环孢菌素A衍生物的合成及其生物学活性研究-药理学专业论文.docxVIP

摘要环孢菌素A衍生物的合成及其生物学活性研究 摘要 环孢菌素A衍生物的合成及其生物学活性研究 摘要 环孢菌素A(CsA)已作为免疫抑制剂广泛应用于器官移植时的抗排斥反 应，在抗真菌、抗寄生虫、抗HIV、抗炎以及逆转肿瘤细胞多药耐药等方面也 有一定的作用。CsA免疫抑制活性的构效关系研究表明其结构中1位上的氨基 酸 MeBmt((2S,3R，4R，6毋．3．羟基-4-甲基-2-甲氨基．6一辛烯酸)对环孢菌素A的生 物学活性起着重要的作用，也是环孢菌素A化学结构修饰的一个重要位点。本 研究以MeBmt作为结构修饰的位点，开展了以下工作： 1．合成并分离纯化了未见文献报道的12个CsA衍生物。对专利文献报道 的合成方法进行改良，提高了收率和简化了反应步骤。 2．建立了以硅胶柱色谱、高速逆流色谱和高效液相色谱等现代分离技术为 主的分离纯化方法，对合成得到的化合物进行了有效而快速的纯化。通过质谱、 红外光谱和核磁共振进行了结构确认。 3．研究合成的化合物对淋巴细胞转化的抑制活性。结果表明合成的CsA衍 生物对淋巴细胞转化的抑制活性均低于环孢菌素A。但这些基团改变后的衍生 物之间抑制活性有明显的变化，初步讨论了他们的构效关系。 J4．研究合成的化合物对真菌的生长抑制活性。结果表明CsA衍生物的抗真 菌谱窄，只对少数真菌有作用，有些化合物对某些特定菌有较强的抑制作用。 关键词：环孢菌素A衍生物 免疫抑制活性 抗真菌活性 摘要Synthesis 摘要 Synthesis and Biological Activities of Cyclosporin A Derivatives Abstract cyclosporin A(CsA)as an important immunosuppressive agent has been widely used in organ transplantation．It has other biological activities such as antifungal， anti-parasite and anti·virus activities and SO on． Structrue．activity relationship(SAR)studies of CsA show that the special amino acid-一一(2S，3R， 4R,6E)一3-hydroxy-4-methyl一2一methylamino一6一octenoic acid(MeBmt)in position 1 of CsA plays a crucial role in immunosuppressive and other biological activities． Therefore MeBmt Can be chosen as an important modifing target in the semi—synthesis of CsA derivatives．CsA derivatives with chemical modifications Oil the MeBmt were synthesized and some of their biological activities were tested． The work was included in the followings： 1．Twelve new CsA derivatives were synthesized and the synthetic routes were modified to increase reaction yield and simplify procedure． 2．Silica gel column chromatograph,HPLC，HSCCC衄咖跗锄counterctment chromatography)and other isolation and purification methods were established for the efficient separation of synthetic compounds．The chemical structures of these compounds were identified by spectrometric methods such as MS，IR and NMR． 3．The immunosuppressive activities of these synthetic compounds were．tested and the results showed that immunosuppressive activ