Total synthesis and biological evaluation of (5Z,9Z)-5,9-hexadecadienoic acid, an inhibitor of human topoisomerase I.
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.
Carballeira
Néstor M
NM
Department of Chemistry, University of Puerto Rico, PO Box 23346, San Juan, Puerto Rico 00931-3346. ncarball@upracd.upr.clu.edu
Betancourt
José E
JE
Orellano
Elsie A
EA
González
Fernando A
FA
D000478:Alkylation; D004247:DNA / Q000187:drug effects*; D004587:Electrophoresis, Agar Gel; D013293:Enterococcus faecalis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013055:Spectrophotometry, Infrared; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D059004:Topoisomerase I Inhibitors
D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D059004:Topoisomerase I Inhibitors; C049916:5,9-hexadecadienoic acid; D004247:DNA