Halichondrin B is a polyethermacrolide 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[2] and, in 1991, was the original test case for identification of mechanism of action (in this case, tubulin-targeted mitotic inhibitor) by NCI's then-brand-new "60-cell line screen"[3][4]
The complete chemical synthesis of halichondrin B was achieved by Yoshito Kishi and colleagues at Harvard University in 1992,[5] an achievement that ultimately enabled the discovery and development of the structurally simplified and pharmaceutically optimized analog eribulin (E7389, ER-086526, NSC-707389).[6][7]Eribulin was approved by the U.S. Food and Drug Administration on November 15, 2010, to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline- and taxane-based chemotherapies.[8]Eribulin is marketed by Eisai Co. under the tradename Halaven.
Biosynthesis
While a producer organism for Halichondrin B has never been isolated in pure culture, the structural features of Halichondrin B, such as the 'odd-even' rule of methylation, and the abundance of oxygen heterocycles, suggest it is a product of dinoflagellate polyether metabolism.[9] In support of this conjecture, the known dinoflagellate toxin okadaic acid was isolated from the same species of sponge.[10] But, Halichondrin B is not found in H. panicea or H. japonica which are found in similar tide pools in Japan as Halichondria okadai.[11]
^Aicher TD, Buszek KR, Fang FG, Forsyth CJ, Jung SH, Kishi Y, Matelich MC, Scola PM, Spero DM, Yoon SK (1992). "Total synthesis of halichondrin B and norhalichondrin B". J. Am. Chem. Soc. 114 (8): 3162–3164. doi:10.1021/ja00034a086.
^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). "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B". Cancer Res. 61 (3): 1013–21. PMID11221827.
^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 (eds.). Anticancer agents from natural products. Washington, DC: Taylor & Francis. ISBN978-0-8493-1863-4.
^Van Wagoner, Ryan M.; Satake, Masayuki; Wright, Jeffrey L. C. (2014-06-16). "Polyketide biosynthesis in dinoflagellates: what makes it different?". Natural Product Reports. 31 (9). Royal Society of Chemistry (RSC): 1101–37. doi:10.1039/c4np00016a. ISSN0265-0568. PMID24930430.
^Tachibana, Kazuo; Scheuer, Paul J.; Tsukitani, Yasumasa; Kikuchi, Hiroyuki; Van Engen, Donna; Clardy, Jon; Gopichand, Yalamanchili; Schmitz, Francis J. (1981). "Okadaic acid, a cytotoxic polyether from two marine sponges of the genus Halichondria". Journal of the American Chemical Society. 103 (9). American Chemical Society (ACS): 2469–2471. doi:10.1021/ja00399a082. ISSN0002-7863.
^Abe, Takahiro; Sahin, Fatma Pinar; Akiyama, Kiyotaka; Naito, Takayuki; Kishigami, Mizoe; Miyamoto, Kenji; Sakakibara, Yasufumi; Uemura, Daisuke (2012-04-23). "Construction of a Metagenomic Library for the Marine Sponge Halichondria okadai". Bioscience, Biotechnology, and Biochemistry. 76 (4): 633–639. doi:10.1271/bbb.110533. ISSN0916-8451.
