Study On The Novel Synthetic Methods Of 13-cis-retinoic Acid 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(ATRA), 13-cis-retinoic acid(13-c-RA) as well as other retinoids are currently used for treatment of dermatological disorders such as acne, keratinizing skin disorders and certain types of cancer including breast, lung, liver, skin and endometrial 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 and treatment of dermatological disorders in higher mammals. They can cause a number of detrimental side effects such as teratogenicity, headache and mucocutaneous toxicity. Therefore development of retinoid analogues possessing a higher therapeutic index is interesting to chemists. The aim of this thesis is to study on the novel synthetic methods of 13-cis-retinoic acid derivatives. The main results were summarized as follows:1. 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(DCC) as reagent under catalysis of 4-dimethyl amino- pyridine(DMAP). Five retinoates(1a～1e) have been synthesized by using the DCC-DMAP method.2. An improved DCC condensation with DMAP p-toluenesulfonate substitute DMAP as the catalyst was described and applied to the synthesis of 13-cis-RA derivatives 3a～3g. 3a～3g were obtained in 80%-95% yields and in high isomeric purity. The side reaction that converts 13-cis-RA to unreactive N-retinoylurea was completely suppressed. The reaction proceeds under mild conditions and is favored in the acylation of alcohol, amine and carboxylic acid.3. On the basis of the special physiological activity of methylene diester prodrugs of biologically active carboxylic acids, methylene diesters (6～9) of RAs were designed and synthesized. Because of that one methylene diester can release two RAs and one formaldehyde by intracellular esterase catalyzed hydrolysis and the released formaldehyde has a pivotal role in inhibiting cancer cell proliferation, it was expected that this type of prodrug will possess higher activity and lower side-effect than the parent RA. A new method for synthesis of methylene diester was also developed. 6~9were obtained in good yield and in unchanged conformation in part of the unsaturated acyl by using this new method. This method can also was used to esterification of other carboxylic acids with unsaturated polyene structure.20 compounds have been synthesized in this thesis. Their structures were characterized and confirmed by IR, 1H NMR, 13C NMR and MS spectra. The bioactivities of them have been evaluating in our lab.