Wikipedia

Halichondrin B

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]

Halichondrin B
Skeletal formula of halichondrin B
Space-filling model of the halichondrin B molecule
Names
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
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
UNII
  • InChI=1S/C60H86O19/c1-26-13-33-7-9-37-27(2)14-35(65-37)11-12-58-23-46-54(78-58)55-56(72-46)57(79-58)53-38(69-55)10-8-34(67-53)16-48(64)73-52-31(6)51-43(68-42(52)17-39(66-33)30(26)5)19-41-45(71-51)22-60(74-41)24-47-50(77-60)29(4)21-59(76-47)20-28(3)49-44(75-59)18-40(70-49)36(63)15-32(62)25-61/h26,28-29,31-47,49-57,61-63H,2,5,7-25H2,1,3-4,6H3/t26-,28+,29+,31+,32?,33+,34-,35+,36?,37+,38+,39-,40+,41-,42+,43+,44+,45-,46-,47+,49+,50+,51+,52-,53+,54+,55+,56-,57+,58+,59-,60+/m1/s1 checkY
    Key: FXNFULJVOQMBCW-CGIYHSFGSA-N checkY
  • InChI=1S/C60H86O19/c1-26-13-33-7-9-37-27(2)14-35(65-37)11-12-58-23-46-54(78-58)55-56(72-46)57(79-58)53-38(69-55)10-8-34(67-53)16-48(64)73-52-31(6)51-43(68-42(52)17-39(66-33)30(26)5)19-41-45(71-51)22-60(74-41)24-47-50(77-60)29(4)21-59(76-47)20-28(3)49-44(75-59)18-40(70-49)36(63)15-32(62)25-61/h26,28-29,31-47,49-57,61-63H,2,5,7-25H2,1,3-4,6H3/t26-,28+,29+,31+,32?,33+,34-,35+,36,37+,38+,39-,40+,41-,42+,43+,44+,45-,46-,47+,49+,50+,51+,52-,53+,54+,55+,56-,57+,58+,59-,60+/m1/s1
  • InChI=1S/C60H86O19/c1-26-13-33-7-9-37-27(2)14-35(65-37)11-12-58-23-46-54(78-58)55-56(72-46)57(79-58)53-38(69-55)10-8-34(67-53)16-48(64)73-52-31(6)51-43(68-42(52)17-39(66-33)30(26)5)19-41-45(71-51)22-60(74-41)24-47-50(77-60)29(4)21-59(76-47)20-28(3)49-44(75-59)18-40(70-49)36(63)15-32(62)25-61/h26,28-29,31-47,49-57,61-63H,2,5,7-25H2,1,3-4,6H3/t26-,28+,29+,31+,32?,33+,34-,35+,36?,37+,38+,39-,40+,41-,42+,43+,44+,45-,46-,47+,49+,50+,51+,52-,53+,54+,55+,56-,57+,58+,59-,60+/m1/s1
    Key: FXNFULJVOQMBCW-CGIYHSFGSA-N
  • OCC(O)CC(O)[C@@H]1C[C@@H]2O[C@@]3(C[C@H](C)[C@@H]2O1)C[C@H](C)[C@@H]4O[C@]%10(C[C@@H]4O3)C[C@H]%11O[C@H]%12[C@H](C)[C@H]%13OC(=O)C[C@H]8CC[C@@H]9O[C@H]7[C@H]6O[C@]5(O[C@H]([C@@H]7O[C@@H]6C5)[C@H]9O8)CC[C@H]%15C/C(=C)[C@H](CC[C@H]%14C[C@@H](C)\C(=C)[C@@H](C[C@@H]%13O[C@H]%12C[C@H]%11O%10)O%14)O%15
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).
☒N verify (what is checkY☒N ?)

Chemical synthesis

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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

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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]

See also

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References

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  1. 1 2 Hirata Y, Uemura D (1986). "Halichondrins - antitumor polyether macrolides from a marine sponge". Pure Appl. Chem. 58 (5): 701–710. Bibcode:1986PApCh..58..701H. doi:10.1351/pac198658050701. S2CID 38138047.
  2. ↑ "Success Story: Halichondrin B (NSC 609395) E7389 (NSC 707389)". Developmental Therapeutics Program, National Cancer Institute. Archived from the original on 2009-07-10.
  3. ↑ "NCI-60 DTP Human Tumor Cell Line Screen". Developmental Therapeutics Program, National Cancer Institute. Archived from the original on 2009-07-10.
  4. ↑ Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E (August 1991). "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. doi:10.1016/S0021-9258(18)98491-7. PMID 1874739.
  5. 1 2 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. PMID 11221827.
  6. 1 2 Yu MJ, Kishi Y, Littlefield BA (2012). "Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B". In Cragg GM, Kingston DG, Newman DJ (eds.). Anticancer agents from natural products (2nd ed.). Boca Raton, FL: CRC Press. pp. 317–345.
  7. ↑ 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. Bibcode:1992JAChS.114.3162A. doi:10.1021/ja00034a086.
  8. ↑ "FDA approves new treatment option for late-stage breast cancer" (Press release). USFDA. 2010-11-15. Archived from the original on November 17, 2010. Retrieved November 15, 2010.
  9. ↑ Cortes, Javier; Schöffski, Patrick; Littlefield, Bruce A. (November 2018). "Multiple modes of action of eribulin mesylate: Emerging data and clinical implications". Cancer Treatment Reviews. 70: 190–198. doi:10.1016/j.ctrv.2018.08.008. ISSN 1532-1967. PMID 30243063.
  10. ↑ Kawano, Satoshi; Ito, Ken; Yahata, Kenzo; Kira, Kazunobu; Abe, Takanori; Akagi, Tsuyoshi; Asano, Makoto; Iso, Kentaro; Sato, Yuki; Matsuura, Fumiyoshi; Ohashi, Isao; Matsumoto, Yasunobu; Isomura, Minetaka; Sasaki, Takeo; Fukuyama, Takashi; Miyashita, Yusuke; Kaburagi, Yosuke; Yokoi, Akira; Asano, Osamu; Owa, Takashi; Kishi, Yoshito (2019-06-17). "A landmark in drug discovery based on complex natural product synthesis" (PDF). Scientific Reports. 9 (1) 8656. Bibcode:2019NatSR...9.8656K. doi:10.1038/s41598-019-45001-9. ISSN 2045-2322. PMC 6572832. PMID 31209263. Retrieved 2025-05-28.
  11. ↑ Kaburagi, Yosuke; Kira, Kazunobu; Yahata, Kenzo; Iso, Kentaro; Sato, Yuki; Matsuura, Fumiyoshi; Ohashi, Isao; Matsumoto, Yasunobu; Isomura, Minetaka; Sasaki, Takeo; Fukuyama, Takashi; Miyashita, Yusuke; Azuma, Hiroshi; Iida, Daisuke; Ishida, Tasuku; Itano, Wataru; Matsuda, Masaaki; Matsukura, Masayuki; Murai, Norio; Nagao, Satoshi; Seki, Masashi; Yamamoto, Akihiko; Yamamoto, Yuji; Yoneda, Naoki; Watanabe, Yuzo; Kamada, Atsushi; Kayano, Akio; Tagami, Katsuya; Asano, Osamu; Owa, Takashi; Kishi, Yoshito (2024-04-12). "Ten-Gram-Scale Total Synthesis of the Anticancer Drug Candidate E7130 to Supply Clinical Trials". Organic Letters. 26 (14): 2837–2842. doi:10.1021/acs.orglett.3c03663. ISSN 1523-7060. PMID 38252895. Retrieved 2025-05-28.
  12. ↑ Sasaki, Takeo; Yahata, Kenzo; Isomura, Minetaka; Ohashi, Isao; Fukuyama, Takashi; Miyashita, Yusuke; Watanabe, Yuzo; Murai, Norio; Matsuda, Masaaki; Kamada, Atsushi; Kaburagi, Yosuke; Kira, Kazunobu; Iso, Kentaro; Sato, Yuki; Matsuura, Fumiyoshi; Matsumoto, Yasunobu; Azuma, Hiroshi; Iida, Daisuke; Ishida, Tasuku; Itano, Wataru; Nagao, Satoshi; Seki, Masashi; Yamamoto, Akihiko; Yamamoto, Yuji; Yoneda, Naoki; Matsukura, Masayuki; Asano, Osamu; Kayano, Akio; Tagami, Katsuya; Owa, Takashi; Kishi, Yoshito (2024-06-21). "What Does It Take to Develop Structurally Complex Molecules by Total Synthesis? Rapid Process Development and GMP Manufacturing of E7130 Drug Substance for First-in-Human Clinical Study". Organic Process Research & Development. 28 (6): 2077–2089. doi:10.1021/acs.oprd.4c00016. ISSN 1083-6160. Retrieved 2025-05-28.
  13. ↑ Eisai Co., Ltd. (2025-03-05). A Phase 1 Study of E7130 in Subjects With Solid Tumor (Report). clinicaltrials.gov.
  14. ↑ 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. ISSN 0265-0568. PMID 24930430.
  15. ↑ 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. Bibcode:1981JAChS.103.2469T. doi:10.1021/ja00399a082. ISSN 0002-7863.
  16. ↑ 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. ISSN 0916-8451. PMID 22484923.
  17. ↑ Pettit, George R.; Herald, Cherry L.; Boyd, Michael R.; Leet, John E.; Dufresne, Claude; Doubek, Dennis L.; Schmidt, Jean M.; Cerny, Ronald L.; Hooper, John N. A.; Rutzler, Klaus C. (1991). "Antineoplastic agents. 219. Isolation and structure of the cell growth inhibitory constituents from the western Pacific marine sponge Axinella sp". Journal of Medicinal Chemistry. 34 (11): 3339–3340. doi:10.1021/jm00115a027. ISSN 0022-2623. PMID 1956053. Retrieved 2025-06-02.
  18. ↑ Pettit, George R.; Tan, Rui; Gao, Feng; Williams, Michael D.; Doubek, Dennis L.; Boyd, Michael R.; Schmidt, Jean M.; Chapuis, Jean Charles; Hamel, Ernest (1993). "Isolation and structure of halistatin 1 from the eastern Indian Ocean marine sponge Phakellia carteri". The Journal of Organic Chemistry. 58 (9): 2538–2543. doi:10.1021/jo00061a030. ISSN 0022-3263. Retrieved 2025-06-02.
  19. ↑ Munro, Murray H.G.; Blunt, John W.; Dumdei, Eric J.; Hickford, Sarah J.H.; Lill, Rachel E.; Li, Shangxiao; Battershill, Christopher N.; Duckworth, Alan R. (1999). "The discovery and development of marine compounds with pharmaceutical potential". Journal of Biotechnology. 70 (1–3): 15–25. doi:10.1016/S0168-1656(99)00052-8. PMID 10412202. Retrieved 2025-06-02.
  20. ↑ Hart, Joanne B.; Lill, Rachel E.; Hickford, Sarah J.H.; Blunt, John W.; Munro, Murray H.G. (2000-01-01). "The Halichondrins: Chemistry, Biology, Supply and Delivery". Drugs from the Sea (PDF). Basel ; New York: Karger Medical and Scientific Publishers. p. 134-153. ISBN 978-3-8055-7098-5.
  21. 1 2 Newman, David J; Cragg, Gordon M; Battershill, Christopher N (2009). "Therapeutic agents from the sea: biodiversity, chemo-evolutionary insight and advances to the end of Darwin's 200th year" (PDF). Diving and Hyperbaric Medicine. 39 (4). South Pacific Underwater Medicine Society (Incorporated in Victoria) AO020660B and the European Underwater and Baromedical Society: 216–225. PMID 22752743.
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