Design, Synthesis, Dynamic Docking, Biochemical Characterization, and in Vivo Pharmacokinetics Studies of Novel Topoisomerase II Poisons with Promising Antiproliferative Activity.,Journal of Medicinal Chemistry

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Design, Synthesis, Dynamic Docking, Biochemical Characterization, and in Vivo Pharmacokinetics Studies of Novel Topoisomerase II Poisons with Promising Antiproliferative Activity.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-30 , DOI: 10.1021/acs.jmedchem.9b01760
Jose M Arencibia ₁ , Nicoletta Brindani ₁ , Sebastian Franco-Ulloa ₁ , Michela Nigro ₁ , Jissy Akkarapattiakal Kuriappan ₁ , Giuliana Ottonello ₂ , Sine Mandrup Bertozzi ₂ , Maria Summa ₂ , Stefania Girotto ₁ , Rosalia Bertorelli ₂ , Andrea Armirotti ₂ , Marco De Vivo ₁

Affiliation

We previously reported a first set of hybrid topoisomerase II (topoII) poisons whose chemical core merges key pharmacophoric elements of etoposide and merbarone, which are two well-known topoII blockers. Here, we report on the expansion of this hybrid molecular scaffold and present 16 more hybrid derivatives that have been designed, synthesized, and characterized for their ability to block topoII and for their overall drug-like profile. Some of these compounds act as topoII poison and exhibit good solubility, metabolic (microsomal) stability, and promising cytotoxicity in three cancer cell lines (DU145, HeLa, A549). Compound 3f (ARN24139) is the most promising drug-like candidate, with a good pharmacokinetics profile in vivo. Our results indicate that this hybrid new chemical class of topoII poisons deserves further exploration and that 3f is a favorable lead candidate as a topoII poison, meriting future studies to test its efficacy in in vivo tumor models.

中文翻译：

具有有望的抗增殖活性的新型拓扑异构酶II毒物的设计，合成，动态对接，生化特性和体内药代动力学研究。

我们之前曾报道过第一组杂化拓扑异构酶II（topoII）毒物，其化学核心融合了依托泊苷和美巴龙的关键药效学元素，这是两种众所周知的topoII阻滞剂。在这里，我们报道了这种杂合分子支架的扩展，并提出了16种杂合衍生物的设计，合成和表征，这些衍生物具有阻断topoII的能力和整体药物样特性。这些化合物中的一些充当topoII毒物，在三种癌细胞系（DU145，HeLa，A549）中表现出良好的溶解性，代谢（微粒体）稳定性和有希望的细胞毒性。化合物3f（ARN24139）是最有前途的药物样候选物，在体内具有良好的药代动力学特征。我们的结果表明，这种新型的topoII毒物化学杂种值得进一步探索，并且3f作为topoII毒物是有利的潜在候选药物，值得进一步研究以测试其在体内肿瘤模型中的功效。

更新日期：2020-03-30

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