2,3-Epoxy-10-aza-10,11-dihydrosqualene, a high-energy intermediate analogue inhibitor of 2,3-oxidosqualene cyclase.
2,3-Epoxy-10-aza-10,11-dihydrosqualene, a high-energy intermediate analogue inhibitor of 2,3-oxidosqualene (SO) cyclase was obtained by total synthesis. This involved the preparation of three main building blocks: (1) C17 squalenoid N-methylamine, (2) 3-(diphenylphosphinoyl)propanal, and (3) 5,6-epoxy-6-methylheptan-2-one. The final stages of the reconstruction of the 6E double bond were obtained by a Wittig-Horner reaction which was modified for poorly reactive systems. This compound was designed to mimic the C-8 carbonium ion formed during SO cyclization. Its inhibitory activity on various SO cyclases was evaluated and compared with the 6 Z isomer which has an unfavorable geometry. Only isomer 6 E, the carbocation analogue, was active on SO cyclases from rat liver, pig liver, S. cerevisiae, and C. albicans microsomes, with an I50 varying from 3 to 5 microM. Both E and Z isomers were inactive on squalene epoxidase at the higher concentrations tested.
Ceruti
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M
Istituto di Chimica Farmaceutica Applicata, Facoltà di Farmacia, Torino, Italy.
Balliano
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G
Viola
F
F
Grosa
G
G
Rocco
F
F
Cattel
L
L
D000818:Animals; D002176:Candida albicans / Q000201:enzymology; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology*; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013185:Squalene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013552:Swine
D004852:Epoxy Compounds; C076124:2,3-epoxy-10-aza-10,11-dihydrosqualene; D013185:Squalene; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase