Base-catalyzed isomerization of retinoic acid. Synthesis and differentiation-inducing activities of 14-alkylated all-trans-, 13-cis-, and 20,14-retro-retinoic acids.
Retinoic acid (1) is isomerized regioselectively by excess amounts of lithium diisopropylamide (LDA) to give 20,14-retro-retinoic acid (3). Alkylation of the intermediate dianion of retinoic acid gave 14-alkylated derivatives of 3. By isomerization of the alkylated retro isomers under basic conditions, several 14-alkyl-all-trans- and -13-cis-retinoic acids were synthesized. The retinoidal activities of these derivatives were examined, based on the ability to induce differentiation of human promyelocytic leukemia cell line HL-60. 20,14-retro-Retinoic acid (3) is 1/50 as active as retinoic acid (1). Although 14-methyl-20,14-retro-retinoic acid (4) is as active as 3, the introduction of a 14-methyl group into all-trans- and 13-cis-retinoic acid resulted in decreased activity. Introduction of bulkier alkyl groups at the C-14 position caused the disappearance of the activity.
Tanaka
H
H
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Kagechika
H
H
Kawachi
E
E
Fukasawa
H
H
Hashimoto
Y
Y
Shudo
K
K
D000478:Alkylation; D002454:Cell Differentiation / Q000187:drug effects*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D014212:Tretinoin