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Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics

Published version
Peer-reviewed

Type

Article

Change log

Authors

Charoenpattarapreeda, Jiraborrirak  ORCID logo  https://orcid.org/0000-0002-0316-9608

Abstract

jats:titleAbstract</jats:title>jats:pHemiasterlin is an antimitotic marine natural product with reported sub‐nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four‐component Ugi reaction (Ugi‐4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI‐286), a similarly potent synthetic analogue. This short synthetic sequence enabled investigation of both hemiasterlin and taltobulin as cytotoxic payloads in antibody–drug conjugates (ADCs). These novel ADCs displayed sub‐nanomolar cytotoxicity against HER2‐expressing cancer cells, while showing no activity against antigen‐negative cells. This study demonstrates an improved synthetic route to a highly valuable natural product, facilitating further investigation of hemiasterlin and its analogues as potential payloads in targeted therapeutics.</jats:p>

Description

Keywords

3405 Organic Chemistry, 34 Chemical Sciences, Women's Health, Biotechnology, Cancer, Cancer, Generic health relevance

Journal Title

Angewandte Chemie

Conference Name

Journal ISSN

0044-8249
1521-3757

Volume Title

132

Publisher

Wiley
Sponsorship
Engineering and Physical Sciences Research Council (EP/P020291/1)