Conformationally restricted retinoids

Abstract

A series of conformationally restricted retinoids was synthesized and screened in two assays used to measure the ability of retinoids to control cell differentiation, namely, 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 meta-substituted analogue 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. In contrast, the vinyl homologue of 2 (4) and the 7,8-dihydro and 7,8-methano analogues (5 and 6) had activity comparable to that of 2. Analogues 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 (10). 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) also decreased activity. Inclusion of the 7,9 double bond system of 1 in an aromatic ring (15 and 16) reduced activity, whereas inclusion of the 5,7 double bond system in an aromatic ring enhanced activity (7 and 19). Inclusion of the 11,13 and 9,11,13 double bond systems in aromatic rings (2 and 18) also reduced activity below that of 1. Retinoic acid, 7, 13, 14, and 19 inhibited papilloma tumor formation in mice. Toxicity testing indicated that 7 was more toxic than 1, 13, 14, and 19, 19 was more toxic than 1, and 13 and 14 were less toxic than 1.

Novel Heteroarotinoids as Potential Antagonists of Mycobacterium bovis BCG

“…After the addition, the reaction mixture was allowed to warm to room temperature and was then stirred (24 h). The solvent was evaporated, and the resulting solid was recrystallized (pentane: HCCl 3 20 (16.00 g, 90.8 mmol) dissolved in THF (10 mL), and the resulting mixture was stirred at reflux for 4 days. The mixture was allowed to cool to room temperature and then was cooled to 0°C (ice bath).…”

Enhancement of Calu-1 human lung carcinoma cell growth in serum-free medium by retinoids: dependence on AP-1 activation, but not on retinoid response element activation

“…Retinol; retinal; ATRA; 13-cis-RA; 9-cis-RA; 4- (5,6,7,8-tetrahydro -5,5,8,8 -tetramethyl -2-naphthalenylcarbamoyl) benzoic acid (Am80) (Kagechika et al, 1989) and 6-(5,6,7,8 -tetrahydro -5,5,8,8 -tetramethyl-2-naphthalenyl)-2-naphthalenecarboxylic acid (TTNN) (Dawson et al, 1983) were provided by Dr Werner Bollag (F Homann-La Roche, Basel, Switzerland); 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437) (Bernard et al, 1992); (E)-4-{2-[3-(1-adamantyl)-4-hydroxyphenyl] propenyl}benzoic acid (CD2325); (E)-7-[3-(1-adamantyl)-4-methoxyphenyl]-3-methylocta-2,4,6-trienoic acid (CD2366) were provided by Drs Braham Shroot and Uwe Reichert (CIRD/Galderma, Valbonne, France); N-(4-hydroxyphenyl)retinamide (4HPR) was provided by Dr Ronald Lubet (Chemoprevention Branch, National Cancer Institute, Bethesda, MD); 6-(3-hydroxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naphthalenecarboxylic acid (SR11363) (Dawson et al, 1995a);6-(5,6,7,8-tetrahydro -3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-naphthalenecarboxylic acid (SR3985) (Dawson et al, 1983), 4-[2-methyl -1-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)propenyl] benzoic acid (SR11217) (Lehmann et al, 1992); 2 -(4 -carboxyphenyl) -2 - (5,6,7,8, -tetrahydro -5,5,8, 8-tetramethyl -2 -naphthalenyl) -1,3 -dithiolane (SR11234) (Lehmann et al, 1992;Dawson et al, 1995b); and 2-(4-carboxyphenyl) -2 -(3,4 -dihydro -4,4-dimethyl-2H-1-benzopyran-6-yl)-1,3-dithiane (SR11238) were synthesized as reported. 5,5,8,6,7,ethenyl]benzoic acid (LG1-069) (Boehm et al, 1994) was provided by Dr Richard A Heyman (Ligand Pharmaceuticals, San Diego, CA).…”

Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists

“…Early efforts to improve the therapeutic ratio involved constraining the RA double-bonds, by inclusion in an aromatic ring of chemical structures called arotinoids. The first arotinoid evaluated, TTNPB, was 10-fold more potent than RA in biological assays of efficacy, but considerably more toxic [9][10][11][12].…”