Synthesis, molecular modeling, and evaluation of nonphenolic indole analogs of mycophenolic acid.
Based on the promising activity of an indole-3-carboxamide derivative, a nonphenolic analog of mycophenolic acid (MPA), we report herein the synthesis of a compound containing two important features for the activity of MPA, the ring methoxy and methyl. The synthesis was accomplished using two strategies; a method dependent on stepwise building of the hexenoate side chain followed by the indolecarboxamide ring system, and a convergent route that depended on 1,3-sigmatropic rearrangement as a key step. Docking experiments on both Chinese Hamster and Human Type-II inosine monophosphate dehydrogenase (IMPDH) showed that this compound has potential binding interactions with the NAD site. The analogs showed no activity against MCF7-S, MCF7-R, or IGR-OV1 cancer cells.
El-Araby
Moustafa E
ME
School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, 14260 USA. melaraby@prdus.jnj.com
Bernacki
Ralph J
RJ
Makara
Gergely M
GM
Pera
Paula J
PJ
Anderson
Wayne K
WK
D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D006224:Cricetinae; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D013329:Structure-Activity Relationship
D007211:Indoles; D009243:NAD; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid