, is also now known to possess weak anticancer efficacy with relatively safe toxicity profile. In this study, we report synthesis and evaluation of novel biaryl type α-noscapine congeners designed by adding aryl unit to the tetrahydroisoquinoline part of natural α-noscapine core. Palladium catalyzed Suzuki cross coupling of 9-bromo α-noscapine with aryl boronic acids was employed using mild and inexpensive reagents to attain desired noscapinoids 5a-g in excellent yields. Screening anti-proliferative activity for new noscapinoids 5b-g, on human cancer cell lines resulted three compounds 5b, 5d and 5f as potent analogues, active against human breast epithelial (MCF-7), human cervix cancer (HeLa) and human lung adenocarcinoma epithelial (A549) cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Noscapine/analogs & derivatives , Noscapine/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Boronic Acids/chemistry , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , HeLa Cells , Humans , MCF-7 Cells , Molecular Conformation , Noscapine/chemical synthesis , Palladium/chemistry , Tetrahydroisoquinolines/chemistryABSTRACT
Facile synthesis of natural α-noscapine analogue, 9-amino-α-noscapine, a potent inhibitor of tubulin polymerization for cancer therapy, is achieved via copper(I) iodide mediated in situ aromatic azidation and reduction of 9-bromo-α-noscapine (obtained by bromination of natural α-noscapine) with NaN(3) in DMSO at 130°C in the presence of L-proline as an amino acid promoter. The protocol developed here avoided isolation of 9-azido-α-noscapine and did not cleave the sensitive C-C bond between two heterocyclic phthalide and isoquinoline units.
