New analogues of benzylacyclouridines, specific and potent inhibitors of uridine phosphorylase from human and mouse livers.
New analogues of benzylacyclouridines, specific and potent inhibitors of uridine phosphorylase from human and mouse livers.
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苄基环尿苷的新类似物，来自人和小鼠肝脏的尿苷磷酸化酶的特异性和有效抑制剂。
DOI：
10.1016/0006-2952(87)90150-x
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发表时间：
1987
影响因子：
5.8
通讯作者：
Cha,S
中科院分区：
文献类型：
--
作者：
Naguib,FN;elKouni,MH;Chu,SH;Cha,S
人类和小鼠肝脏的尿苷磷酸化酶 (UrdPase) 的磷酸解活性的动力学参数已确定。这些参数的值为：KPi= 279.0 ± 66.0μM，KUrd= 242.0 ± 63.0μM，Vmax= 3940 ± 175 pmol/min/mg，KPi= 76.0 ± 7.0μM，KUrd= 143.0 ± 9.0μM，Vmax= 293.0 ± 5.0 pmol/min/mg，分别针对人类和小鼠肝脏。苄基环尿苷（UrdPase 的特异性抑制剂）和 17 种新合成的衍生物（在嘧啶环、苄基部分或 acycio 尾部进行修饰）已测试其抑制人和小鼠肝脏中 UrdPase 和胸苷磷酸化酶 (dThdPase) 的效力。没有一个抑制 dThdPase。相反，所有测试的化合物均抑制 UrdPase。在所有情况下都观察到竞争性抑制。几种新化合物对 UrdPase 的抑制作用优于母体化合物。这些化合物与来自人肝脏的 UrdPase 的抑制效力大致与使用来自小鼠肝脏的 UrdPase 获得的抑制效力相同。这些化合物中最有效的是 AM-BBAU（氨基甲基-BBAU 或 5-(3'-苯甲氧基苯甲基)-1-[(1'-氨基甲基-2'-羟基乙氧基)甲基]尿嘧啶），与小鼠肝脏的 UrdPase 的 Ki 值为 18 nM。讨论了这些 UrdPase 抑制剂的结合的结构-活性关系。
Kinetic parameters for the phosphorolytic activity of uridine phosphorylase (UrdPase) from human and mouse livers have been determined. The values of these parameters are:KPi= 279.0 ± 66.0μM,KUrd= 242.0 ± 63.0μM andVmax= 3940 ± 175 pmol/min/mg, andKPi= 76.0 ± 7.0μM,KUrd= 143.0 ± 9.0μM andVmax= 293.0 ± 5.0 pmol/min/mg, for human and mouse livers respectively. Benzylacyclouridines, the specific inhibitors of UrdPase, and seventeen newly synthesized derivatives, modified at the pyrimidine ring, the benzyl moiety or the acycio tail, have been tested for their potency to inhibit UrdPase and thymidine phosphorylase (dThdPase) from both human and mouse livers. None inhibited dThdPase. In contrast, all of the compounds tested inhibited UrdPase. Competitive inhibition was observed in all cases. Several of the new compounds were superior in their inhibition of UrdPase to the parent compounds. The inhibitory potencies of these compounds with UrdPase from human liver roughly paralleled those obtained with UrdPase from mouse liver. The most potent of these compounds was AM-BBAU (aminomethyl-BBAU or 5-(3'-benzyloxybenzyl)-1-[(1'-aminomethyl-2'-hydroxy-ethoxy)methyl]uracil) with aKivalue of 18 nM with UrdPase from mouse liver. Structure-activity relationships of the binding of these inhibitors of UrdPase are discussed.