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

Hodaya Gutman; Andrii Bazylevich; Chandrashekhar Prasad; Ortal Dorfman; Arkadi Hesin; Vered Marks; Leonid Patsenker; Gary Gellerman

doi:10.1021/acsmedchemlett.1c00432

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

ACS Med Chem Lett. 2021 Sep 7;12(10):1596-1604. doi: 10.1021/acsmedchemlett.1c00432. eCollection 2021 Oct 14.

Authors

Hodaya Gutman¹, Andrii Bazylevich¹, Chandrashekhar Prasad¹, Ortal Dorfman¹, Arkadi Hesin², Vered Marks¹, Leonid Patsenker¹, Gary Gellerman¹

Affiliations

¹ Department of Chemical Sciences, Ariel University, Ariel 40700, Israel.
² Department of Molecular Biology, Ariel University, Ariel 40700, Israel.

Abstract

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-terminus-modified dolastatin-10-based microtubule inhibitors for anticancer treatment.