Synthesis and Antiproliferative Activity of 9-Formyl and 9-Ethynyl Noscapines

Appending functional groups to the core skeleton of natural -noscapine, an FDA approved cough medicine, resulted in analogues with anticancer activity. In this study, we report the synthesis and antiproliferative activity of 9-formyl and 9-ethynylnoscapines. 9-Formylnoscapine 5 was synthesized from 9-bromonoscapine 2cvia a three-step reaction sequence involving palladium catalysed Heck reaction with ethyl acrylate leading to noscapinoid 7, dihydroxylation of 7 with OsO4 and oxidative cleavage of diol 8. Further, Seyferth-Gilbert homologation of 9-formylnoscapine using Bestmann-Ohira reagent resulted in 9-ethynylnoscapine 6 in excellent yield. Antiproliferative activity screening of new noscapinoids 5-7 against NCI60 human tumor cell lines resulted in 9-ethynylnoscapine 6 as a potent anticancer agent with the lowest mean percentage growth against the full 60-cell line panel.