Inhibition of papilloma formation by analogues of 7,8-dihydroretinoic acid.
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.
Southern Research Institute, P.O. Box 55305, Birmingham, Alabama 35255-5305, USA. muglach@sri.org
Y Fulmer
YF
Shealy
James M
JM
Riordan
Jerry L
JL
Frye
Linda
L
Simpson-Herren
Brahma P
BP
Sani
Donald L
DL
Hill
D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D010212:Papilloma / Q000517:prevention & control*; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D012878:Skin Neoplasms / Q000517:prevention & control*
C474572:7-(2,3,5-trimethylphenoxy)-3,5-dimethyl-2,4,6-octatrienoic acid; D016588:Anticarcinogenic Agents; D005231:Fatty Acids, Unsaturated; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C082927:retinoic acid binding protein I, cellular