人拓扑异构酶I抑制剂（5Z,9Z）-5,9-十六碳二烯酸的全合成及生物学评价
Total synthesis and biological evaluation of (5Z,9Z)-5,9-hexadecadienoic acid, an inhibitor of human topoisomerase I.
作者信息
Carballeira Néstor M, Betancourt José E, Orellano Elsie A, González Fernando A
机构信息
Department of Chemistry, University of Puerto Rico, PO Box 23346, San Juan, Puerto Rico 00931-3346.
出版信息
J Nat Prod. 2002 Nov;65(11):1715-8. doi: 10.1021/np0202576.
The naturally occurring (5Z,9Z)-5,9-hexadecadienoic acid was synthesized stereochemically pure in six steps starting with commercially available 1,5-hexadiyne. The title compound was antimicrobial against the Gram-positive bacteria Staphylococcus aureus (MIC 80 microM) and Streptococcus faecalis (MIC 200 microM), but inactive against Gram-negative bacteria such as Pseudomonas aeruginosa. In addition, the (5Z,9Z)-5,9-hexadecadienoic acid completely inhibits human topoisomerase I at a concentration of 800 microM, while 5,9-hexadecadiynoic acid and hexadecanoic acid do not inhibit topoisomerase I (>1000 microM). This comparison reveals that the cis double bond geometry in the title compound is required for topoisomerase I inhibition. Moreover, these results suggest that the antimicrobial activity of (5Z,9Z)-5,9-hexadecadienoic acid against either S. aureus or S. faecalis could be a result, at least in part, of the inhibitory activity of the acid against topoisomerases.
以市售的1,5 -己二炔为起始原料，通过六步反应立体化学纯地合成了天然存在的(5Z,9Z)-5,9 -十六碳二烯酸。标题化合物对革兰氏阳性菌金黄色葡萄球菌（最低抑菌浓度为80微摩尔/升）和粪肠球菌（最低抑菌浓度为200微摩尔/升）具有抗菌活性，但对革兰氏阴性菌如铜绿假单胞菌无活性。此外，(5Z,9Z)-5,9 -十六碳二烯酸在浓度为800微摩尔/升时完全抑制人拓扑异构酶I，而5,9 -十六碳二炔酸和十六烷酸不抑制拓扑异构酶I（>1000微摩尔/升）。这种比较表明标题化合物中的顺式双键构型是抑制拓扑异构酶I所必需的。此外，这些结果表明(5Z,9Z)-5,9 -十六碳二烯酸对金黄色葡萄球菌或粪肠球菌的抗菌活性至少部分可能是该酸对拓扑异构酶的抑制活性的结果。
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