Behe M J, Englander W S
Biochemistry. 1979 Sep 18;18(19):4196-201. doi: 10.1021/bi00586a025.
The ability of a variety of phenyl derivatives to inhibit sickle cell hemoglobin gelation was placed on a quantitative scale by parallel equilibrium and kinetic assays. Modifications of the phenyl ring studied include polar, nonpolar, and charged substituents, added aromatic rings, and loss of aromaticity. Other noncovalent inhibitors previously reported to have high potency were measured and placed on the same quantitative scale. Some phenyl derivatives were found to be as effective an any other known noncovalent antigelling agent. The phenyl compounds penetrate easily into red cells, and their potency is tolerant to chemical modification, which holds out the possibility of designing low-toxicity derivatives. On the negative side, the level of potency obtainable appears to be inadequate for clinical use. The best phenyl inhibitors display a functionally defined inhibitory constant (K1) of 75 mM, and it can be estimated that inhibitor concentrations over 20 mM would be necessary to obtain minimal clinically significant benefit. Furthermore, with the variety of modifications tested here, no impressive increase in activity could be achieved over that found in the simplest phenyl compounds.
通过平行平衡和动力学分析，将多种苯基衍生物抑制镰状细胞血红蛋白凝胶化的能力进行了定量评估。所研究的苯环修饰包括极性、非极性和带电荷的取代基、添加的芳环以及芳香性的丧失。对先前报道具有高效力的其他非共价抑制剂进行了测定，并将其置于相同的定量尺度上。发现一些苯基衍生物与任何其他已知的非共价抗凝胶剂一样有效。苯基化合物易于渗透到红细胞中，并且它们的效力对化学修饰具有耐受性，这为设计低毒性衍生物提供了可能性。不利的一面是，可获得的效力水平似乎不足以用于临床。最佳的苯基抑制剂显示出功能定义的抑制常数（K1）为75 mM，可以估计，要获得最小的临床显著益处，抑制剂浓度需要超过20 mM。此外，在这里测试的各种修饰中，与最简单的苯基化合物相比，活性没有显著提高。
