Expeditious Total Synthesis of Hemiasterlin via a Convergent Multi-component Strategy and Its Use in Targeted Cancer Therapeutics.

Charoenpattarapreeda, Jiraborrirak; Walsh, Stephen J; Carroll, Jason S; Spring, David R

Hemiasterlin is an anti-mitotic 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 a potential payload in targeted therapeutics.