Discovery of Dolastatinol: A Synthetic Analog of Dolastatin 10 and Low Nanomolar Inhibitor of Tubulin Polymerization

We developed a highly potent anticancer agent, dolastatinol, which is a methylene hydroxyl derivative of dolastatin 10. Dolastatinol is a synthetic analog of dolastatin 10, synthesized by a solid-phase peptide Fmoc chemistry protocol on 2-chlorotrityl chloride resin utilizing a pH-triggering self-immolative monosuccinate linker. The introduction of the C-terminus hydroxyl methylene functionality preserves the anticancer properties of the parent dolastatin 10, including strong suppression of the cell proliferation, migration, high cytotoxicity. Our research establishes a new facile route toward the further development of C-terminusmodified dolastatin-10-based microtubule inhibitors for anticancer treatment.

Automated summary

The developed dolastatinol is a highly potent anticancer agent with preserved anticancer properties of dolastatin 10 due to the introduction of C-terminus methylene hydroxyl functionality. This research establishes a new route for the further development of C-terminus-modified dolastatin-10-based microtubule inhibitors for anticancer treatment.