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

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

Research output: Contribution to journal › Article › peer-review

7 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 language	English
Pages (from-to)	1596-1604
Number of pages	9
Journal	ACS Medicinal Chemistry Letters
Volume	12
Issue number	10
DOIs	https://doi.org/10.1021/acsmedchemlett.1c00432
State	Published - 14 Oct 2021

Keywords

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

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10.1021/acsmedchemlett.1c00432

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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.",

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AU - Bazylevich, Andrii

AU - Prasad, Chandrashekhar

AU - Dorfman, Ortal

AU - Hesin, Arkadi

AU - Marks, Vered

AU - Patsenker, Leonid

AU - Gellerman, Gary

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KW - self-immolative

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

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Keywords

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