Inhibitory activity of 8-azadecalin derivatives towards 2,3-oxidosqualene:lanosterol cyclases from baker's yeast and pig's liver.
The inhibitors of 2,3-oxidosqualene:lanosterol cyclase were investigated by comparative studies between pig's liver and Baker's yeast. The fundamental skeleton of the inhibitors was 8-azadecalin. To the nitrogen atom, an isoprenoid-like chain [nerylacetone (Z-form), geranylacetone (E-form) or its hydrogenated form] was attached by the reaction of reductive amination with NaCNBH3. Among the three forms, the Z-isomer was the most potent inhibitors toward both the pig's liver and yeast cyclases. To examine the effect of carbon chain length (lipophilicity), various fatty acids (C6-C18) were appended to the 8-azadecalin derivatives. Strong inhibitory activity was observed for those compounds having carbon chains around C12. Interestingly, the amide compounds (not the carbocationic intermediate) exhibited remarkably strong inhibition toward the liver cyclase, whereas they had an insignificant effect on the yeast cyclase (about 10(2)-fold less active). The yeast cyclase needed the amine functionality (carbocationic intermediate), which was prepared by using LiAlH4 from the corresponding amides, to exhibit potent inhibition. We found that N-dodecyl-8-aza-4,4,10 beta-trimethyl-trans-decal-3 beta-ol (7i) was the most potent inhibitor (IC50 = 1 microM) toward the yeast cyclase amongst any known material. Kinetic studies showed that the inhibition pattern was dependent only on whether the side chains on the 8-azadecalin were linear or branched; the compounds having isoprenoid-like chains were non-competitive inhibitors, while those having linear hydrocarbon chains (amides or amines) were competitive inhibitors.
Hoshino
T
T
Department of Applied Biological Chemistry, Faculty of Agriculture, Niigata University, Japan.
Kobayashi
N
N
Ishibashi
E
E
Hashimoto
S
S
D000818:Animals; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D013552:Swine
D011804:Quinolines; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase