The Research On The Synthesis And Characterization Of Retinoyl Sugar Derivatives

Retinoids play an essential role in vertebrate growth and development, supporting cell differentiation; embryonic development, vision, the immune response and reproduction. All-trans-retinoic acid(2, ATRA), 13-cis-retinoic acid(3, 13-c-RA) as well as other retinoids are currently used for treatment of dermatological disorders and certain types of cancer. The actions of retinoids are mediated through binding and activation of the retinoic acid receptors (RARs) or retinoid X receptors (RXRs), which function as ligand-dependent transcription factors. Unfortunately, Retinoids, including retinoic acids, have been found to be too toxic at high dosage levels to be of practical value for cancer prevention in higher mammals. Therefore development of retinoid analogues possessing a higher therapeutic index is of interest. Carbohydrates are a large group of biomolecules which are distributed widely in nature and involved in a great variety of physiological and pathological processes. Sugar modification can decrease the toxicity and increase absorption of some nature drugs. Nowadays , synthesis of sugar compounds to modify nature drugs has become an important field of pharmaceutical chemistry.In order to decrease toxicities of retinods and enhance pharmacal effects and gain the relative derivatives with better curing effect and selectivity, structures of retinoic acids were modified by inducing glycosyl groups in this paper. Nine glucuronide conjugates(6a~6d, 7, 9a, 17a, 17b, 21) of 13-cis-retinoic acid and 4-oxo-13-cis-retinoic acid were synthesized in three ways and not reported in literatures until now.In one way, the relative glycosyl esters(6a~6d) of 13-cis-retinoic acid were prepared by the reaction of O-acetylglucopyranosyl bromide, O-acetylxylopyranosyl bromide, O-acetyllactosyl bromide and O-acetylmaltobiosyl bromide with 13-cis-retinonic acid in the presence of potassium hydroxide and 4-dimethylaminopyridine (DMAP) as phase transfer catalyst in 53 ~ 65 % yields. This method has advantages of mild reaction conditions, easy seperation of products and high stereospecificity. l-0-(4-oxo-retinoyl)-2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranose(7) was synthesized by oxidizing 6a with manganese dioxide in 66.5 % yields.In second way, 6-O-13-c/s-retinoyl-1, 2 ' 3, 4-diisopropenegalactose(9a) was obtained from the reaction of 13-cis-retinonic acid with 1, 2 : 3, 4- diisopropenegalactose(8a) when N, N'-dicyclohexyl carbodiimide (DCC) and DMAP existing in 73% yield. After investigating various reaction conditions, a new synthetic method with mild reaction conditions was built up to synthesize retinoates from 13-cis-retinoic acid by use of dicyclohexylcarbodiimide...