AZULENIC RETINOIDS - NOVEL NONBENZENOID AROMATIC RETINOIDS WITH ANTICANCER ACTIVITY

Several novel azulene-containing retinoids were prepared and evaluated for their ability to suppress carcinogen-induced neoplastic transform ation and to concomitantly up-regulate gap junctional communication in the in vitro mouse fibroblast C3H/10T1/2 cell bioassay. The azulenic retinoids were divided into two groups: compounds 1-6 were modeled aft er retinoic acid with flexible polyenic side chain whereas retinoids 7 -13 featured a benzoic acid moiety analogous to the prototypic retinob enzoate 8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TTNPB ). Within this latter group the side chains for compounds 7, 10, and 1 1 were attached at the 1-, 2-, and 8-positions of the azulenic terminu s, respectively. Biological activities were determined for all the new compounds. Two of these novel retinoids, azulenic retinobenzoic acid derivatives 7 and 11, were completely effective inhibitors of transfor mation at 10(-6) M. The most active azulenic retinoids also enhanced g ap junctional communication in untransformed cells; this was associate d with up-regulated expression of connexin 43, a structural protein of the gap junction. Two fluorinated analogs were also tested. The azule nic fluoro acid 5 was found to be more potent than the trifluoromethyl analog 6. Azulenic analogs with hydroxyl or carboxaldehyde side chain functional groups were ineffective transformation inhibitors. In gene ral, azulenic retinobenzoic acid analogs structurally akin to TTNPB we re more effective than flexible side chain analogs related to retinoic acid.