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

• Published in: Angewandte Chemie International Edition 2020-12, Vol.59 (51), p.23045-23050
• Main Authors: Charoenpattarapreeda, Jiraborrirak, Walsh, Stephen J., Carroll, Jason S., Spring, David R.
• Format: Article
• Language: English
• Subjects: Antibodies; antibody–drug conjugates; Antigens; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Communication; Communications; Convergence; Cytotoxicity; Drug Screening Assays, Antitumor; ErbB-2 protein; hemiasterlin; Humans; Molecular Conformation; multicomponent reactions; Natural products; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Payloads; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; targeted therapeutics; total synthesis; Toxicity; Tumor cell lines
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202010090

Hemiasterlin 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. Hemiasterlin, a highly cytotoxic marine natural product (see structure), was synthesised by a multicomponent approach with a longest linear sequence of 10 steps. Its use in a targeted therapeutic was demonstrated by incorporation as a payload in an antibody–drug conjugate (ADC), which showed mid‐picomolar cytotoxicity against HER2‐expressing cancer cell lines.