Synthesis and Biological Evaluation of Indolyl-Pyridinyl-Propenones Having Either Methuosis or Microtubule Disruption Activity

Methuosis is a form of nonapoptotic
cell death characterized by
an accumulation of macropinosome-derived vacuoles with eventual loss
of membrane integrity. Small molecules inducing methuosis could offer
significant advantages compared to more traditional anticancer drug
therapies that typically rely on apoptosis. Herein we further define
the effects of chemical substitutions at the 2- and 5-indolyl positions
on our lead compound 3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propene-1-one
(MOMIPP). We have identified a number of compounds that induce methuosis
at similar potencies, including an interesting analogue having a hydroxypropyl
substituent at the 2-position. In addition, we have discovered that
certain substitutions on the 2-indolyl position redirect the mode
of cytotoxicity from methuosis to microtubule disruption. This switch
in activity is associated with an increase in potency as large as
2 orders of magnitude. These compounds appear to represent a new class
of potent microtubule-active anticancer agents.