Herein,
we disclose a powerful strategy for the functionalization
of the antitumor natural alkaloid noscapine by utilizing photoredox/nickel
dual-catalytic coupling technology. A small collection of 37 new noscapinoids
with diverse (hetero)alkyl and (hetero)cycloalkyl groups and enhanced
sp3 character was thus synthesized. Further in
vitro antiproliferative activity screening and SAR study
enabled the identification of 6o as a novel, potent,
and less-toxic anticancer agent. Furthermore, 6o exerts
superior cellular activity via an unexpected S-phase arrest mechanism
and could significantly induce cell apoptosis in a dose-dependent
manner, thereby further highlighting its potential in drug discovery
as a promising lead compound.