Conformationally restricted retinoids

Abstract

A series of conformationally restricted retinoids was synthesized and screened in 2 assays used to measure the ability of retinoids to control cell differentiation, i.e., the reversal of keratinization in tracheal organ culture from vitamin A deficient hamsters and the inhibition of the induction of mouse epidermal ornithine decarboxylase by a tumor promoter. These compounds had bonds corresponding to selected bonds of the E-tetraene chain of retinoic acid (1) held in a planar cisoid conformation by inclusion in an aromatic ring. The m-substituted analog 3 of 4-[(E)-2-methyl-4-(2,6,6-trimethylcyclohexenyl)-1,3-butadienyl]benzoic acid (2) was far less active than 2 in both assays. The vinyl homologue of 2 (4) and the 7,8-dihydro and 7,8-methano analogs had activity comparable to that of 2. Analogs of 4-[(E)-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-6-naphthyl)propenyl]benzoic acid (7) were also screened. Replacement of the tetrahydronaphthalene ring of 7 by a benzonorbornenyl group (9) significantly reduced activity, as did removal of the vinylic methyl group from 9. Replacement of the propenyl group of 9 by a cyclopropane ring (12) also reduced activity. Replacement of the tetrahydronaphthalene ring of 7 by 4,4-dimethyl-3,4-dihydro-2H-1-benzopyran and -benzothiopyran rings (13 and 14 [4,4-dimethyl-6-[(E)-1-(4-carboxyphenyl)-1-propen-2-yl]-3,4-dihydro-2H-1-benzothiopyran]) also decreased activity. Inclusion of the 7,9 double bond system of 1 in an aromatic ring reduced activity, whereas inclusion of the 5,7 double bond system in an aromatic ring enhanced activity (7). Inclusion of the 11,13 and 9,11,13 double bond systems in aromatic rings (2) also reduced activity below that of 1. Retinoic acid, 7 13 and 14 inhibited papilloma tumor formation in mice. Toxicity testing indicated that 7 was more toxic than 1, 13 and 14; 13 and 14 were less toxic than 1.