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Synthesis of new hemiasterlin derivatives with α,β-unsaturated carbonyl-thiophene groups in fragment A

In this article, we synthesized new simplified derivatives of hemiasterlin in which the α,α-dimethylbenzylic group in fragment A is replaced by α,β-unsaturated carbonyl-thiophene group. These new compounds will be prepared by classical peptide coupling approach between the carboxylic acid fragments A 12 and dipeptide 13. | Vietnam Journal of Chemistry, International Edition, 55(4): 484-488, 2017 DOI: 10.15625/2525-2321.2017-00495 Synthesis of new hemiasterlin derivatives with α,β-unsaturated carbonyl-thiophene groups in fragment A Pham The Chinh1*, Pham Thi Tham2, Nguyen Van Tuyen3 1 Thai Nguyen University of Science 2 Hanoi University of Industry 3 Insitute of Chemistry, Vietnam Academy of Science and Technology Received 19 February 2017; Accepted for publication 28 August 2017 Abstract Hemiasterlin, an antimitotic tripeptide, exhibits cytotoxicity in the nanomolar range against a variety of cultured human and murine cell lines. For this reason, the synthesis of new hemiasterlin derivatives has attracted a lot of interest in the organic chemistry community recently. In this article, we synthesized new simplified derivatives of hemiasterlin in which the α,α-dimethylbenzylic group in fragment A is replaced by α,β-unsaturated carbonyl-thiophene group. These new compounds will be prepared by classical peptide coupling approach between the carboxylic acid fragments A 12 and dipeptide 13. We expect that this derivative will possess interesting biological activities due to the high reactivity of the α,β-unsaturated carbonyl group as Michael receptor with biological nucleophiles, such as DNA, RN5A, and enzymes. Keywords.Synthesis, hemiasterlin, α,β-unsaturated; tripeptides, nanomolar. 1. INTRODUCTION Hemiasterlins belong to a family of naturally occurring tripeptides from marine sponges [1]. The important derivatives of hemiasterlin are hemiasterlin A, hemiasterlin B, and hemiasterlin C, which were isolated from marine sponge Auletta and Cymbastella (figure 1) [2, 3]. These naturally occurring substances exhibited potent cytotoxicity in vitro against murine leukemia P388 and human breast, ovarian, colon, and lung cancer cell lines [2,3,5]. Hemiasterlins suppress microtubule depolymerization presumably by binding to the vinca alkaloid site of tubulin and causing mitotic arrest and cell