WestCHEM, Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK.
Future Med Chem. 2012 May;4(8):971-89. doi: 10.4155/fmc.12.52.
Natural products that bind to DNA in the minor groove are valuable templates for drug design. Examples include distamycin, netropsin, duocarmycin and anthramycin. Anticancer and anti-infective drugs feature strongly amongst their derivatives. The structures and activities of chemotypes with various therapeutic actions are discussed in the context of the broader field of therapeutically active minor groove binders. The evolution of a series of exceptionally potent and nontoxic antibacterial compounds is discussed using the general design principle of introducing additional hydrophobicity into the distamycin template to increase the strength of binding to DNA. As well as potent antibacterial compounds, antifungal and antiparasitic compounds with exceptional cellular activity against trypanosomes have been identified. Possible mechanisms of action including gene regulation and topoisomerase inhibition are discussed with the need in mind to understand selective toxicity in the series to support future drug discovery.
与 DNA 小沟结合的天然产物是药物设计的有价值模板。例如，放线菌素、氮芥霉素、双胞菌素和蒽环霉素。它们的衍生物在抗癌和抗感染药物中占有重要地位。本文讨论了具有各种治疗作用的化学型结构和活性，将其置于治疗性活性小沟结合物的更广泛领域中。通过在放线菌素模板中引入额外的疏水性来增加与 DNA 结合的强度，从而设计出一系列非常有效且无毒的抗菌化合物。除了具有强大抗菌活性的化合物外，还发现了具有针对锥虫的异常细胞活性的抗真菌和抗寄生虫化合物。讨论了可能的作用机制，包括基因调控和拓扑异构酶抑制，需要了解该系列化合物的选择性毒性，以支持未来的药物发现。
