紫杉醇C-2位结构改造及构效关系研究
摘要
紫杉醇(paclitaxel)最初是从短叶红豆杉(也称太平洋紫杉)的树皮中分离出的抗肿瘤活性成分,因其独特的作用机理和良好的抗癌临床效果,被认为是二十世纪抗癌药研究的重要成就之一。广泛应用于治疗转移和复发性卵巢癌和乳腺癌,肺癌、食道癌、胃癌等多种癌症。近年又发现紫杉醇的其他作用,例如治疗艾滋病并发的卡波济氏肉瘤,和治疗心脏冠状动脉再狭窄等疾病。但是在紫杉醇的开发过程中,紫杉醇的药源问题和水溶性成为其广泛应用的制约因素。
紫杉醇的构效关系研究是紫杉醇化学研究最活跃的领域。我们可以通过对其化学结构的改造修饰,得到易溶于水,抗癌活性高,毒副作用低的新型紫杉醇类似物。我们利用一个已知的紫杉烷类化合物7-表-10-去乙酰紫杉醇作为起始物,选择性脱除C-13侧链,对其母核进行一系列改造,在C-2位形成2位甲磺酸酯以及1,2β环氧化物的混合物20&21。
通过一个邻基参与的双SN2亲核取代反应对所形成的1,2-β环氧中间体开环,合成2位各种杂原子取代的紫杉醇类似物,如2位硫羟基苯甲酸酯,苄基硫醚取代,2位苯甲酰胺,苄胺取代,2位苄醚取代的紫杉醇类似物。OAc OOTESHO OMsOOAcOOAc OOTESO OOAcSN2 OSN2OAc OOTESHO OOAcONuNuHOOAcOOHS AcOOOXOPhOH32 R = Bz, X = HRNH33 R = Boc, X = H34 R = Bz, X = O35 R = Boc, X = O HOOAcOOHXAcOOOOPhOH40 R = Bz, X =ORNH41 R = Boc, X = O42 R = Bz, X = N43 R = Boc, X = N同时发现了合成1,2位亚硫酸酯取代的巴卡亭类似物49的新合成法并推测了其反应机理。HOOAcOOTESHOAcOOTESO48OOAcOOTESOAcOOTESOOS49MsClEt3N / TolueneMsClHOOAcOOTESOAcOOTESOSOO-OOAcOOTESOAcOOTESOSOO甲基迁移B--CH3O另外也合成了紫杉醇侧链同A环类似物的拼合物54a和54b,并对其可能具有的生物活性进行了初步计算。同时对化合物51的C-3位羟
基的空间构型通过化学方法给予证明。OHO OHOHO ON OPhOTESR51 52a b OOOOOHNHR54a: R= Bz5533ba:: RR == BBzoc54b: R= Boca: CH2N2 b: LHMDS, then HF/Py对所合成的紫杉醇类似物的细胞毒活性及微管结合能力进行了测试,并初步探讨了C-2位杂原子取代的构效关系。并通过计算机模拟了类似物和微管蛋白的具体结合方式。利用二维核磁技术对合成的紫杉醇类似物35进行构象研究。通过与紫杉醇的构象进行对比,解释了化合物35在核磁中信号异常现象。本论文共计合成了45个化合物,其中新化合物33个。通过NMR,MS等表征手段对新化合物的结构进行了确证。
Paclitaxel ( = Taxol), an antitumor agent isolated from bark of pacificyew Taxus breviforlia originally, has been considered as one of the mosteffective drugs for its unique action mechanism and anti-cancer activity. It isused at present for the treatment of breast, lung, and ovarian carcinomas,and also for AIDS-related Kaposi's sarcoma. But its resource andwater-solubility are the drawbacks in this drug's development.Structure activity relationship (SAR) studies of paclitaxel analogues aremost active in recent years. By structure modifications on pactitaxel, manyanalogues are synthesized with better water solubility and more active. Aknown taxoid 7-epi-10-deacetylpaclitaxel 23 was used as the startingmaterial. By selectively cleaving the C-13 side chain, several modificationson the core structure, the mixture 2-mesylate 20 & 1,2-epoxide 21 wereobtained.
The 1,2-epoxide 21 arose from intramolecular attack on the 2-mesylate20 by the 1-hydroxyl, then the nucleophile could attack on the 1,2-expoxide21. Several nucleophiles were used to afford 2α-N, O, S-linked baccatinsfrom compounds 20 & 21.OAc OOTESHO OMsOOAcOOAc OOTESO OOAcSN2 OSN2OAc OOTESHO OOAcONuNuHOOAcOOHS AcOOOXOPhOH32 R = Bz, X = HRNH33 R = Boc, X = H34 R = Bz, X = O35 R = Boc, X = O HOOAcOOHXAcOOOOPhOH40 R = Bz, X =ORNH41 R = Boc, X = O42 R = Bz, X = N43 R = Boc, X = NThe new synthesis route of compound 49 were founded, and thereaction's process was presumed.HOOAcOOTESHOAcOOTESO48OOAcOOTESOAcOOTESOOS49MsClEt3N / TolueneMsClHOOAcOOTESOAcOOTESOSOO-OOAcOOTESOAcOOTESOSOO甲基迁移B--CH3OAnd a new type of compounds (54a and 54b) were associated with2,2,4-trimethyl-3-hydroxy-4-cyclohexenecarboxylate and (S)-Isoserine
derivatives. The space location of compound 51 ‘s C-3 hydroxyl group wasidentified.OHO OHOHO ON OPhOTESR51 52a b OOOOOHNHR54a: R= Bz5533ba:: RR == BBzoc54b: R= Boca: CH2N2 b: LHMDS, then HF/PyThe cytotoxicity and tubulin polymerization activity of paclitaxel'sanalogues were tested. We discussed SAR of paclitaxel's analogs at thebinding sites in paclitaxel.Then the low activities of those analogs wasrationalized by computational simulations. The compound 35'sconformation was studies with 2D-NMR technique. The conformationdifferences of 35 and paclitaxel explain that the abnormal signals ofcompound 35's NMR spectra.
化合物结构一览表HOOAcOOTESS AcOOO28HOOAcOOTESS AcOOHO29HOOAcOOTESS AcOOOO30HOOAcOOTESS AcOOHOO 31HOOAcOOHS AcOOOOPhOHBzNH32HOOAcOOHS AcOOOOPhOHBocNH33HOOAcOOHS AcOOOOPhOHBzNH34OHOOAcOOHS AcOOOOPhOHBocNH35O
HOOAcOOTESO AcOOO36HOOAcOOTESO AcOOHO37HOOAcOOTESHN AcOOO38HOOAcOOTESHN AcOOHO39HOOAcOOHO AcOOOOPhOHBzNH40HOOAcOOHO AcOOOOPhOHBocNH41HOOAcOOHHN AcOOOOPhOHBzNH42HOOAcOOHHN AcOOOOPhOHBocNH43
HOOAcOOTESO AcOOTESO46OOAcOOTESOAcOOTESO47HOOAcOOTESHO AcOOTESO48OOAcOOTESO AcOOTESOO S49OOOOOHBocNH54aOOOOOHNH54bBz
紫杉醇的构效关系研究是紫杉醇化学研究最活跃的领域。我们可以通过对其化学结构的改造修饰,得到易溶于水,抗癌活性高,毒副作用低的新型紫杉醇类似物。我们利用一个已知的紫杉烷类化合物7-表-10-去乙酰紫杉醇作为起始物,选择性脱除C-13侧链,对其母核进行一系列改造,在C-2位形成2位甲磺酸酯以及1,2β环氧化物的混合物20&21。
通过一个邻基参与的双SN2亲核取代反应对所形成的1,2-β环氧中间体开环,合成2位各种杂原子取代的紫杉醇类似物,如2位硫羟基苯甲酸酯,苄基硫醚取代,2位苯甲酰胺,苄胺取代,2位苄醚取代的紫杉醇类似物。OAc OOTESHO OMsOOAcOOAc OOTESO OOAcSN2 OSN2OAc OOTESHO OOAcONuNuHOOAcOOHS AcOOOXOPhOH32 R = Bz, X = HRNH33 R = Boc, X = H34 R = Bz, X = O35 R = Boc, X = O HOOAcOOHXAcOOOOPhOH40 R = Bz, X =ORNH41 R = Boc, X = O42 R = Bz, X = N43 R = Boc, X = N同时发现了合成1,2位亚硫酸酯取代的巴卡亭类似物49的新合成法并推测了其反应机理。HOOAcOOTESHOAcOOTESO48OOAcOOTESOAcOOTESOOS49MsClEt3N / TolueneMsClHOOAcOOTESOAcOOTESOSOO-OOAcOOTESOAcOOTESOSOO甲基迁移B--CH3O另外也合成了紫杉醇侧链同A环类似物的拼合物54a和54b,并对其可能具有的生物活性进行了初步计算。同时对化合物51的C-3位羟
基的空间构型通过化学方法给予证明。OHO OHOHO ON OPhOTESR51 52a b OOOOOHNHR54a: R= Bz5533ba:: RR == BBzoc54b: R= Boca: CH2N2 b: LHMDS, then HF/Py对所合成的紫杉醇类似物的细胞毒活性及微管结合能力进行了测试,并初步探讨了C-2位杂原子取代的构效关系。并通过计算机模拟了类似物和微管蛋白的具体结合方式。利用二维核磁技术对合成的紫杉醇类似物35进行构象研究。通过与紫杉醇的构象进行对比,解释了化合物35在核磁中信号异常现象。本论文共计合成了45个化合物,其中新化合物33个。通过NMR,MS等表征手段对新化合物的结构进行了确证。
Paclitaxel ( = Taxol), an antitumor agent isolated from bark of pacificyew Taxus breviforlia originally, has been considered as one of the mosteffective drugs for its unique action mechanism and anti-cancer activity. It isused at present for the treatment of breast, lung, and ovarian carcinomas,and also for AIDS-related Kaposi's sarcoma. But its resource andwater-solubility are the drawbacks in this drug's development.Structure activity relationship (SAR) studies of paclitaxel analogues aremost active in recent years. By structure modifications on pactitaxel, manyanalogues are synthesized with better water solubility and more active. Aknown taxoid 7-epi-10-deacetylpaclitaxel 23 was used as the startingmaterial. By selectively cleaving the C-13 side chain, several modificationson the core structure, the mixture 2-mesylate 20 & 1,2-epoxide 21 wereobtained.
The 1,2-epoxide 21 arose from intramolecular attack on the 2-mesylate20 by the 1-hydroxyl, then the nucleophile could attack on the 1,2-expoxide21. Several nucleophiles were used to afford 2α-N, O, S-linked baccatinsfrom compounds 20 & 21.OAc OOTESHO OMsOOAcOOAc OOTESO OOAcSN2 OSN2OAc OOTESHO OOAcONuNuHOOAcOOHS AcOOOXOPhOH32 R = Bz, X = HRNH33 R = Boc, X = H34 R = Bz, X = O35 R = Boc, X = O HOOAcOOHXAcOOOOPhOH40 R = Bz, X =ORNH41 R = Boc, X = O42 R = Bz, X = N43 R = Boc, X = NThe new synthesis route of compound 49 were founded, and thereaction's process was presumed.HOOAcOOTESHOAcOOTESO48OOAcOOTESOAcOOTESOOS49MsClEt3N / TolueneMsClHOOAcOOTESOAcOOTESOSOO-OOAcOOTESOAcOOTESOSOO甲基迁移B--CH3OAnd a new type of compounds (54a and 54b) were associated with2,2,4-trimethyl-3-hydroxy-4-cyclohexenecarboxylate and (S)-Isoserine
derivatives. The space location of compound 51 ‘s C-3 hydroxyl group wasidentified.OHO OHOHO ON OPhOTESR51 52a b OOOOOHNHR54a: R= Bz5533ba:: RR == BBzoc54b: R= Boca: CH2N2 b: LHMDS, then HF/PyThe cytotoxicity and tubulin polymerization activity of paclitaxel'sanalogues were tested. We discussed SAR of paclitaxel's analogs at thebinding sites in paclitaxel.Then the low activities of those analogs wasrationalized by computational simulations. The compound 35'sconformation was studies with 2D-NMR technique. The conformationdifferences of 35 and paclitaxel explain that the abnormal signals ofcompound 35's NMR spectra.
化合物结构一览表HOOAcOOTESS AcOOO28HOOAcOOTESS AcOOHO29HOOAcOOTESS AcOOOO30HOOAcOOTESS AcOOHOO 31HOOAcOOHS AcOOOOPhOHBzNH32HOOAcOOHS AcOOOOPhOHBocNH33HOOAcOOHS AcOOOOPhOHBzNH34OHOOAcOOHS AcOOOOPhOHBocNH35O
HOOAcOOTESO AcOOO36HOOAcOOTESO AcOOHO37HOOAcOOTESHN AcOOO38HOOAcOOTESHN AcOOHO39HOOAcOOHO AcOOOOPhOHBzNH40HOOAcOOHO AcOOOOPhOHBocNH41HOOAcOOHHN AcOOOOPhOHBzNH42HOOAcOOHHN AcOOOOPhOHBocNH43
HOOAcOOTESO AcOOTESO46OOAcOOTESOAcOOTESO47HOOAcOOTESHO AcOOTESO48OOAcOOTESO AcOOTESOO S49OOOOOHBocNH54aOOOOOHNH54bBz
引文
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