Tubulysins are antimitotic natural products with potent anticancer activity against multidrug-resistant (MDR) cancer cells, acting by inhibition of tubulin polymerization. The promising activity of these tetrapeptides makes them attractive leads, but the limited quantity available by fermentation and poor therapeutic index has hampered their clinical development. Synthetically accessible, highly cytotoxic tubulysins are therefore prime candidates for use in targeted delivery strategies such as drug-antibody conjugates. Comparison of the antiproliferative activities of tubulysins V and U exemplifies the importance of the tubuvaline (Tuv) acetate for potent activity. Yet, the potential in vivoefficacy of tubulysin U could be limited due to the lability of this acetate under mildly acidic or basic conditions. To address this issue, we have prepared two series of tubulysin analogues wherein the acetate in replaced with hydrolysis-resistant functional groups. The synthesis and early biochemical studies of these derivatives will be presented. Development of an optimized second-generation synthesis of tubulysin V enabled the synthesis of novel Tuv constructs, and rapid target analogue generation was possible using shared, late-stage intermediates. Initial evaluation of the target analogues' anticancer activity revealed some tolerance to changes at R'' with groups exhibiting increased hydrolytic stability. Several analogues have demonstrated exceptionally potent antiproliferative activity, and their potential for use in targeted delivery systems such as drug-antibody conjugates will be discussed.

Synthesis of exceptionally potent tubulysins for drug-antibody conjugates

248th National Meeting (2014)

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