Tubulysins are natural products isolated from myxobacterial species. They are potent mitotic poisons as they inhibit the polymerization of tubulin into microtubules. Majority of natural isolated tubulysins possess an acid-, base-, and enzyme-sensitive <i>N</i>-acyloxymethyl substituent, as well as an enzyme-labile acetate group. Both of these functional groups are essential for their potent cytotoxicity. Herein, we present the design and synthesis of more stable tubulysin analogs based on our reported synthesis of tubulysin B. These synthetic tubulysin analogs are less prone to degradation under acidic/basic conditions and enzymatic hydrolysis. Folate conjugates of these highly potent tubulysin analogs were also synthesized.

Design and synthesis of <i>N</i>-alkylated tubulysin analogs and their folate conjugates

254th National Meeting (2017)

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Design and synthesis of N-alkylated tubulysin analogs and their folate conjugates