ABSTRACT
Ethyl (E,Z,E,E)-3,7-dimethyl-4-fluoro-9-(4-methoxy-2,3,6-trimethylphenyl)nonatetraenoate (10a) has been found to cause a marked regression of chemically induced skin papillomas in mice. A new synthesis of this compound was achieved by condensation of 4-fluoro aldehyde 7 or 8 with the aromatic phosphonium salt 9a. Several analogues (101-e) having different substituted aromatic moieties were also prepared and tested for their antipapilloma effect. The monochloro analogue 10b was shown to have comparable activity to the parent compound 10a.
Subject(s)
Antineoplastic Agents/chemical synthesis , Tretinoin/analogs & derivatives , Animals , Chemical Phenomena , Chemistry , Hypervitaminosis A , Mice , Neoplasms, Experimental/drug therapy , Papilloma/drug therapy , Tretinoin/chemical synthesis , Tretinoin/pharmacologyABSTRACT
(4-Methoyx-2,3,6-trimethylphenyl)nonatetraenoic acids, esters, and amides (analogues of retinoic acid) bearing a fluorine atom(s) or a trifluoromethyl group on the polyene side chain were synthesized. The biological activities of these compounds and of 10-, 12-, and 14-fluororetinoic acid esters were evaluated in vivo in a chemically induced mouse papilloma test; the toxicities were assessed in an in vivo mouse hypervitaminosis A test. Antipapilloma activity greater than the parent nonfluorinated ester was found for 1c (ethyl 12-fluororetinoate) and 23 and 39 (aromatic 4- and 6-fluororetinoid esters, respectively). A similar increase in antipapilloma activity was observed for 71 and 72, the aromatic 4- and 6-fluororetinoic acids, respectively, relative to 2 and for 73 (aromatic 4-fluororetinoid amide) relative to 4.
