Synthesis and biological evaluation of N-substituted noscapine analogues

Abstract

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.