Shealy Y Fulmer, Riordan James M, Frye Jerry L, Simpson-Herren Linda, Sani Brahma P, Hill Donald L
Southern Research Institute, P.O. Box 55305, Birmingham, Alabama 35255-5305, USA.
J Med Chem. 2003 May 8;46(10):1931-9. doi: 10.1021/jm020324t.
The design of analogues of 7,8-dihydroretinoic acid (7,8-dihydro-RA) was based on reported biological activities of this retinoid and its dihydro-TMMP(1) analogue and on structural hypotheses. 7-Oxa-7,8-dihydroretinoids (5, 6) were prepared by O-alkylation of phenoxides by methyl 8-bromo-3,7-dimethyl-2,4,6-octatrienoate. In some cases, C-alkylation also occurred. 7-Aza-8-oxo-7,8-dihydroretinoids (12, 13) were synthesized from benzeneamines and the acyl cyano or bromo derivative of the monomethyl ester of 3,7-dimethyl-2,4,6-octatriene-1,8-dioic acid. These monomethyl ester precursors were synthesized from the known analogous aldehyde via an O-trimethylsilyl cyanohydrin. 7-(2,3,5-Trimethylphenoxy)-3,5-dimethyl-2,4,6-octatrienoic acid (6b) was the most active of the 7-oxa-7,8-dihydro-RAs in inhibiting DMBA-initiated and TPA-promoted mouse-skin papillomas. The ED(50) was about 4-fold that of etretinate. Two additional 7-oxa-7,8-dihydro-RAs exhibited modest activity in the papilloma assay. Some of the 7-oxa-7,8-dihydro-RAs bind to CRABP and RARalpha.
7,8-二氢视黄酸（7,8-二氢-RA）类似物的设计基于该类视黄醇及其二氢-TMMP(1)类似物已报道的生物活性以及结构假说。通过用8-溴-3,7-二甲基-2,4,6-辛三烯酸甲酯对酚盐进行O-烷基化反应制备了7-氧杂-7,8-二氢视黄醇（5, 6）。在某些情况下，也会发生C-烷基化反应。7-氮杂-8-氧代-7,8-二氢视黄醇（12, 13）由苯胺与3,7-二甲基-2,4,6-辛三烯-1,8-二酸单甲酯的酰基氰化物或溴代衍生物合成。这些单甲酯前体由已知的类似醛通过O-三甲基甲硅烷基氰醇合成。7-(2,3,5-三甲基苯氧基)-3,5-二甲基-2,4,6-辛三烯酸（6b）是7-氧杂-7,8-二氢-RA中抑制二甲基苯并蒽（DMBA）引发和佛波酯（TPA）促进的小鼠皮肤乳头瘤活性最强的。半数有效剂量（ED(50)）约为依曲替酯的4倍。另外两种7-氧杂-7,8-二氢-RA在乳头瘤试验中表现出适度活性。一些7-氧杂-7,8-二氢-RA与细胞视黄醇结合蛋白（CRABP）和视黄酸受体α（RARα）结合。
