Structure Guided Design, Synthesis, and Biological Evaluation of Novel Benzosuberene Analogues as Inhibitors of Tubulin Polymerization

A promising
design paradigm for small-molecule inhibitors of tubulin
polymerization that bind to the colchicine site draws structural inspiration
from the natural products colchicine and combretastatin A-4 (CA4).
Our previous studies with benzocycloalkenyl and heteroaromatic ring
systems yielded promising inhibitors with dihydronaphthalene and benzosuberene
analogues featuring phenolic (KGP03 and KGP18) and aniline (KGP05
and KGP156) congeners emerging as lead agents. These molecules demonstrated
dual mechanism of action, functioning both as potent vascular disrupting
agents (VDAs) and as highly cytotoxic anticancer agents. A further
series of analogues was designed to extend functional group diversity
and investigate regioisomeric tolerance. Ten new molecules were effective
inhibitors of tubulin polymerization (IC50 < 5 μM)
with seven of these exhibiting highly potent activity comparable to
CA4, KGP18, and KGP03. For one of the most effective agents, dose-dependent
vascular shutdown was demonstrated using dynamic bioluminescence imaging
in a human prostate tumor xenograft growing in a rat.