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Synthesis and Biological Evaluation of N ‐Substituted Noscapine Analogues
Author(s) -
DeBono Aaron J.,
Xie Jin Han,
Ventura Sabatino,
Pouton Colin W.,
Capuano Ben,
Scammells Peter J.
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200365
Subject(s) - noscapine , chemistry , alkaloid , cytotoxicity , stereochemistry , hela , bromide , ether , cancer cell , cell growth , biochemistry , cell , organic chemistry , biology , cancer , in vitro , genetics
Noscapine is a phthalideisoquinoline alkaloid isolated from the opium poppy Papaver somniferum . It has long been used as an antitussive agent, but has more recently been found to possess microtubule‐modulating properties and anticancer activity. Herein we report the synthesis and pharmacological evaluation of a series of 6′‐substituted noscapine derivatives. To underpin this structure–activity study, an efficient synthesis of N ‐nornoscapine and its subsequent reduction to the cyclic ether derivative of N ‐nornoscapine was developed. Reaction of the latter with a range of alkyl halides, acid chlorides, isocyanates, thioisocyanates, and chloroformate reagents resulted in the formation of the corresponding N ‐alkyl, N ‐acyl, N ‐carbamoyl, N ‐thiocarbamoyl, and N ‐carbamate derivatives, respectively. The ability of these compounds to inhibit cell proliferation was assessed in cell‐cycle cytotoxicity assays using prostate cancer (PC3), breast cancer (MCF‐7), and colon cancer (Caco‐2) cell lines. Compounds that showed activity in the cell‐cycle assay were further evaluated in cell viability assays using PC3 and MCF‐7 cells.