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

Ariel University

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

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Access to Document

10.1021/acsmedchemlett.1c00432

Cite this

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title = "Discovery of Dolastatinol: A Synthetic Analog of Dolastatin 10 and Low Nanomolar Inhibitor of Tubulin Polymerization",

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.",

keywords = "Dolastatin 10, Fmoc chemistry, inhibition of tubulin polymerization, self-immolative, solid phase peptide synthesis",

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

year = "2021",

month = oct,

day = "14",

doi = "10.1021/acsmedchemlett.1c00432",

language = "English",

volume = "12",

pages = "1596--1604",

journal = "ACS Medicinal Chemistry Letters",

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T1 - Discovery of Dolastatinol

T2 - A Synthetic Analog of Dolastatin 10 and Low Nanomolar Inhibitor of Tubulin Polymerization

AU - Gutman, Hodaya

AU - Bazylevich, Andrii

AU - Prasad, Chandrashekhar

AU - Dorfman, Ortal

AU - Hesin, Arkadi

AU - Marks, Vered

AU - Patsenker, Leonid

AU - Gellerman, Gary

PY - 2021/10/14

Y1 - 2021/10/14

N2 - 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.

AB - 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.

KW - Dolastatin 10

KW - Fmoc chemistry

KW - inhibition of tubulin polymerization

KW - self-immolative

KW - solid phase peptide synthesis

UR - https://www.scopus.com/pages/publications/85115607158

U2 - 10.1021/acsmedchemlett.1c00432

DO - 10.1021/acsmedchemlett.1c00432

M3 - Article

C2 - 34676042

SN - 1948-5875

VL - 12

SP - 1596

EP - 1604

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 10

ER -

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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