Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.
Facultad de Farmacia, Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.
Med Res Rev. 2019 May;39(3):775-830. doi: 10.1002/med.21541. Epub 2018 Oct 25.
Tubulin, the microtubules and their dynamic behavior are amongst the most successful antitumor, antifungal, antiparasitic, and herbicidal drug targets. Sulfonamides are exemplary drugs with applications in the clinic, in veterinary and in the agrochemical industry. This review summarizes the actual state and recent progress of both fields looking from the double point of view of the target and its drugs, with special focus onto the structural aspects. The article starts with a brief description of tubulin structure and its dynamic assembly and disassembly into microtubules and other polymers. Posttranslational modifications and the many cellular means of regulating and modulating tubulin's biology are briefly presented in the tubulin code. Next, the structurally characterized drug binding sites, their occupying drugs and the effects they induce are described, emphasizing on the structural requirements for high potency, selectivity, and low toxicity. The second part starts with a summary of the favorable and highly tunable combination of physical-chemical and biological properties that render sulfonamides a prototypical example of privileged scaffolds with representatives in many therapeutic areas. A complete description of tubulin-binding sulfonamides is provided, covering the different species and drug sites. Some of the antimitotic sulfonamides have met with very successful applications and others less so, thus illustrating the advances, limitations, and future perspectives of the field. All of them combine in a mechanism of action and a clinical outcome that conform efficient drugs.
微管、微管蛋白及其动态行为是最成功的抗肿瘤、抗真菌、抗寄生虫和除草药物靶点之一。磺胺类药物是具有临床、兽医和农业化学工业应用的典型药物。这篇综述从靶点及其药物的双重观点总结了这两个领域的现状和最新进展，特别关注结构方面。本文首先简要描述了微管蛋白的结构及其动态组装和分解为微管和其他聚合物。在微管密码中简要介绍了翻译后修饰和许多调节和调节微管生物学的细胞方法。接下来，描述了结构上有特征的药物结合位点、占据这些位点的药物以及它们诱导的作用，强调了高效力、选择性和低毒性的结构要求。第二部分首先总结了物理化学和生物性质的有利且高度可调的组合，使磺胺类药物成为具有代表性的特权支架的原型，在许多治疗领域都有代表。提供了与微管蛋白结合的磺胺类药物的完整描述，涵盖了不同的物种和药物靶点。一些抗有丝分裂的磺胺类药物已经得到了非常成功的应用，而其他的则不然，因此说明了该领域的进展、局限性和未来前景。它们都结合在作用机制和临床结果中，形成有效的药物。
