Halichondrin B

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Chemical structure of halichondrin B

Halichondrin B is a naturally-occurring compound originally isolated from the marine sponge Halichondria okadai by Hirata and Uemura in 1986.[1] In the same report, these authors also reported the exquisite anticancer activity of halichondrin B against murine cancer cells both in culture and in in vivo studies. Halichondrin B was highly prioritized for development as a novel anticancer therapeutic by the United States National Cancer Institute [1] and, in 1991, was the original test case for identification of mechanism of action (in this case, tubulin-targeted mitotic inhibitor) by NCI's now famous but then-brand new "60-cell line screen"[2].[2] The complete chemical synthesis of halichondrin B, a large (MW = 1,110) polyether macrolide, was achieved by Yoshito Kishi and colleagues at Harvard University in 1992,[3] an achievement that ultimately enabled the discovery and development of the structurally-simplified and pharmaceutically-optimized analog eribulin (E7389, ER-086526, NSC-707389).[4][5] Eribulin is currently being investigated by Eisai Co. for the third-line treatment of advanced breast cancer in patients who have been previously treated with anthracyclines, taxanes and capecitabine, as well as a variety of other solid tumors, including non-small cell lung cancer, prostate cancer and sarcoma.[6]

References

  1. Hirata Y, Uemura D (1986). [Expression error: Missing operand for > "Halichondrins - antitumor polyether macrolides from a marine sponge"]. Pure Appl. Chem. 58 (5): 701-710. doi:10.1351/pac198658050701. 
  2. Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E (August 1991). [Expression error: Missing operand for > "Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data"]. J. Biol. Chem. 266 (24): 15882–9. PMID 1874739. 
  3. Aicher TD, Buszek KR, Fang FG, Forsyth CJ, Jung SH, Kishi Y, Matelich MC, Scola PM, Spero DM, Yoon SK (1992). [Expression error: Missing operand for > "Total synthesis of halichondrin B and norhalichondrin B"]. J. Am. Chem. Soc. 114 (8): 3162–3164. doi:10.1021/ja00034a086. 
  4. Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsk BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (February 2001). [Expression error: Missing operand for > "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B"]. Cancer Res. 61 (3): 1013–21. PMID 11221827. 
  5. Yu MJ, Kishi Y, Littlefield BA (2005). "Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B". In Newman DJ, Kingston DGI, Cragg, GM. Anticancer agents from natural products. Washington, DC: Taylor & Francis. ISBN 0-8493-1863-7. 
  6. "Drugs.com, Eisai Announces Change in U.S. Submission Schedule for E7389 New Drug Application". http://www.drugs.com/nda/e7389_080201.html. Retrieved on 2008-02-06.
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