Halichondrin B

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Halichondrin B
Halichondrin B.svg
Halichondrin B 3D ball A.png
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
PubChem CID
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 Yes check.svgY
    Key: FXNFULJVOQMBCW-CGIYHSFGSA-N Yes check.svgY
  • 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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Halichondrin B is a polyether macrolide 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]

Contents

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]

See also

Related Research Articles

In organic chemistry, polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone and methylene groups: [−C(=O)−CH2−]n. First studied in the early 20th century, discovery, biosynthesis, and application of polyketides has evolved. It is a large and diverse group of secondary metabolites caused by its complex biosynthesis which resembles that of fatty acid synthesis. Because of this diversity, polyketides can have various medicinal, agricultural, and industrial applications. Many polyketides are medicinal or exhibit acute toxicity. Biotechnology has enabled discovery of more naturally-occurring polyketides and evolution of new polyketides with novel or improved bioactivity.

<span class="mw-page-title-main">Palytoxin</span> Chemical compound

Palytoxin, PTX or PLTX is an intense vasoconstrictor, and is considered to be one of the most poisonous non-protein substances known, second only to maitotoxin in terms of toxicity in mice.

<span class="mw-page-title-main">Bryostatin</span> Chemical compound

Bryostatins are a group of macrolide lactones from the marine organism Bugula neritina that were first collected and provided to JL Hartwell’s anticancer drug discovery group at the National Cancer Institute (NCI) by Jack Rudloe. Bryostatins are potent modulators of protein kinase C. They have been studied in clinical trials as anti-cancer agents, as anti-AIDS/HIV agents and in people with Alzheimer's disease.

Okadaic acid, C44H68O13, is a toxin produced by several species of dinoflagellates, and is known to accumulate in both marine sponges and shellfish. One of the primary causes of diarrhetic shellfish poisoning, okadaic acid is a potent inhibitor of specific protein phosphatases and is known to have a variety of negative effects on cells. A polyketide, polyether derivative of a C38 fatty acid, okadaic acid and other members of its family have shined light upon many biological processes both with respect to dinoflagellete polyketide synthesis as well as the role of protein phosphatases in cell growth.

<span class="mw-page-title-main">Macrocycle</span> Molecule with a large ring structure

Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry.

<span class="mw-page-title-main">Epothilone</span> Class of chemical compounds

Epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes.

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death. Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.

<span class="mw-page-title-main">Rhizoxin</span> Chemical compound

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<span class="mw-page-title-main">Cryptophycin</span>

Cryptophycins are a family of macrolide molecules that are potent cytotoxins and have been studied for potential antiproliferative properties useful in developing chemotherapy. They are members of the depsipeptide family.

<span class="mw-page-title-main">Mitotic inhibitor</span> Cell division inhibitor

A mitotic inhibitor, microtubule inhibitor, or tubulin inhibitor, is a drug that inhibits mitosis, or cell division, and is used in treating cancer, gout, and nail fungus. These drugs disrupt microtubules, which are structures that pull the chromosomes apart when a cell divides. Mitotic inhibitors are used in cancer treatment, because cancer cells are able to grow through continuous division that eventually spread through the body (metastasize). Thus, cancer cells are more sensitive to inhibition of mitosis than normal cells. Mitotic inhibitors are also used in cytogenetics, where they stop cell division at a stage where chromosomes can be easily examined.

<i>Halichondria</i> Genus of sponges

Halichondria is a genus of sea sponges belonging to the family Halichondriidae. These are massive, amorphous sponges with clearly separated inner and outer skeletons consisting of bundles of spicules arranged in a seemingly random pattern.

<span class="mw-page-title-main">Eribulin</span> Pharmaceutical drug

Eribulin, sold under the brand name Halaven among others, is an anti-cancer medication used to treat breast cancer and liposarcoma.

<span class="mw-page-title-main">Maitansine</span> Chemical compound

Maitansine (INN), or maytansine (USAN), is a cytotoxic agent. It inhibits the assembly of microtubules by binding to tubulin at the rhizoxin binding site.

The salinosporamides are a group of closely related chemical compounds isolated from marine bacteria in the genus Salinispora. They possess a densely functionalized γ-lactam-β-lactone bicyclic core.

<span class="mw-page-title-main">Oroidin</span> Chemical compound

Oroidin is a bromopyrrole alkaloid, originally isolated from marine sponges in the genus Agelas. It appears to have a wide range of biological activities, which makes Oroidin a potential drug candidate for various diseases. It also serves as chemical defense in marine sponges.

<span class="mw-page-title-main">Sponge isolates</span>

Lacking an immune system, protective shell, or mobility, sponges have developed an ability to synthesize a variety of unusual compounds for survival. C-nucleosides isolated from Caribbean Cryptotethya crypta, were the basis for the synthesis of zidovudine (AZT), aciclovir (Cyclovir), cytarabine (Depocyt), and cytarabine derivative gemcitabine (Gemzar).

<span class="mw-page-title-main">Onnamide A</span> Chemical compound

Onnamide A is a bioactive natural product found in Theonella swinhoei, a species of marine sponge whose genus is well known for yielding a diverse set of biologically active natural products, including the swinholides and polytheonamides. It bears structural similarities to the pederins, a family of compounds known to inhibit protein synthesis in eukaryotic cells. Onnamide A and its analogues have attracted academic interest due to their cytotoxicity and potential for combating the growth and proliferation of cancer cells.

Gymnascella dankaliensis is a moderate to slow growing fungus commonly found in the soil of warmer climates. It is characterized by round yellow, orange or red-brown ascospores encircled by undifferentiated filaments. They have been found in ear, nail and skin infections. Their metabolites have been isolated and shown to have cytotoxic and anti-tumor properties.

Laucysteinamide A (LcA) is a marine natural product isolated from a cyanobacterium, Caldora penicillata.

<span class="mw-page-title-main">Altohyrtin A</span> Chemical compound

Altohyrtin A is a polyether macrolide originally isolated from the Okinawan marine sponge Hyrtios altum by Kobayashi et al. in 1993, the Indian marine sponge Spongia sp. by Pettit et al. in 1993, and the Japanese marine sponge Cinachyra sp. by Fusetani et al. in 1993. It has potent anti-cancer activity.

References

  1. ↑ Hirata Y, Uemura D (1986). "Halichondrins - antitumor polyether macrolides from a marine sponge". Pure Appl. Chem. 58 (5): 701–710. 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. ↑ 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.
  6. ↑ 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.
  7. ↑ 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. ISBN   978-0-8493-1863-4.
  8. ↑ "FDA approves new treatment option for late-stage breast cancer" (Press release). USFDA. 2010-11-15. Retrieved November 15, 2010.
  9. ↑ 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.
  10. ↑ 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. ISSN   0002-7863.
  11. ↑ 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.
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