本文選題：喜樹堿　切入點：半合成　出處：《東北林業(yè)大學》2014年碩士論文

【摘要】：喜樹堿(Camptothecin, CPT)是從中國喜樹(Camptotheca acuminata)中分離得到的天然生物堿,由于具有較強的抗腫瘤活性和獨特的拓撲異構(gòu)酶抑制機制而受到了廣泛的關(guān)注。喜樹堿E環(huán)的內(nèi)酯結(jié)構(gòu)極易斷裂而產(chǎn)生強的毒性。 本研究旨在20(S)-OH上引入取代基團以增強內(nèi)酯結(jié)構(gòu)穩(wěn)定性,降低喜樹堿的毒副作用。在喜樹堿20位引入N-乙酰二肽酰和N端不同酰胺基保護的甘氨酰得到一系列喜樹堿酯類衍生物,另外還在甲氧基喜樹堿20位引入N-乙酰氨基酰得到兩種衍生物；利用核磁共振和質(zhì)譜等分析方法進行了結(jié)構(gòu)鑒定。 采用MTT法進行體外抗腫瘤活性篩選,結(jié)果表明所合成的新化合物對人卵巢癌細胞系(2774)、人前列腺癌細胞系(DU145)、人胰腺癌細胞系(MPC2)均有良好的抑制活性。與母體化合物相比,大部分衍生物的體外抗腫瘤活性均有所降低,但化合物13體外細胞毒活性優(yōu)于母體化合物,化合物4、8、12、14的抗腫瘤活性則與母體化合物CPT相當；除化合物14、16、17外,其它衍生物對于人前列腺癌細胞系毒性也有所降低；對人卵巢癌細胞系2774,化合物12、13、14的體外活性比母體化合物略差,化合物17的體外活性則優(yōu)于母體化合物HCPT。所合成的化合物可進一步用于體內(nèi)安全性評價。
[Abstract]:Camptothecin (CPT) is a natural alkaloid isolated from Camptotheca acuminata. it has attracted wide attention because of its strong antitumor activity and unique topoisomerase inhibition mechanism.The lactone structure of camptothecin E ring is easy to break and produce strong toxicity.The aim of this study was to introduce substituents into 20(S)-OH to enhance the structural stability of lactones and to reduce the toxicity and side effects of camptothecin.A series of camptothecin derivatives were obtained by introducing N-acetyldipeptidyl and N-terminal glycosyl protected at the 20 position of camptothecin, and two derivatives were obtained by introducing N-acetyl aminoacyl at the 20 position of methoxycamptothecin.The structure was identified by nuclear magnetic resonance (NMR) and mass spectrometry (MS).MTT assay was used to screen the antitumor activity in vitro. The results showed that the new compounds had good inhibitory activity against human ovarian cancer cell line, human prostate cancer cell line DU145and human pancreatic cancer cell line MPC2.The in vitro antitumor activity of most derivatives was lower than that of the parent compound, but the cytotoxic activity of compound 13 was superior to that of the parent compound.The synthesized compounds can be further used to evaluate the safety in vivo.
【學位授予單位】：東北林業(yè)大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R914.5

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本文編號：1695167