Session: Posters:

Tubulin-disrupting compounds can arrest cell division and many of them are approved for clinical application as anticancer agents. While all clinically used agents target beta-tubulin, pironetin displays a different mechanism of action by binding to alpha-tubulin. Pironetin is a polyketide natural product that inhibits the growth of cancer cells with excellent potency, including cancers that are resistant to other tubulin-binding anticancer agents. However, the in vitro potency was not reflected in the in vivo tumor model due to poor PK/PD properties and off-target toxicities. We identified the major human liver microsome-derived metabolites of pironetin and designed new analogs to block the site of metabolism. Analogs were synthesized using multistep stereoselective reactions and evaluated for cytotoxic activity using several cancer cell lines. Several of the analogs showed cytotoxicity comparable to pironetin and are modest improvements in metabolic stability.

Design of pironetin analogs to block metabolic degradation

Design of pironetin analogs to block metabolic degradation

Md Abdullah Al Noman

Graduate Student, University of Minnesota

Appearances