棘白菌素B新型衍生物的设计合成及体外抗真菌活性  

Design,Synthesis and in vitro Antifungal Activities of Novel Echinocandin B Derivatives

作　　者：朱冰 东圆珍 张喜全 马洁 ZHU Bing;DONG Yuanzhen;ZHANG Xiquan;MA Jie(School of Pharmacy,Fudan University,Shanghai 201203;Shanghai Duomirui Biotechnology Ltd.,Shanghai 201203;Chitai Tianqing Pharmaceutical Group Co.,Ltd.,Nanjing 210000)

机构地区：[1]复旦大学药学院,上海201203 [2]上海多米瑞生物技术有限公司,上海201203 [3]正大天晴药业集团股份有限公司,江苏南京210000

出　　处：《中国医药工业杂志》2020年第6期704-712,共9页Chinese Journal of Pharmaceuticals

基　　金：国家重点研发计划“新型畜禽药创制与产业化研究”项目(2017YFD0501404)。

摘　　要：本研究以棘白菌素B母核(ECBN)为基础,在侧链中引入了多肽结构,并探索出了棘白菌素B新型衍生物的固相及液相联合合成的路线。以不同芳香性氨基酸、极性带正电荷氨基酸以及脂肪酸为原料合成了14个新的棘白菌素B衍生物,分别对其进行了抗真菌活性、溶血毒性、水溶性评估,筛选得到了ECBN-[3-(2-萘基)-D-丙氨酸]-(2,4-二氨基丁酸)-月桂酸(ECBN-D-2-Nal-Dab-C12,13)。相比于阿尼芬净,13在保留抗真菌活性的同时,溶血毒性大大降低,并且水溶性得到极大改善,时间-杀菌曲线也证实二者对白念珠菌和克柔念珠菌有相似的杀菌效果。因此,13可作为候选化合物进一步研究和开发。In this study,some peptides were introduced into the side chain on the nucleus of echinocandin B(ECBN)by a new solid-liquid synthesis route to obtain a series of novel echinocandin B derivatives.Using aromatic amino acids,positively charged polar amino acids and fatty acids as materials,fourteen derivatives were synthesized.According to the evaluation results of antifungal activity,hemolytic toxicity and water solubility,ECBN-[3-(2-naphthyl)-D-alanine]-(2,4-diaminobutyric acid)-lauric acid(ECBN-D-2-Nal-Dab-C12,13)was found,which showed a comparable fungicidal effect,high water solubility and low hemolytic toxicity compared with anidulafungin.Moreover,the time-killing assay against Candida.albicans and C.krusei also confirmed that both compound 13 and anidulafungin showed the similar fungicidal effect,so compound 13 could be recommended as a candidate for further research and development.

关 键 词：棘白菌素B衍生物 抗真菌药 固-液相合成 抗真菌活性 水溶性 

分 类 号：R914.2[医药卫生—药物化学] R978.5[医药卫生—药学]