替莫唑胺衍生物的合成及生物活性研究
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摘要
替莫唑胺是一种新型的咪唑四嗪类化合物,具有较好的脑胶质瘤抑制作用,同时对白血病、黑色素瘤、淋巴瘤和实体瘤也有较好的疗效。大量的研究工作在3-位、4-位、6-位、8-位进行取代,合成了各种类型的替莫唑胺衍生物,构效实验表明,8-位酰胺类衍生物有较好的肿瘤抑制作用。
本文以5-氨基咪唑-4-甲酰胺与甲氨基甲酰氯为起始原料,分别经过重氮化和消去反应得5-重氮基咪唑-4-甲酰胺与异氰酸甲酯,再将两种中间体常温下反应得先导化合物替莫唑胺,并进行了条件优化,总产率由65.66%提高到69.69%。针对替莫唑胺及其衍生物的作用特点,为增加替莫唑胺的脂溶性,通过羧酸化、酰氯化,再与芳香胺类直接反应,在8-位引入了芳基,共合成14个N-取代-3-甲基-4-氧代咪唑[5,1-d][1,2,3,5]四嗪-8-甲酰胺类衍生物;用酰氯与二胺反应合成了3个芳香类双替莫唑胺衍生物和三个3个脂肪类双替莫唑胺衍生物,20个目标化合物均未见文献报道。通过元素分析、IR、~1H-NMR、及~(13)C-NMR对目标化合物的结构进行了表征,并以化合物TD-2为例进行了结构解析。初步体外抗前列腺肿瘤(PC3)细胞实验表明:TD-5、TD-6、TD-9、TD-10在浓度为1μM时有一定的抗前列腺肿瘤活性;TD-7、TD-8、TD-13、TD一19在浓度为10μM时有一定的抗前列腺肿瘤活性。
Temozolomide is one of the new imidazoletetrazine compounds,which has good antitumour active to brain glioma,leukemia,melanoma,lymphoma and solid tumor. Many research workers have synthesized many temozolomide derivatives which were substituted in 3-,4-,6- and 8-,and the testing of biological activity indicated that 8-substituted amide derivatives of temozolomide had better antitumour active.
On the base of the characteristics of temozolomide and its derivatives, 5-diazoimidazole-4-carboxamide was prepared from 5-aminoimidazole-4-carboxa mide through diazotization reaction,methyl isocyanate was prepared from methyl carbamyl chloride by elimination reaction,the two intermediates was stirred at room temperature and temozolomide was gotten.General yield was increased to 69.69% from 65.66%under the optimum reaction condition.In order to inhencing the fat-soluble we could introduce aryl in 8- of temozolomide.Temozolomide was carboxylated and acyl chloridized,then reacted with aryl amines and obtained fourteen N-substituted-3-methyl-imidazol[5,1 -d][1,2,3,5]tetrazine-8-carboxamide derivatives,three bis-temozolomide aryl derivatives and three bis-temozolomide acyclic derivatives were synthsized as control study,all of them have never been reported in literature.The structure of final products were characterized correcttly by elemental analysis,IR,~1H-NMR,and ~(13)C-NMR,the structure and spectral data of TD-2 were elucidated in details in the paper.Preliminary studies on inhibitory activity of temozolomide derivatives against prostatic neoplasms(PC3) showed that TD-5, TD-6,TD-9,TD-10 and TD-20 had certain antitumor actives to PC3 at 1μM and TD-7,TD-8,TD-11,TD-13,TD-19 had certain antitumor actives to PC3 at 10μM.
本文以5-氨基咪唑-4-甲酰胺与甲氨基甲酰氯为起始原料,分别经过重氮化和消去反应得5-重氮基咪唑-4-甲酰胺与异氰酸甲酯,再将两种中间体常温下反应得先导化合物替莫唑胺,并进行了条件优化,总产率由65.66%提高到69.69%。针对替莫唑胺及其衍生物的作用特点,为增加替莫唑胺的脂溶性,通过羧酸化、酰氯化,再与芳香胺类直接反应,在8-位引入了芳基,共合成14个N-取代-3-甲基-4-氧代咪唑[5,1-d][1,2,3,5]四嗪-8-甲酰胺类衍生物;用酰氯与二胺反应合成了3个芳香类双替莫唑胺衍生物和三个3个脂肪类双替莫唑胺衍生物,20个目标化合物均未见文献报道。通过元素分析、IR、~1H-NMR、及~(13)C-NMR对目标化合物的结构进行了表征,并以化合物TD-2为例进行了结构解析。初步体外抗前列腺肿瘤(PC3)细胞实验表明:TD-5、TD-6、TD-9、TD-10在浓度为1μM时有一定的抗前列腺肿瘤活性;TD-7、TD-8、TD-13、TD一19在浓度为10μM时有一定的抗前列腺肿瘤活性。
Temozolomide is one of the new imidazoletetrazine compounds,which has good antitumour active to brain glioma,leukemia,melanoma,lymphoma and solid tumor. Many research workers have synthesized many temozolomide derivatives which were substituted in 3-,4-,6- and 8-,and the testing of biological activity indicated that 8-substituted amide derivatives of temozolomide had better antitumour active.
On the base of the characteristics of temozolomide and its derivatives, 5-diazoimidazole-4-carboxamide was prepared from 5-aminoimidazole-4-carboxa mide through diazotization reaction,methyl isocyanate was prepared from methyl carbamyl chloride by elimination reaction,the two intermediates was stirred at room temperature and temozolomide was gotten.General yield was increased to 69.69% from 65.66%under the optimum reaction condition.In order to inhencing the fat-soluble we could introduce aryl in 8- of temozolomide.Temozolomide was carboxylated and acyl chloridized,then reacted with aryl amines and obtained fourteen N-substituted-3-methyl-imidazol[5,1 -d][1,2,3,5]tetrazine-8-carboxamide derivatives,three bis-temozolomide aryl derivatives and three bis-temozolomide acyclic derivatives were synthsized as control study,all of them have never been reported in literature.The structure of final products were characterized correcttly by elemental analysis,IR,~1H-NMR,and ~(13)C-NMR,the structure and spectral data of TD-2 were elucidated in details in the paper.Preliminary studies on inhibitory activity of temozolomide derivatives against prostatic neoplasms(PC3) showed that TD-5, TD-6,TD-9,TD-10 and TD-20 had certain antitumor actives to PC3 at 1μM and TD-7,TD-8,TD-11,TD-13,TD-19 had certain antitumor actives to PC3 at 10μM.
引文
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[2]马廉廷.脑胶质瘤治疗的现状与进展[J].中华实验外科杂志,1999,(16):388-389.
[3]王维剑,张君仁,庞华.替莫唑胺含量测定方法的研究[J].药物分析杂志,2003,23(5):344-346.
[4]孙兵.神经干细胞与脑肿瘤基因治疗[J].国外医学(神经病学神经外科分册),2002,29(3):128.
[5]李伟,章翔,顾建文,等.神经导航系统手术92例[J].第四军医大学学报,2002,23(24):231.
[6]李展鹏,何炳辉,张锐强,等.超选择性动脉灌注化疗治疗脑恶性胶质瘤24例[J].实用医学杂志,2000,16(5):394.
[7]杨建国.替莫唑胺类似物的设计合成及其抗癌活性研究[D].沈阳:沈阳药科大学制药工程学院,2003.
[8]陈忠平,黄强.肿瘤耐药基因.见:黄强,主编;陈忠平,兰青,副主编.脑肿瘤分子外科学[M].北京:中国科技出版社,1998,4:38-49.
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[12]曹晓运.脑胶质瘤的抑癌基因研究进展[J].中国癌症杂志,2001,11(2):181-183.
[13]章翔,吴景文,荆俊杰,等.人骨形成蛋白-2诱导人脑胶质细胞瘤凋亡的实验研究[J].中华医学杂志,2000,80(8):610-13.
[14]野村和弘.日本脑肿瘤治疗的现状[J].日本医学介绍,2002,23(8):376.
[15]黄强.胶质瘤起源细胞探讨[J].中国微侵袭神经外科杂志,2003,8(8): 337-340。
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