Synthesis and antimitotic/cytotoxic activity of hemiasterlin analogues.
The antimitotic sponge tripeptide hemiasterlin (1) and a number of structural analogues have been synthesized and evaluated in cell-based assays for both cytotoxic and antimitotic activity in order to explore the SAR for this promising anticancer drug lead. One synthetic analogue, SPA110 (8), showed more potent in vitro cytotoxicty and antimitotic activity than the natural product hemiasterlin (1), and consequently it has been subjected to thorough preclinical evaluation and targeted for clinical evaluation. The details of the synthesis of hemiasterlin (1) and the analogues and a discussion of how their biological activities vary with their structures are presented in this paper.
Nieman
James A
JA
Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z1.
Coleman
John E
JE
Wallace
Debra J
DJ
Piers
Edward
E
Lim
Lynette Y
LY
Roberge
Michel
M
Andersen
Raymond J
RJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D004354:Drug Screening Assays, Antitumor; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011161:Porifera / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009842:Oligopeptides; C103465:hemiasterlin A