Halichondrin B
Chemical compound
From Wikipedia, the free encyclopedia
Halichondrin B is a polyether macrolide originally isolated from the marine sponge Halichondria okadai by Hirata and Uemura in 1986.[1] In that report, the authors described the purification, chemical structure and exquisite anticancer activity of halichondrin B against murine cancer cells in vitro and murine tumor models in vivo.[1] Shortly thereafter, the Developmental Therapeutics Program (DTP) at the U.S. National Cancer Institute (NCI) designated halichondrin B a high priority for development as a novel anticancer drug.[2] In 1991, halichondrin B 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] In 1992, it was discovered that halichondrin B's anticancer activity resided in its so-called "Right Half" macrocyclic lactone moiety (C1-C38), which represents about 2/3 of the size of the full halichondrin B molecule.[5][6]
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| IUPAC name
(1S,2S,2′S,3S,3aS,3a′S,5R,6S,7S,7′S,7aS,7a′S,9S,12S,14R,16R,18S,20S,22R,26R,28S,29S,30R,34R,37S,39R,40S,41R,43R,44S)-7,7′,14′′,29′′-tetramethyl-8′′,15′′-dimethylidene-2-(1,3,4-trihydroxybutyl)decahydro-3′H,32′′H-dispiro[furo[3,2-b]pyran-5,5′-furo[3,2-b]pyran-2′,24′′-[2,19,23,27,31,38,42,45,47,48,49]undecaoxaundecacyclo[32.9.2.1~3,40~.1~3,41~.1~6,9~.1~12,16
~.0~18,30~.0~20,28~.0~22,26~.0~37,44~.0~39,43~]nonatetracontan]-32′′-one | |
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3D model (JSmol) |
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CompTox Dashboard (EPA) |
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| Properties | |
| C60H86O19 | |
| Molar mass | 1111.329 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Chemical synthesis
The complete chemical synthesis of halichondrin B was achieved by Yoshito Kishi and colleagues at Harvard University in 1992,[7] an achievement that enabled discovery and development of the structurally simplified, pharmaceutically optimized analog eribulin (previously, B1939, ER-086526, E7389, NSC-707389).[5][6] Eribulin is approved in the U.S., EU, Japan, Canada and other jurisdictions for treatment of certain patients with breast cancer or liposarcoma,[8][9] and is marketed by Eisai under the tradename Halaven.
More recently, a "full-sized" halichondrin analog, E7130, was synthesized under collaborative efforts between the Kishi group at Harvard and chemists at Eisai's Tsukuba Research Laboratories (Tsukuba, Japan).[10][11][12] E7130 entered clinical trials for cancer in Japan (NCT03444701).[13] Prior to his death in 2023, Kishi had developed a deep interest in the chemical nature and biological activities of the so-called "Left Half" of the halichondrins. Sadly, none of his extensive work in this area had reached publication at the time of his death.
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[14] In support of this conjecture, the known dinoflagellate toxin okadaic acid was isolated from the same species of sponge.[15] Yet, halichondrin B is not found in the geographically and relatively phylogenetically close sponges H. panicea or H. japonica which are found in similar tide pools in Japan as Halichondria okadai.[16] In constrast, halichondrins have been reported from geographically and phylogenetically distant sponges to Halichondria okadai, including Axinella sp.,[17] Phakellia carteri,[18] and Lissodendoryx. Aquaculture of the New Zealand sponge Lissodendoryx n. sp. 1 over at least 7 years, distant from its original range (at ~10 m depth near Wellington versus its native range ~90 m deep off the Kaikōura Peninsula), established it could produce halichondrin B at a relatively high yield over a time course of years, suggesting that halichondrins were being produced by vertically inherited symbionts, rather than being concentrated from a dietary source present in the environment.[19][20][21] In fact, the bulk of halichondrin B used by the U.S. NCI for its therapeutic evaluation, was isolated from New Zealand Lissodendoryx rather than from Halichondria okadai.[21]