含L-4-氧代赖氨酸和N^(3)-(4-甲氧基富马酰)-L-2,3-二氨基丙酸寡肽类似物的合成及其抗白念珠菌活性  

SYNTHESIS AND ANTICANDIDA ALBICANS PROPERTIES OF L4OXALYSINEN34METHOXYFUMAROYLL2,3DIAMINOPROPANOICCONTAINING PEPTIDE ANALOGUES

作　　者：冯胜昔[1,2] 徐修容[1,2] 张鸿龙 

机构地区：[1]广州白云山制药股份有限公司合成药物研究所 [2]中国科学院上海药物研究所

出　　处：《药学学报》1998年第6期429-435,共7页Acta Pharmaceutica Sinica

摘　　要：运用“违法传递”概念，根据白念珠菌对寡肽的传送特点，设计并合成了８个含Ｌ４氧代赖氨酸（以下称Ｉ６７７）和Ｎ３（４甲氧基富马酰）Ｌ２，３二氨基丙酸（以下称ＦＭＤＰ）的寡肽类似物，均系新化合物。体外抗白念珠菌试验表明：Ｉ６７７ＦＭＤＰ肽（Ｉ６７７ＦＭＤＰ，Ｉ６７７ＡＡＦＭＤＰ，其中ＡＡ＝Ｎｖａ，Ｖａｌ，Ｌｅｕ，Ｐｈｅ，Ｐｒｏ，Ｄ，ＬｐＣｌＰｈｅ，ＤＰｇｌｙ）是Ｉ６７７单体摩尔活性的４０～７７０倍，是ＦＭＤＰ的６０～１１３０倍，其摩尔最低抑菌浓度为６５６×１０－９～３５×１０－１０ｍｏｌ·ｄｉｓｋ－１。羧肽酶Ａ存在时化合物Ｉ６７７ＦＭＤＰ体外抗菌试验表明，含ＦＭＤＰ的化合物Ｉ６７７ＦＭＤＰ能抵抗羧肽酶Ａ的酶解。In order to improve the inhibitory activity of L4oxalysine(abbreviated as I677) against clinically important pathogen Candida albicans, double warheads peptide analogues containing I677 and N34methoxyfumaroylL2,3diaminopropanoic acid( FMDP) were designed based on the concept of “Illicit Transport” and peptide transport specificities of C. albicans. One compound of I677FMDP and seven compounds of I677AAFMDP(AA=Nva, Leu, Val, Phe, Pro, DPgly, D,LpClPhe) were synthesized and examined for antifungal activities. The results of antiCandida albicans test in vitro of these double warheads peptide analogues containing I677 and FMDP showed very high activities against Candida albicans. The molar MIC(molar minimum inhibitory concentration) ratio of free I677 to I677AAFMDP is 40～770 and that of FMDP is 60～1130. The values of molar MIC of I677AAFMDP varied from 656×10-9　 mol·disk-1 to 35×10-10 　mol·disk-1. The results of competitive antagonism studies indicated that I677AAFMDP were transported into Candida albicans cells by the ditripeptide permease and subsequently hydrolyzed by intracellular peptidases, releasing free I677 and FMDP inside cells. The result of antienzymic degradation test in vitro of I677FMDP showed that compound I677FMDP was resistant to the hydrolysis by carboxypeptidase A.

关 键 词：氧代赖氨酸 二氨基丙酸 寡肽 类似物 白念珠菌 

分 类 号：TQ464.7[化学工程—制药化工] R978.5[医药卫生—药品]