Synthesis and modeling studies with monocyclic analogues of mycophenolic acid.
Two stepwise procedures, developed for the introduction of the (E)-4-methyl-4-hexenoic acid side chain of mycophenolic acid, were used in the synthesis of monocyclic mycophenolic acid analogues 2a-i. The derivatives with a methyl group or hydrogen at C-4 and lacking the lactone moiety were much less cytotoxic than mycophenolic acid. The monocyclic analogues with a C-4 chloro group did show some activity, albeit much less than mycophenolic acid. The observed differences in potency are rationalized by semiempirical calculations of intramolecular H-bonds.
Anderson
W K
WK
Department of Medicinal Chemistry, School of Pharmacy, State University of New York at Buffalo 14260, USA.
Boehm
T L
TL
Makara
G M
GM
Swann
R T
RT
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007939:Leukemia L1210; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid