Gossypol
From Wikipedia the free encyclopedia
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| Names | |
|---|---|
| Preferred IUPAC name 1,1′,6,6′,7,7′-Hexahydroxy-3,3′-dimethyl-5,5′-di(propan-2-yl)[2,2′-binaphthalene]-8,8′-dicarbaldehyde | |
| Identifiers | |
3D model (JSmol) | |
| ChEMBL | |
| ChemSpider | |
| DrugBank | |
| ECHA InfoCard | 100.164.654 |
| KEGG | |
PubChem CID | |
| UNII | |
CompTox Dashboard (EPA) | |
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| Properties | |
| C30H30O8 | |
| Molar mass | 518.562 g·mol−1 |
| Appearance | Brown solid |
| Density | 1.4 g/mL |
| Melting point | 177 to 182 °C (351 to 360 °F; 450 to 455 K) (decomposes) |
| Boiling point | 707 °C (1,305 °F; 980 K) |
| Hazards | |
| GHS labelling: | |
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| Warning | |
| H351 | |
| P201, P202, P281, P308+P313, P405, P501 | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
Gossypol (/ˈɡɒsəpɒl/) is a natural phenol derived from the cotton plant (genus Gossypium). Gossypol is a phenolic aldehyde that permeates cells and acts as an inhibitor for several dehydrogenase enzymes. It is a yellow pigment. The structure exhibits atropisomerism, with the two enantiomers having different biochemical properties.[1]
Among other applications, it has been tested as a male oral contraceptive in China. In addition to its putative contraceptive properties, gossypol has also long been known to possess antimalarial properties.[2]
Biosynthesis
[edit]Gossypol is a terpenoid aldehyde which is formed metabolically through acetate via the isoprenoid pathway.[3] The sesquiterpene dimer undergoes a radical coupling reaction to form gossypol.[4] The biosynthesis begins when geranyl pyrophosphate (GPP) and isopentenyl pyrophosphate (IPP) are combined to make the sesquiterpene precursor farnesyl diphosphate (FPP). The cadinyl cation (1) is oxidized to 2 by (+)-δ-cadinene synthase. The (+)-δ-cadinene (2) is involved in making the basic aromatic sesquiterpene unit, homigossypol, by oxidation, which generates the 3 (8-hydroxy-δ-cadinene) with the help of (+)-δ-cadinene 8-hyroxylase. Compound 3 goes through various oxidative processes to make 4 (deoxyhemigossypol), which is oxidized by one electron into hemigossypol (5, 6, 7) and then undergoes a phenolic oxidative coupling, ortho to the phenol groups, to form gossypol (8).[5] The coupling is catalyzed by a hydrogen peroxide-dependent peroxidase enzyme, which results in the final product.[5]
Research
[edit]Contraception
[edit]A 1929 investigation in Jiangxi showed correlation between low fertility in males and use of crude cottonseed oil for cooking. The compound causing the contraceptive effect was determined to be gossypol.[6] In the 1970s, the Chinese government began researching the use of gossypol as a contraceptive. Their studies involved over 10,000 subjects, and continued for over a decade. They concluded that gossypol provided reliable contraception, could be taken orally as a tablet, and did not upset men's balance of hormones.
However, gossypol also had serious flaws. The studies also discovered an abnormally high rate (0.75%) of hypokalemia (low blood potassium levels) among subjects.[6][7] Hypokalemia causes symptoms of fatigue, muscle weakness, and at its most extreme, paralysis. In addition, about 7% of subjects reported effects on their digestive systems,[6] about 12% had increased fatigue, some subjects experienced impotence or reduced libido, and 9.9% became irreversibly infertile, apparently associated with longer treatment and greater total dose of gossypol.[6] Most subjects recovered after stopping treatment and taking potassium supplements. The same study showed taking potassium supplements during gossypol treatment did not prevent hypokalemia in primates.[7] The potassium deficiency may also be a result of the Chinese diet or genetic predisposition.[7]
In the mid-1990s, the Brazilian pharmaceutical company Hebron announced plans to market a low-dose gossypol pill called Nofertil, but the pill never came to market. Its release was indefinitely postponed due to unacceptably high rates of permanent infertility.[citation needed] 5% to 25% of the men remained azoospermic up to a year after stopping treatment.[7]
Researchers have suggested gossypol might make a good noninvasive alternative to surgical vasectomy.[8]
In 1986, in conjunction with the Chinese Ministry of Public Health and the Rockefeller Foundation, the World Health Organization formalized a decision to discontinue research into gossypol as a male contraceptive drug.[9] In addition to the other side effects, the WHO researchers were concerned about gossypol's toxicity: the LD50 in primates is less than 10 times the contraceptive dose,[7] creating a small therapeutic window. This report effectively ended further studies of gossypol as a temporary contraceptive, but research into using it as an alternative to vasectomy continues in Austria, Brazil, Chile, China, the Dominican Republic, and Nigeria.
Toxicity
[edit]Food and animal agricultural industries must manage cotton-derivative product levels to avoid toxicity. For example, only ruminant microflora can digest gossypol, and then only to a certain level, and cottonseed oil must be refined. Genetically engineered cotton plants that contain little gossypol in the seed may still contain the compound in the stems and leaves.[10]
References
[edit]- ^ Beise, Chase L.; Dowd, Michael K.; Reilly, Peter J. (2005). "Conformational analysis of gossypol and its derivatives by molecular mechanics". Journal of Molecular Structure: THEOCHEM. 730 (1–3): 51–58. doi:10.1016/j.theochem.2005.05.010.
- ^ Dodou, Kalliopi (2005-10-28). "Investigations on gossypol: past and present developments". Expert Opinion on Investigational Drugs. 14 (11): 1419–1434. doi:10.1517/13543784.14.11.1419. ISSN 1354-3784. PMID 16255680. S2CID 32120983.
- ^ Burgos, M.; Ito, S.; Segal, J. S.; Tran, T. P. (1997). "Effect of Gossypol on Ultrastructure of Spisula Sperm". The Biological Bulletin. 193 (2): 228–229. doi:10.1086/BBLv193n2p228. PMID 28575607.
- ^ Heinstein, P. F.; Herman, L. D.; Tove, B. S.; Smith, H. F. (1970). "Biosynthesis of Gossypol". Journal of Biological Chemistry. 245 (18): 4658–4665. doi:10.1016/S0021-9258(18)62845-5. PMID 4318479.
- ^ a b Dewick, P. M. (2008). Medicinal Natural Product: A Biosynthetic Approach (PDF) (3rd ed.). ISBN 978-0-470-74167-2.[permanent dead link]
- ^ a b c d YU, ZONG-HAN; CHAN, HSIAO CHANG (1998). "Gossypol as a male antifertility agent - why studies should have been continued". International Journal of Andrology. 21 (1): 2–7. doi:10.1046/j.1365-2605.1998.00091.x. ISSN 0105-6263. PMID 9639145.
- ^ a b c d e "Gossypol". Malecontraceptives.org. 2011-07-27. Archived from the original on 2013-05-18.
- ^ Coutinho, F. M. (2002). "Gossypol: a contraceptive for men". Contraception. 65 (4): 259–263. doi:10.1016/S0010-7824(02)00294-9. PMID 12020773.
- ^ Waites, G. M. H.; Wang, C.; Griffin, P. D. (1998). "Gossypol: Reasons for its failure to be accepted as a safe, reversible male antifertility drug". Point of View Review. International Journal of Andrology. 21 (1) (published April 1998): 8–12. doi:10.1046/j.1365-2605.1998.00092.x. ISSN 0105-6263. PMID 9639146.
- ^ "Seeding Hope for Millions". Texas A&M Today. 2018-10-16. Retrieved 2019-10-07.
External links
[edit]
Media related to Gossypol at Wikimedia Commons
