Wright G E, Brown N C
J Med Chem. 1980 Jan;23(1):34-8. doi: 10.1021/jm00175a007.
Substituted 6-anilinouracils were found to be potent inhibitors of the replication-specific enzyme, DNA polymerase III, from Bacillus subtilis. Inhibition potency was maximized by inclusion of small alkyl groups or halogens in the meta and para positions of the phenyl ring; polar substituents decreased activity considerably. Qualitative structure--activity relationships indicated that the meta position can tolerate larger groups, suggesting that this position may be suitable for the introduction of a group capable of irreversibly binding to the enzyme. Several 6-(alkylamino)uracils were weak inhibitors of DNA polymerases III; the optimum alkyl groups for enzyme binding were n-pentyl and n-hexyl, which apparently can occupy the planar enzyme binding site. The varied activities of 6-anilinouracils on a mutant DNA polymerase, resistant to 6-(phenylhydrazino)- and 6-(benzylamino)uracils bearing a p-OH or NH2 group, have altered previous postulates for the structural basis of inhibitor resistance and have permitted construction of a refined model for inhibitor conformation in the latter series.
已发现取代的6-苯胺基尿嘧啶是来自枯草芽孢杆菌的复制特异性酶DNA聚合酶III的有效抑制剂。通过在苯环的间位和对位引入小烷基或卤素，抑制效力可达到最大化；极性取代基会显著降低活性。定性构效关系表明，间位能够耐受更大的基团，这表明该位置可能适合引入能够与酶不可逆结合的基团。几种6-（烷基氨基）尿嘧啶是DNA聚合酶III的弱抑制剂；与酶结合的最佳烷基是正戊基和正己基，它们显然可以占据平面的酶结合位点。6-苯胺基尿嘧啶对一种突变DNA聚合酶具有不同的活性，该突变酶对带有对羟基或氨基的6-（苯肼基）尿嘧啶和6-（苄氨基）尿嘧啶具有抗性，这改变了先前关于抑制剂抗性结构基础的假设，并使得能够构建后一系列抑制剂构象的精确模型。
