【作者】 易卫国；

【导师】 向建南；

【作者基本信息】 湖南大学 ， 化学工程， 2006， 硕士

【摘要】 类维生素A在脊椎动物的生长、发育、促进细胞分化、胚胎发育、视觉、免疫反应以及繁殖等过程中发挥十分重要的作用。类维生素A的两种重要化合物——全反式维A酸(ATRA)和异维A酸(13-c-RA)已临床用于治疗皮肤病和某些癌症。类维A酸受体(RAR)和类维A酸X受体(RXR)是配体依赖的转录因子,研究表明类维生素A是通过与之结合并激活受体而表现活性并发挥作用的。遗憾的是,类维生素A因在高剂量使用时毒性太强,而难以发挥其在高级哺乳动物癌症预防方面的实际价值。因而寻找具有更高治疗效果的类维生素A衍生物引起人们的极大兴趣。本论文主要进行13-cis-维A酰衍生物的合成新方法研究,取得了以下主要研究结果:1.考察了多个不同反应条件的基础上,建立了以二环己基碳酰亚胺(DCC)为脱水剂、4-二甲氨基吡啶(DMAP)为催化剂合成异维A酸酯的条件温和的合成方法。并以DCC- DMAP法成功合成了5个异维A酸酯(1a～1e)2.改进了DCC缩合法,即改用DMAP·PTSA替代DMAP作为DCC缩合法的催化剂,并应用该方法合成了化合物3a～3g。该方法有效地抑制了生成N-异维A酰基脲的副反应。同时由于该反应在室温和几乎中性的pH下进行,因此非常适用于含共轭多烯链的醇、胺或酸的酯化。3.根据生物活性羧酸甲二酯前药的特殊生理活性,设计合成了四种结构对称的RA甲二酯前药6～9。由于合成的甲二酯分子6～9在细胞内由酯酶催化水解能生成两分子RA和一分子甲醛,而水解释放的甲醛也是一个很重要的抗增生因子,因此我们预计这类RA甲二酯将比RA具有更好的疗效和更少的副作用。此外本文还拓展了一种甲二酯合成的新方法。该方法应用于RA甲二酯的合成,产率较高,操作简单,而且产物构型均保持不变,结果令人满意。其它具有类似共轭多烯链结构的羧酸的酯化也可以采用该法。本论文共合成化合物20个。用核磁共振谱(1H NMR、13C NMR)、红外(IR)和质谱(MS)对所合成的异维A酸衍生物进行了结构表征与确认,生物活性测试工作正在进行中。更多还原

【Abstract】 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.更多还原