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 transformation 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 after retinoic acid with flexible polyenic side chain whereas retinoids 7-13 featured a benzoic acid moiety analogous to the prototypic retinobenzoate (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-1-propenyl]benzoic acid (TTNPB). Within this latter group the side chains for compounds 7, 10, and 11 were attached at the 1-, 2-, and 8-positions of the azulenic terminus, 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 transformation at 10(-6) M. The most active azulenic retinoids also enhanced gap junctional communication in untransformed cells; this was associated with up-regulated expression of connexin 43, a structural protein of the gap junction. Two fluorinated analogs were also tested. The azulenic 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 general, azulenic retinobenzoic acid analogs structurally akin to TTNPB were more effective than flexible side chain analogs related to retinoic acid.
Asato
A E
AE
Chemistry Department, University of Hawaii at Manoa, Honolulu 96822.
Peng
A
A
Hossain
M Z
MZ
Mirzadegan
T
T
Bertram
J S
JS
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052176:Azulenes; D002478:Cells, Cultured; D003198:Computer Simulation; D003508:Cycloheptanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008958:Models, Molecular; D012176:Retinoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D052176:Azulenes; D003508:Cycloheptanes; D012176:Retinoids; C005525:azulene