抗癌环肽药物放线菌素D新类似物的化学全合成研究  

Total Chemical Synthesis of Three Novel Actinomycin D Analogs Used as Antitumor Drugs

作　　者：张邦治[1] 王则周[1] 王小丽[1] 李欣檑[1] 倪京满[1] 王锐[1] 

机构地区：[1]兰州大学生命科学学院功能有机分子化学国家重点实验室,兰州730000

出　　处：《高等学校化学学报》2004年第10期1857-1859,共3页Chemical Journal of Chinese Universities

基　　金：国家"十五"重大科技专项博士基金 (批准号 :2 0 0 3 A A2 Z3 5 40 );教育部高校优秀青年教师教学科研奖励计划基金 (教人司 [2 0 0 1] 182号 );教育部科技重点项目资助 .

摘　　要：Actinomycin D(AMD) is well known for its specific inhibition of DNA transcription, and has been used clinically as an antitumor drug for the treatment of some highly malignant tumors. Based on the former research, two [D-Phe 2] 2AMD analogs with L-MeVal(the fifth amino acid residue in the cyclic depsipeptide of AMD) substituted by D-MeVal and D-MePhe were designed to reduce the toxicity and increase the antitumor activity. Another analog in which the D-Val residue replaced with D-MeVal was designed to eliminate or to weaken the hydrogen bonds of D-Val residues between α and β rings. All three novel compounds were prepared from C terminal to N terminal in solution phase to form linear pentapeptides, and cyclized by BOP-Cl/Et 3N in DCM. Condensation of pentapeptide lactone with BMNBCA, followed by catalytic reduction, controlling oxidation by K 3Fe(CN) 6 and purification afforded the analogs as red solid. The spectrum data of all three analogs including HR-MS, 1H NMR and [α] D were given.Actinomycin D(AMD) is well known for its specific inhibition of DNA transcription, and has been used clinically as an antitumor drug for the treatment of some highly malignant tumors. Based on the former research, two [D-Phe 2] 2AMD analogs with L-MeVal(the fifth amino acid residue in the cyclic depsipeptide of AMD) substituted by D-MeVal and D-MePhe were designed to reduce the toxicity and increase the antitumor activity. Another analog in which the D-Val residue replaced with D-MeVal was designed to eliminate or to weaken the hydrogen bonds of D-Val residues between α and β rings. All three novel compounds were prepared from C terminal to N terminal in solution phase to form linear pentapeptides, and cyclized by BOP-Cl/Et 3N in DCM. Condensation of pentapeptide lactone with BMNBCA, followed by catalytic reduction, controlling oxidation by K 3Fe(CN) 6 and purification afforded the analogs as red solid. The spectrum data of all three analogs including HR-MS, 1H NMR and [α] D were given.

关 键 词：抗癌环肽药物 放线菌素D 类似物 化学全合成 抗肿瘤活性 

分 类 号：TQ463[化学工程—制药化工] R979.1[医药卫生—药品]