Butler M M, Dudycz L W, Khan N N, Wright G E, Brown N C
Department of Pharmacology, University of Massachusetts Medical School, Worcester 01655.
Nucleic Acids Res. 1990 Dec 25;18(24):7381-7. doi: 10.1093/nar/18.24.7381.
6-(p-Hydroxyphenylhydrazino)uracil (H2-HPUra) is a selective and potent inhibitor of the replication-specific class III DNA polymerase (pol III) of Gr+ bacteria. Although formally a pyrimidine, H2-HPUra derives its inhibitory activity from its specific capacity to mimic the purine nucleotide, dGTP. We describe the successful conversion of the H2-HPUra inhibitor prototype to a bona fide purine, using N2-(benzyl)guanine (BG) as the basis. Structure-activity relationships of BGs carrying a variety of substituents on the aryl ring identified N2-(3,4-dichlorobenzyl)guanine (DCBG) as a nucleus equivalent to H2-HPUra with respect to potency and inhibitor mechanism. DCBdGTP, the 2'-deoxyribonucleoside 5'-triphosphate form of DCBG, was synthesized and characterized with respect to its action on wild-type and mutant forms of B. subtilis DNA pol III. DCBdGTP acted on pol III by the characteristic inhibitor mechanism and formally occupied the dNTP binding site with a fit which permitted its polymerization.
6-（对羟基苯肼基）尿嘧啶（H2-HPUra）是革兰氏阳性菌复制特异性III类DNA聚合酶（pol III）的一种选择性强效抑制剂。尽管从形式上看H2-HPUra是一种嘧啶，但它的抑制活性源于其模拟嘌呤核苷酸dGTP的特殊能力。我们描述了以N2-（苄基）鸟嘌呤（BG）为基础，将H2-HPUra抑制剂原型成功转化为一种真正嘌呤的过程。对芳环上带有各种取代基的BG进行构效关系研究，确定N2-（3,4-二氯苄基）鸟嘌呤（DCBG）在效力和抑制机制方面与H2-HPUra相当。合成了DCBG的2'-脱氧核糖核苷5'-三磷酸形式DCBdGTP，并对其作用于枯草芽孢杆菌DNA pol III野生型和突变型的情况进行了表征。DCBdGTP通过特征性抑制机制作用于pol III，并以一种允许其聚合的契合方式正式占据dNTP结合位点。
