Synthesis and evaluation of some new retinoids for cancer chemoprevention.
Many derivatives and analogs of the natural vitamin A compounds have been synthesized, and some of these retinoids are very active in various bioassays that may be predictive for cancer chemopreventive activity. Analogs have been synthesized in which parts of one, or more, of the three traditional subdivisions of the retinoid structure--the terminal polar group, the conjugated side chain, and the cyclohexenyl region--have been altered or replaced. In addition, structural alterations have produced compounds (arotinoids) in which two, or more, aromatic rings replace much of the classical retinoid structure. Further structural modifications that effected replacement of the entire retinoid structure by aromatic groups and certain linking groups have been made. Some of the arotinoids and further structural variants, which appear superficially to represent immense alteration of the classical retinoid structure, have potent activity in various retinoid bioassays. Four types of new classical retinoids (retinoylamino acids, bifunctional analogs, retinyl ethers, and 4-oxoretinoid derivatives) have been synthesized and evaluated in our laboratories. All-trans- and 13-cis-retinoyl alpha-amino acids are active in a hamster trachea organ culture assay and show much promise in potentiating immune responses. Retinoic acid analogs that have a bifunctional terminus bind to CRABP even though they have a bulky alpha-substituent, induce differentiation of F9 embryonal carcinoma cells, and have good activity in an immune-potentiation assay. A new retinyl either, retinyl propynyl ether, has chemopreventive activity against mammary carcinogenesis in vivo. Oral administration of this retinoid produces high and sustained concentrations in the rat mammary gland. New congeners of 4-oxoretinoic acid demonstrate high activity in a spectrum of bioassays.
Shealy
Y F
YF
Medicinal Chemistry Division, Southern Research Institute, Birmingham, Alabama 35255.
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006224:Cricetinae; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000517:prevention & control*; D051381:Rats; D012176:Retinoids / Q000627:therapeutic use*
D012176:Retinoids