Inhibition of papilloma formation by analogues of 7,8-dihydroretinoic acid.
Abstract |
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.
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Authors | Y Fulmer Shealy, James M Riordan, Jerry L Frye, Linda Simpson-Herren, Brahma P Sani, Donald L Hill |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 46
Issue 10
Pg. 1931-9
(May 08 2003)
ISSN: 0022-2623 [Print] United States |
PMID | 12723955
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- 7-(2,3,5-trimethylphenoxy)-3,5-dimethyl-2,4,6-octatrienoic acid
- Anticarcinogenic Agents
- Fatty Acids, Unsaturated
- Rara protein, mouse
- Receptors, Retinoic Acid
- Retinoic Acid Receptor alpha
- retinoic acid binding protein I, cellular
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Topics |
- Animals
- Anticarcinogenic Agents
(chemical synthesis, chemistry, pharmacology)
- Fatty Acids, Unsaturated
(chemical synthesis, chemistry, pharmacology)
- Mice
- Papilloma
(prevention & control)
- Protein Binding
- Receptors, Retinoic Acid
(metabolism)
- Retinoic Acid Receptor alpha
- Skin Neoplasms
(prevention & control)
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