Lanopylins A1, B1, and B2, novel lanosterol synthase inhibitors from Streptomyces sp. K99-5041

Abstract

From an actinomycete strain, Streptomyces sp. K99-5041, lanopylins A1, B1, A2 and B2 were isolated as new natural products that inhibited the reaction of recombinant human lanosterol synthase. The crude extract from the whole broth of this strain was fractionated by silica gel column chromatography to afford an active fraction that showed a single spot on TLC. Detailed analyses of this fraction with liquid chromatography-atmospheric pressure chemical ionization mass spectrometry revealed that it contained 20 homologous compounds with differing side chain lengths. The fraction was separated by preparative HPLC to afford four of these homologues, lanopylins A1, B1, A2 and B2. Detailed spectroscopic analyses of these isolated compounds led to the identification of their structures. Lanopylins A1 and B1 were (3E -isohexadecylmethylidene-2-methyl-1-pyrroline and (3E -hexadecylmethylidene-2-methyl-1-pyrroline, respectively, and lanopylins A2 and B2 were homologues with the insertion of one cis-ethylenylidene in the side chain of lanopylins A1 and B1, respectively. These compounds inhibited recombinant human lanosterol synthase with IC50 values of 15, 18, 33, and 41 μM, respectively.