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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Pages (from-to)1596-1604
Number of pages9
JournalACS Medicinal Chemistry Letters
Volume12
Issue number10
DOIs
StatePublished - 14 Oct 2021

Keywords

  • Dolastatin 10
  • Fmoc chemistry
  • inhibition of tubulin polymerization
  • self-immolative
  • solid phase peptide synthesis

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