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

Pham The Chinh, Pham Thi Tham, Nguyen Van Tuyen


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.


Synthesis, hemiasterlin, α,β-unsaturated; tripeptides, nanomolar


Talpir R., Benayahu Y., Kashman Y., Pannell L., Schleyer M. Hemiasterlin and geodiamolide TA- two new cytotoxic peptides from the marine sponge Hemiasterella minor, Tetrahedron Lett., 35, 4453-4456 (1994).

Gamble W. R., Durso N. A., Fuller R. W., Westergaard C. K., Johnson T. R., Sackett, D. L.; Hamel E., Cardellina II J. H., Boyd M. R. Cytotoxic and tubulin-interactive hemiasterlins from Auletta sp. and Siphonochalina spp. Sponges, Bioorg. Med. Chem., 7, 1611-1615 (1999).

Coleman J. E., Silva E. D., Kong F., Andersen R. J., Allen T. M. Cytotoxic peptides from the marine sponge Cymbastela sp., Tetrahedron, 51, 10653 (1995).

Anderson H. J., Coleman J. E., Andersen R. J., Roberge M. Cytotoxic peptides hemiasterlin, hemiasterlin A and hemiasterlin B induce mitotic arrest and abnormal spindle formation, Cancer Chemother. Pharmacol., 39, 223-226 (1997).

Yamashita A., Norton E. B., Kaplan J. A., Niu C., Loganzo F., Hernand R., Beyer C. F., Annable T., Musto S., Discafani C., Zask A., Ayral-Kaloustian A. Synthesis and activity of novel analoges of hemiasterlin as inhibitors of tubulin polymerization: modification of the A segment, Bioorg. Med. Chem. Lett., 14, 5317-5322 (2004).

Niew J. A., Coleman J. E., Wallace D. J., Piers E., Lim L. Y., Roberge M., Andersen R. J. Synthesis and Antimitotic/Cytotoxic Activity of Hemiasterlin Analogues, J. Nat. Prod., 6, 183 (2003).

Hayashi Y. et al. Synthesis and Structure-Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2,5-dione Structure, J. Med. Chem., 55, 1056-1071 (2012).

Pijus K. M., Zhiyong R., Xiaomin C., Chiyi X., McMurray J. S. Structure-Affinity Relationships of Glutamine Mimics Incorporated into Phosphopeptides Targeted to the SH2 Domain of Signal Transducer and Activator of Transcription 3, J. Med. Chem., 52, 6126-6141 (2009).

Thomas C., Jodie B., Flavio C. One-pot process to Z-α-benzoylamino-acrylic acid methyl esters via potassium phosphate-catalyzed Erlenmeyer reaction, Tetrahedron Lett., 51, 625-628 (2010).

Chinh Pham The, Tuyet Anh Dang Thi, Thi Phuong Hoang, Quoc Anh Ngo, Duy Tien Doan, Thu Ha Nguyen Thi, Tham Pham Thi, Thu Ha Vu Thi, M. Jean, P. van de Weghe, Tuyen Nguyen Van. Synthesis of New simplified hemiasterlin derivatives with α,β-unsaturated carbonyl moiety, Bioorganic & Medicinal Chemistry Letters, 24, 2244-2246 (2014).

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