Tubulysins are natural products isolated from myxobacterial species. They are potent mitotic poisons as they inhibit the polymerization of tubulin into microtubules. Structurally, tubulysins are linear tetrapeptides comprised of N-methyl pipecolic acid (Mep), isoleucine (Ile), tubuvaline (Tuv), and tubutyrosine (Tut). All isolated tubulysins possess an acid-, base-, and enzyme-sensitive N-acyloxymethyl substituent, which is 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 highly potent tubulysin analogs are less prone to degradation under acidic/basic conditions or by esterases, thus, making them easier to be developed as payloads for targeted therapy. Structural features, essential for the cytotoxicity of the tubulysin analogs, were established. Folate conjugates of these tubulysin analogs were shown to exhibit remarkable cytotoxicity against (FR)-positive KB cells.

Synthesis of highly potent tubulysin analogs as payloads for targeting therapies of cancer

248th National Meeting (2014)

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