嘌呤衍生物及环磷酯前体药物的合成和生物活性研究
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摘要
嘌呤本身不存在于自然界中,但其衍生物在自然界分布很广。嘌呤与特定的嘧啶碱基一起时是DNA和RNA的组成部分,生命过程中非常重要。近年来,嘌呤衍生物因其具有重要的生理学和药理学性质而成为一类重要的药物,药物化学家研究开发了一大批具有抗肿瘤和抗病毒(尤其是抗艾滋病)作用的核苷类似物,使嘌呤化学发展迅速。除了嘌呤环的9位接入糖基合成核苷类药物以外,嘌呤母环中可以作为分子修饰的位置还有2,6,8三个位置,在这些位置引入某些取代基团后,所得的嘌呤衍生物具有抗病毒、抗癌、抗寄生虫等重要的生物医学活性,例如,以‘'Reversine"为代表的一类嘌呤2,6位R-NH-取代的衍生物显示了非常好的生物活性。因此,嘌呤环的结构修饰及药物活性研究一直是人们研究嘌呤类化合物的重点。
设计并合成了12个2-取代苯胺基-6-环己胺基嘌呤(化合物33a-331)和4个2-取代苯胺基-6-正丁胺基嘌呤(化合物34a-34d),以及9个6-芳胺基嘌呤衍生物(化合物63a～63i)。研究了嘌呤2,6位取代衍生物的合成方法,探索出了一条产率高、反应条件温和、产物易纯化的合成路线；将微波辐射方法应用于嘌呤衍生物的合成中,探索了‘'Reversine"及其衍生物的微波辅助合成,通过微波辐射快速的合成了嘌呤6位取代衍生物40～44、47及2位取代衍生物化合物32a和"Reversine",为嘌呤衍生物的合成探索出了一条更为快速的合成方法。研究了嘌呤2位、6位连有不同的烷胺基、取代苯胺基、(4-吗啉基)苯胺基化合物对肿瘤细胞的抑制活性,结果表明,2-[(4-苄氧基)苯胺基]-6-环己胺基嘌呤(化合物33g)、2-(4-氯苯胺基)-6-正丁胺基嘌呤(化合物34b)和2-[4-(4-吗啉基)苯胺基]-6-(4-羟基)苯胺基]嘌呤(化合物63i)具有较好的活性,其对肝脏肿瘤细胞Be1-7402的IC50值分别为13.0μM、40.8μM和27.7μM。
设计了一组新颖的2位含有糖基苯氧苷修饰的嘌呤衍生物,研究了四种糖基供体(葡萄糖、半乳糖、乳糖、木糖)与嘌呤环连接顺序,并成功的合成了一组2-[(4-糖基)苯胺基]-6-环己胺基嘌呤衍生物。活性研究结果显示,该组化合物中糖基为葡萄糖基(化合物36)、半乳糖基(化合物37)、木糖(化合物39)基时均具有一定的的抗肿瘤活性,其对肝脏肿瘤细胞Bel-7402的IC50值分别为82.8μM、38.2μM和75.3μM。
设计了一组6位含有硫原子的嘌呤衍生物(62b-62g)和-个嘌呤9位含有硫原子取代衍生物(45),探索了合成方法。生物活性研究结果显示,化合物62b、62c具有一定的抗肿瘤活性,其1μM浓度时对肝脏肿瘤细胞Bel-7402的抑制率分别为54.71%和66.86%,为进一步研究嘌呤衍生物奠定了基础。
前体药物经过体内代谢后可以增加药物的生物利用度,加强靶向性,降低药物的毒性和副作用。以HepDirect前药为代表的,是新一代以核苷为基础的一类1,3-二醇环磷酸前药,显示出了有效的不增加细胞毒性的抗HIV病毒活性,并具有良好的化学及酶稳定性。癌症的化学治疗近年来取得迅猛发展,喜树碱衍生物、紫杉醇以及维生素甲类化合物抗癌治疗作用的证实被誉为90年代抗癌药物的三大发现。由于喜树碱(Campothecin,简称CPT)不溶于水,其钠盐毒副作用较大,所以研究者们对喜树碱的结构改造进行了广泛研究。本文研究了10-羟基喜树碱环磷酸酯前药的合成路线,以取代苯乙酮为起始原料,经酮酯缩合、还原、硅醚化及手性拆分等7步反应得到目标化合物喜树碱的环磷酯前药；探索了手性中间体1-芳基-1,3-丙二醇的手性合成方法,以烷基咪唑-L-脯氨酸盐手性离子液体为手性试剂,探索手性诱导还原方法合成1-芳基-1,3-丙二醇,产物的光学纯度达到了82%。
所合成的42个目标化合物中39个为未见文献报道的新化合物,所有化合物均经核磁共振(1H NMR、13C NMR)口质谱(MS)进行了结构鉴定。
Purine does not exist in nature, but its derivatives are widely distributed in nature. Purine are the part of DNA and RNA bounding with specific pyrimidine. They exert the important function in the biological processes. Purine and its derivatives are a class of important pharmaceutical compounds with their significant physiological and pharmacological properties. Many nucleoside analogues have been investigated for their antiviral(especially anti-Aids) and anticancer activities. There are three position can be substituted for purine, except nucleoside drugs with glycosylation at9-position. The2,6or8-position substituted purine derivatives have been shown to have biological activitys of antiviral, antitumor, anti-parasite, and so on. A series of2,6-substituted purine derivatives by R-NH, typically "Reversine", have been shown excellent biological activity.Therefore, the structure modification of purine ring and pharmaceutical activity evaluation has been the focus of the study of purine compounds.
In this dissertation, twelve compounds of2-substituted anilino-6-cyclohexylamino purine (compounds33a～331), four compounds of2-substituted anilino-6-n-butylamino-purine (compounds34a-34d), and nine compounds of6-arylamino purine derivatives (compounds63a-63i) were designed and synthesized. The synthetic methods with a high yield, mild reaction conditions and the purified product of2,6-disubstituted purine derivatives were explored. The microwave radiation were used for the synthesis of purine derivatives. A practical synthesis of2-substituted derivative compounds32a,"Reversine"(32e) and6-substituted purine derivatives40～44,47by microwave radiation rapid were investigated. The synthesized compounds of purine derivatives bonding with different alkylamino-, substituted anilino-, morpholino anilino-were evaluated for their inhibitory activities against liver cancer cell lines of Bel-7402. Moderate antitumor activity were exhibited of2-(4-benzyl-O-phenylamino)-6-cyclohexylamino-purine (compound33g),2-(4- chloro-phenylamino)-6-n-butylamino-purine (compound34b) and2-(4-morpholinoamino)-6-(4-chloro-phenylamino)-purine(compound63i). Their IC50values against liver tumor cell line Bel-7402were13.0μM,40.8μM and27.7μM respectively.
A group of novel modified purine derivatives containing phenoxy glycosides were designed and synthsized in this dissertation. Four kinds of glycosylation donor (glucose, galactose, lactose, xylose) were bonding with purine ring at2-position in available order of reaction. Four2-(4-O-glyco-phenylamino)-6-(cyclohexylamino) purine derivatives (compounds36～39) were synthesized successfully. Moderate antitumor activity were exhibited, based the sugar group of glucose group (compound36), and galactose (compound37), xylose (compound39). Their IC50values against liver tumor cell line Bel-7402were82.8μM,38.2μM and75.3μM respectively.
Six purine derivatives containing a sulfur atom at6-position(compounds62b-62g) or9-position (compounds45) were designed and synthesized. Moderate antitumor activity were exhibited of compound62b and62c, with54.71%and66.86%inhibition rate respectively at1μM concentration against liver tumor cell line Bel-7402. The strategy of the synthesis were explored for the developing of purine derivatives.
Prodrugs has been reported to increase the bioavailability, enhance targeting, reduce the toxicity and side effects of drugs. Typically the prodrug, HepDirect, a class of novel cyclic1-aryk-1,3-propanyl phosphonate prodrug dased nucleoside is attributed to the effective anti-HIV activity, and good chemical and enzyme stability, does not increase the cytotoxicity. The pharmacotherapy of cancer is progressing rapidly and new anti-cancer drugs is emerging prominently. The anti-cancer drugs of Camptothecin, Paclitaxel and Vitamin A have been believed to be the most important discovery in the90's. Campothecin cannot be dissolved in water. The clinical therapeutic of the sodium salt of Campothecin indicated the high toxicity and side effects. So, the structural transformation of Camptothecin were investigate widely. The cyclic phosphate prodrugs of Camptothecin were prepared from10-hydroxycamptothecin by condensation of ketoester reduction, silicon etherified and chiral separation reaction in this dissertation. The chiral synthesis methods of the chiral intermediate1-aryl-1,3-propanediol were explored.1-Aryl-1,3-propanediol were prepared by chiral reduction reaction in chiral ionic liquid alkylimidazole-L-proline salts. The optical purity of the product was82%.
Forty-two target compounds, including thirty-nine novel compounds, were synthesized. Their structures were determined by1H NMR,13C NMR and MS.
设计并合成了12个2-取代苯胺基-6-环己胺基嘌呤(化合物33a-331)和4个2-取代苯胺基-6-正丁胺基嘌呤(化合物34a-34d),以及9个6-芳胺基嘌呤衍生物(化合物63a～63i)。研究了嘌呤2,6位取代衍生物的合成方法,探索出了一条产率高、反应条件温和、产物易纯化的合成路线；将微波辐射方法应用于嘌呤衍生物的合成中,探索了‘'Reversine"及其衍生物的微波辅助合成,通过微波辐射快速的合成了嘌呤6位取代衍生物40～44、47及2位取代衍生物化合物32a和"Reversine",为嘌呤衍生物的合成探索出了一条更为快速的合成方法。研究了嘌呤2位、6位连有不同的烷胺基、取代苯胺基、(4-吗啉基)苯胺基化合物对肿瘤细胞的抑制活性,结果表明,2-[(4-苄氧基)苯胺基]-6-环己胺基嘌呤(化合物33g)、2-(4-氯苯胺基)-6-正丁胺基嘌呤(化合物34b)和2-[4-(4-吗啉基)苯胺基]-6-(4-羟基)苯胺基]嘌呤(化合物63i)具有较好的活性,其对肝脏肿瘤细胞Be1-7402的IC50值分别为13.0μM、40.8μM和27.7μM。
设计了一组新颖的2位含有糖基苯氧苷修饰的嘌呤衍生物,研究了四种糖基供体(葡萄糖、半乳糖、乳糖、木糖)与嘌呤环连接顺序,并成功的合成了一组2-[(4-糖基)苯胺基]-6-环己胺基嘌呤衍生物。活性研究结果显示,该组化合物中糖基为葡萄糖基(化合物36)、半乳糖基(化合物37)、木糖(化合物39)基时均具有一定的的抗肿瘤活性,其对肝脏肿瘤细胞Bel-7402的IC50值分别为82.8μM、38.2μM和75.3μM。
设计了一组6位含有硫原子的嘌呤衍生物(62b-62g)和-个嘌呤9位含有硫原子取代衍生物(45),探索了合成方法。生物活性研究结果显示,化合物62b、62c具有一定的抗肿瘤活性,其1μM浓度时对肝脏肿瘤细胞Bel-7402的抑制率分别为54.71%和66.86%,为进一步研究嘌呤衍生物奠定了基础。
前体药物经过体内代谢后可以增加药物的生物利用度,加强靶向性,降低药物的毒性和副作用。以HepDirect前药为代表的,是新一代以核苷为基础的一类1,3-二醇环磷酸前药,显示出了有效的不增加细胞毒性的抗HIV病毒活性,并具有良好的化学及酶稳定性。癌症的化学治疗近年来取得迅猛发展,喜树碱衍生物、紫杉醇以及维生素甲类化合物抗癌治疗作用的证实被誉为90年代抗癌药物的三大发现。由于喜树碱(Campothecin,简称CPT)不溶于水,其钠盐毒副作用较大,所以研究者们对喜树碱的结构改造进行了广泛研究。本文研究了10-羟基喜树碱环磷酸酯前药的合成路线,以取代苯乙酮为起始原料,经酮酯缩合、还原、硅醚化及手性拆分等7步反应得到目标化合物喜树碱的环磷酯前药；探索了手性中间体1-芳基-1,3-丙二醇的手性合成方法,以烷基咪唑-L-脯氨酸盐手性离子液体为手性试剂,探索手性诱导还原方法合成1-芳基-1,3-丙二醇,产物的光学纯度达到了82%。
所合成的42个目标化合物中39个为未见文献报道的新化合物,所有化合物均经核磁共振(1H NMR、13C NMR)口质谱(MS)进行了结构鉴定。
Purine does not exist in nature, but its derivatives are widely distributed in nature. Purine are the part of DNA and RNA bounding with specific pyrimidine. They exert the important function in the biological processes. Purine and its derivatives are a class of important pharmaceutical compounds with their significant physiological and pharmacological properties. Many nucleoside analogues have been investigated for their antiviral(especially anti-Aids) and anticancer activities. There are three position can be substituted for purine, except nucleoside drugs with glycosylation at9-position. The2,6or8-position substituted purine derivatives have been shown to have biological activitys of antiviral, antitumor, anti-parasite, and so on. A series of2,6-substituted purine derivatives by R-NH, typically "Reversine", have been shown excellent biological activity.Therefore, the structure modification of purine ring and pharmaceutical activity evaluation has been the focus of the study of purine compounds.
In this dissertation, twelve compounds of2-substituted anilino-6-cyclohexylamino purine (compounds33a～331), four compounds of2-substituted anilino-6-n-butylamino-purine (compounds34a-34d), and nine compounds of6-arylamino purine derivatives (compounds63a-63i) were designed and synthesized. The synthetic methods with a high yield, mild reaction conditions and the purified product of2,6-disubstituted purine derivatives were explored. The microwave radiation were used for the synthesis of purine derivatives. A practical synthesis of2-substituted derivative compounds32a,"Reversine"(32e) and6-substituted purine derivatives40～44,47by microwave radiation rapid were investigated. The synthesized compounds of purine derivatives bonding with different alkylamino-, substituted anilino-, morpholino anilino-were evaluated for their inhibitory activities against liver cancer cell lines of Bel-7402. Moderate antitumor activity were exhibited of2-(4-benzyl-O-phenylamino)-6-cyclohexylamino-purine (compound33g),2-(4- chloro-phenylamino)-6-n-butylamino-purine (compound34b) and2-(4-morpholinoamino)-6-(4-chloro-phenylamino)-purine(compound63i). Their IC50values against liver tumor cell line Bel-7402were13.0μM,40.8μM and27.7μM respectively.
A group of novel modified purine derivatives containing phenoxy glycosides were designed and synthsized in this dissertation. Four kinds of glycosylation donor (glucose, galactose, lactose, xylose) were bonding with purine ring at2-position in available order of reaction. Four2-(4-O-glyco-phenylamino)-6-(cyclohexylamino) purine derivatives (compounds36～39) were synthesized successfully. Moderate antitumor activity were exhibited, based the sugar group of glucose group (compound36), and galactose (compound37), xylose (compound39). Their IC50values against liver tumor cell line Bel-7402were82.8μM,38.2μM and75.3μM respectively.
Six purine derivatives containing a sulfur atom at6-position(compounds62b-62g) or9-position (compounds45) were designed and synthesized. Moderate antitumor activity were exhibited of compound62b and62c, with54.71%and66.86%inhibition rate respectively at1μM concentration against liver tumor cell line Bel-7402. The strategy of the synthesis were explored for the developing of purine derivatives.
Prodrugs has been reported to increase the bioavailability, enhance targeting, reduce the toxicity and side effects of drugs. Typically the prodrug, HepDirect, a class of novel cyclic1-aryk-1,3-propanyl phosphonate prodrug dased nucleoside is attributed to the effective anti-HIV activity, and good chemical and enzyme stability, does not increase the cytotoxicity. The pharmacotherapy of cancer is progressing rapidly and new anti-cancer drugs is emerging prominently. The anti-cancer drugs of Camptothecin, Paclitaxel and Vitamin A have been believed to be the most important discovery in the90's. Campothecin cannot be dissolved in water. The clinical therapeutic of the sodium salt of Campothecin indicated the high toxicity and side effects. So, the structural transformation of Camptothecin were investigate widely. The cyclic phosphate prodrugs of Camptothecin were prepared from10-hydroxycamptothecin by condensation of ketoester reduction, silicon etherified and chiral separation reaction in this dissertation. The chiral synthesis methods of the chiral intermediate1-aryl-1,3-propanediol were explored.1-Aryl-1,3-propanediol were prepared by chiral reduction reaction in chiral ionic liquid alkylimidazole-L-proline salts. The optical purity of the product was82%.
Forty-two target compounds, including thirty-nine novel compounds, were synthesized. Their structures were determined by1H NMR,13C NMR and MS.
引文
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