(+)-Discodermolide, a polyketide natural product is a potent microtubule stabilizing agent. Unfortunately, discodermolide failed in an early Phase I clinical trial due to pneumotoxicity, that we reason likely due to senescence-associated toxicity in lung tissue. To explore this possibility, we initiated a synthesis program to evaluate novel discodermolide analogues, focusing on the suppression of senescence possessing an increase in cancer cell kill. Towards this end, we report here the design, synthesis and biological evaluation of a series of novel discodermolide analogues. Chemical modifications of the diene and the lactone fragments of discodermolide proved to increase suppression of senescence. Equally important, these analogues also displayed superior cancer cell killing ability compared to discodermolide and Taxol.<br/>

Design, synthesis and biological evaluation of novel discodermolide analogues leading to suppression of senescence and an increase cancer cell death

256th National Meeting (2018)

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