TY - JOUR
T1 - Azasterols as inhibitors of sterol 24-methyltransferase in leishmania species and Trypanosoma cruzi
AU - Magaraci, Filippo
AU - Jimenez, Carmen
AU - Rodrigues, Carlos
AU - Rodrigues, Juliany C. F.
AU - Braga, Marina Vianna
AU - Yardley, Vanessa
AU - de Luca-Fradley, Kate
AU - Croft, Simon L.
AU - de Souza, Wanderley
AU - Ruiz-Perez, Luis M.
AU - Urbina, Julio
AU - Pacanowska, Dolores Gonzalez
AU - Gilbert, Ian H.
PY - 2003/10/23
Y1 - 2003/10/23
N2 - This paper describes the synthesis of some novel azasterols based on (20R,22xi)-5alpha-pregnan-20-(piperidin-2-yl)-3ß,20-diol. These compounds are potential inhibitors of the enzyme sterol 24-methyltransferase (24-SMT), which is a vital enzyme in the biosynthesis of ergosterol and related 24-alkyl sterols. Structure-activity studies were undertaken to understand the important features for activity against the enzyme, with the aim of increasing activity and selectivity. The compounds were evaluated for inhibition of recombinant Leishmania major 24-SMT and the effect of compounds on sterol composition and parasite proliferation. Essentially, compounds which showed good activity against the recombinant enzyme had a significant effect on the sterol composition and growth of parasites. The activity of compounds was found to be related to the basicity and stereochemical location of the nitrogen. Also, presence of an unprotected 3ß-OH seemed to be important for activity. However, some azasterols which were not good inhibitors of 24-SMT also showed antiproliferative activity, suggesting that there may be other modes of actions of these compounds.
AB - This paper describes the synthesis of some novel azasterols based on (20R,22xi)-5alpha-pregnan-20-(piperidin-2-yl)-3ß,20-diol. These compounds are potential inhibitors of the enzyme sterol 24-methyltransferase (24-SMT), which is a vital enzyme in the biosynthesis of ergosterol and related 24-alkyl sterols. Structure-activity studies were undertaken to understand the important features for activity against the enzyme, with the aim of increasing activity and selectivity. The compounds were evaluated for inhibition of recombinant Leishmania major 24-SMT and the effect of compounds on sterol composition and parasite proliferation. Essentially, compounds which showed good activity against the recombinant enzyme had a significant effect on the sterol composition and growth of parasites. The activity of compounds was found to be related to the basicity and stereochemical location of the nitrogen. Also, presence of an unprotected 3ß-OH seemed to be important for activity. However, some azasterols which were not good inhibitors of 24-SMT also showed antiproliferative activity, suggesting that there may be other modes of actions of these compounds.
U2 - 10.1021/jm021114j
DO - 10.1021/jm021114j
M3 - Article
SN - 0022-2623
VL - 46
SP - 4714
EP - 4727
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 22
ER -