Synthesis and biological evaluation of indolyl-pyridinyl-propenones having either methuosis or microtubule disruption activity

Area of Science:

• Biochemistry and Molecular Biology
• Cell Biology
• Medicinal Chemistry

Background:

• Methuosis is a non-apoptotic cell death pathway involving vacuole accumulation.
• Small molecules targeting methuosis present an alternative to traditional apoptosis-reliant cancer therapies.
• The lead compound MOMIPP (3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propene-1-one) was investigated for its methuosis-inducing properties.

Purpose of the Study:

• To investigate the impact of chemical substitutions on the 2- and 5-indolyl positions of MOMIPP.
• To identify novel compounds that induce methuosis.
• To explore the potential for redirecting cytotoxicity from methuosis to other cell death mechanisms, such as microtubule disruption.

Main Methods:

• Systematic chemical modification of the lead compound MOMIPP.
• Evaluation of methuosis-inducing activity of synthesized analogues.
• Assessment of cytotoxicity and mechanism of cell death, including microtubule disruption assays.

Main Results:

• Several analogues were identified that induce methuosis with potencies comparable to MOMIPP.
• A specific analogue with a hydroxypropyl substituent at the 2-position showed significant methuosis-inducing activity.
• Certain substitutions at the 2-indolyl position effectively switched the mode of cytotoxicity from methuosis to potent microtubule disruption.
• This switch resulted in a significant increase in anticancer potency, up to two orders of magnitude.

Conclusions:

• Chemical modifications of MOMIPP can modulate its mechanism of cell death.
• Compounds that redirect cytotoxicity to microtubule disruption represent a promising new class of anticancer agents.
• These findings offer new avenues for developing potent anticancer drugs with novel mechanisms of action.