halichondrin B

{{Chembox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 476997373

| ImageFile = Halichondrin B.svg

| ImageSize = 280

| ImageAlt = Skeletal formula of halichondrin B

| ImageFile1 = Halichondrin B 3D ball A.png

| ImageSize1 = 280

| ImageAlt1 = Space-filling model of the halichondrin B molecule

| IUPACName = (1S,2S,2{{prime}}S,3S,3aS,3a{{prime}}S,5R,6S,7S,7{{prime}}S,7aS,7a{{prime}}S,9S,12S,14R,16R,18S,20S,22R,26R,28S,29S,30R,34R,37S,39R,40S,41R,43R,44S)-7,7{{prime}},14{{prime}}{{prime}},29{{prime}}{{prime}}-tetramethyl-8{{prime}}{{prime}},15{{prime}}{{prime}}-dimethylidene-2-(1,3,4-trihydroxybutyl)decahydro-3{{prime}}H,32{{prime}}{{prime}}H-dispiro[furo[3,2-b]pyran-5,5{{prime}}-furo[3,2-b]pyran-2{{prime}},24{{prime}}{{prime}}-[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{{prime}}{{prime}}-one

| OtherNames =

|Section1={{Chembox Identifiers

| 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

| InChIKey1 = FXNFULJVOQMBCW-CGIYHSFGSA-N

| InChI1 = 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

| CASNo_Ref = {{cascite|changed|??}}

| CASNo = 103614-76-2

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 269R6PFM59

| PubChem = 5488895

| ChEMBL = 387466

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 10256208

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = FXNFULJVOQMBCW-CGIYHSFGSA-N

| SMILES = 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

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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

}}

|Section2={{Chembox Properties

| C=60 | H=86 | O=19

| MolarMass =

| Appearance =

| Density =

| MeltingPt =

| BoilingPt =

| Solubility =

}}

|Section3={{Chembox Hazards

| MainHazards =

| FlashPt =

| AutoignitionPt =

}}

}}

Halichondrin B is a polyether macrolide originally isolated from the marine sponge Halichondria okadai by Hirata and Uemura in 1986.{{ cite journal |vauthors=Hirata Y, Uemura D | title=Halichondrins - antitumor polyether macrolides from a marine sponge | journal=Pure Appl. Chem. | year = 1986 | volume = 58 | issue = 5 | pages = 701–710 | doi = 10.1351/pac198658050701| s2cid=38138047 | doi-access = free }} 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{{cite web | url = http://www.dtp.nci.nih.gov/timeline/noflash/success_stories/S4_halichondrinB.htm | title = Success Story: Halichondrin B (NSC 609395) E7389 (NSC 707389) | publisher = Developmental Therapeutics Program, National Cancer Institute | url-status = dead | archive-url = https://web.archive.org/web/20090710205200/http://dtp.nci.nih.gov/timeline/noflash/success_stories/S4_halichondrinB.htm | archive-date = 2009-07-10 }} 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"{{cite web | url = http://www.dtp.nci.nih.gov/branches/btb/ivclsp.html | title = NCI-60 DTP Human Tumor Cell Line Screen | publisher = Developmental Therapeutics Program, National Cancer Institute | url-status = dead | archive-url = https://web.archive.org/web/20090710183850/http://dtp.nci.nih.gov/branches/btb/ivclsp.html | archive-date = 2009-07-10 }}{{cite journal |vauthors=Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E | title = 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 | journal = J. Biol. Chem. | volume = 266 | issue = 24 | pages = 15882–9 |date=August 1991 | doi = 10.1016/S0021-9258(18)98491-7 | pmid = 1874739 | doi-access = free }}

The complete chemical synthesis of halichondrin B was achieved by Yoshito Kishi and colleagues at Harvard University in 1992,{{cite journal | vauthors = Aicher TD, Buszek KR, Fang FG, Forsyth CJ, Jung SH, Kishi Y, Matelich MC, Scola PM, Spero DM, Yoon SK | author6-link = Kishi Y | title = Total synthesis of halichondrin B and norhalichondrin B | journal = J. Am. Chem. Soc. | year = 1992 | volume = 114 | issue = 8 | pages = 3162–3164 | doi = 10.1021/ja00034a086}} an achievement that ultimately enabled the discovery and development of the structurally simplified and pharmaceutically optimized analog eribulin (E7389, ER-086526, NSC-707389).{{cite journal | vauthors = 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 | author19-link = Kishi Y | title = In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B | journal = Cancer Res. | volume = 61 | issue = 3 | pages = 1013–21 |date=February 2001 | pmid = 11221827 }}{{cite book | veditors = Newman DJ, Kingston DG, Cragg GM | title = Anticancer agents from natural products | publisher = Taylor & Francis | location = Washington, DC | year = 2005 | chapter = Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B | vauthors = Yu MJ, Kishi Y, Littlefield BA | author2-link = Kishi Y | isbn = 978-0-8493-1863-4 }} 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.{{cite press release | title = FDA approves new treatment option for late-stage breast cancer | publisher = USFDA | date = 2010-11-15 | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm233863.htm | archive-url = https://web.archive.org/web/20101117013510/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm233863.htm | url-status = dead | archive-date = November 17, 2010 | access-date = November 15, 2010}} Eribulin is marketed by Eisai Co. under the tradename Halaven.

More recently, another halichondrin B derivative, E7130, was synthesized in collabortaion by Eisai Co. and the Kishi lab, and has entered clinical trials{{cite journal | last=Kawano | first=Satoshi | last2=Ito | first2=Ken | last3=Yahata | first3=Kenzo | last4=Kira | first4=Kazunobu | last5=Abe | first5=Takanori | last6=Akagi | first6=Tsuyoshi | last7=Asano | first7=Makoto | last8=Iso | first8=Kentaro | last9=Sato | first9=Yuki | last10=Matsuura | first10=Fumiyoshi | last11=Ohashi | first11=Isao | last12=Matsumoto | first12=Yasunobu | last13=Isomura | first13=Minetaka | last14=Sasaki | first14=Takeo | last15=Fukuyama | first15=Takashi | last16=Miyashita | first16=Yusuke | last17=Kaburagi | first17=Yosuke | last18=Yokoi | first18=Akira | last19=Asano | first19=Osamu | last20=Owa | first20=Takashi | last21=Kishi | first21=Yoshito | title=A landmark in drug discovery based on complex natural product synthesis | journal=Scientific Reports | volume=9 | issue=1 | date=2019-06-17 | issn=2045-2322 | pmid=31209263 | pmc=6572832 | doi=10.1038/s41598-019-45001-9 | doi-access=free | url=https://www.nature.com/articles/s41598-019-45001-9.pdf | access-date=2025-05-28 | page=}}{{cite journal | last=Kaburagi | first=Yosuke | last2=Kira | first2=Kazunobu | last3=Yahata | first3=Kenzo | last4=Iso | first4=Kentaro | last5=Sato | first5=Yuki | last6=Matsuura | first6=Fumiyoshi | last7=Ohashi | first7=Isao | last8=Matsumoto | first8=Yasunobu | last9=Isomura | first9=Minetaka | last10=Sasaki | first10=Takeo | last11=Fukuyama | first11=Takashi | last12=Miyashita | first12=Yusuke | last13=Azuma | first13=Hiroshi | last14=Iida | first14=Daisuke | last15=Ishida | first15=Tasuku | last16=Itano | first16=Wataru | last17=Matsuda | first17=Masaaki | last18=Matsukura | first18=Masayuki | last19=Murai | first19=Norio | last20=Nagao | first20=Satoshi | last21=Seki | first21=Masashi | last22=Yamamoto | first22=Akihiko | last23=Yamamoto | first23=Yuji | last24=Yoneda | first24=Naoki | last25=Watanabe | first25=Yuzo | last26=Kamada | first26=Atsushi | last27=Kayano | first27=Akio | last28=Tagami | first28=Katsuya | last29=Asano | first29=Osamu | last30=Owa | first30=Takashi | last31=Kishi | first31=Yoshito | title=Ten-Gram-Scale Total Synthesis of the Anticancer Drug Candidate E7130 to Supply Clinical Trials | journal=Organic Letters | volume=26 | issue=14 | date=2024-04-12 | issn=1523-7060 | doi=10.1021/acs.orglett.3c03663 | pages=2837–2842 | url=https://pubs.acs.org/doi/10.1021/acs.orglett.3c03663 | access-date=2025-05-28| url-access=subscription }}{{cite journal | last=Sasaki | first=Takeo | last2=Yahata | first2=Kenzo | last3=Isomura | first3=Minetaka | last4=Ohashi | first4=Isao | last5=Fukuyama | first5=Takashi | last6=Miyashita | first6=Yusuke | last7=Watanabe | first7=Yuzo | last8=Murai | first8=Norio | last9=Matsuda | first9=Masaaki | last10=Kamada | first10=Atsushi | last11=Kaburagi | first11=Yosuke | last12=Kira | first12=Kazunobu | last13=Iso | first13=Kentaro | last14=Sato | first14=Yuki | last15=Matsuura | first15=Fumiyoshi | last16=Matsumoto | first16=Yasunobu | last17=Azuma | first17=Hiroshi | last18=Iida | first18=Daisuke | last19=Ishida | first19=Tasuku | last20=Itano | first20=Wataru | last21=Nagao | first21=Satoshi | last22=Seki | first22=Masashi | last23=Yamamoto | first23=Akihiko | last24=Yamamoto | first24=Yuji | last25=Yoneda | first25=Naoki | last26=Matsukura | first26=Masayuki | last27=Asano | first27=Osamu | last28=Kayano | first28=Akio | last29=Tagami | first29=Katsuya | last30=Owa | first30=Takashi | last31=Kishi | first31=Yoshito | title=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 | journal=Organic Process Research & Development | volume=28 | issue=6 | date=2024-06-21 | issn=1083-6160 | doi=10.1021/acs.oprd.4c00016 | pages=2077–2089 | url=https://pubs.acs.org/doi/10.1021/acs.oprd.4c00016 | access-date=2025-05-28| url-access=subscription }}.