Dual-Functional <i>abeo</i>-Taxane Derivatives Destabilizing Microtubule Equilibrium and Inhibiting NF-κB Activation
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Abstract
Taxchinin
A, with a 11(15→1)-<i>abeo</i>-taxane
skeleton, is a major, but inactive taxoid contained in leaves of Taxus chinensis. In our design of dual-functional
antitumor <i>abeo</i>-taxane derivatives, two fragments
from antitumor agents with different molecular targets (the <i>N</i>-acyl-3′-phenylisoserine side chain from the antimitotic
agent paclitaxel and an α,β-unsaturated carbonyl system
from NF-κB inhibitors) were incorporated into the scaffold of
taxchinin A. The resulting compounds displayed broad inhibitory effects
against proliferation of tumor cell lines, with notable selectivity
toward colon cancer, melanoma, and renal cancer, when evaluated in
the NCI-60 human tumor cell line screening panel. On the basis of
the NCI-60 assay data, structure–activity relationship (SAR)
correlations were elucidated. Mechanistic studies indicated that this
new compound type can both destabilize microtubules and inhibit NF-κB
activation, thereby inducing tumor cell apoptosis. This first report
of the dual-functional taxoid-core compounds thus provides new opportunities
for future drug development based on natural axoid scaffolds