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Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2020-11-16 , DOI: 10.1016/j.bmc.2020.115827
Lorenzo Cianni 1 , Fernanda Dos Reis Rocho 1 , Vinícius Bonatto 1 , Felipe Cardoso Prado Martins 1 , Jerônimo Lameira 2 , Andrei Leitão 1 , Carlos A Montanari 1 , Anwar Shamim 1
Affiliation  

Human cathepsin B (CatB) is an important biological target in cancer therapy. In this work, we performed a knowledge-based design approach and the synthesis of a new set of 19 peptide-like nitrile-based cathepsin inhibitors. Reported compounds were assayed against a panel of human cysteine proteases: CatB, CatL, CatK, and CatS. Three compounds (7h, 7i, and 7j) displayed nanomolar inhibition of CatB and selectivity over CatK and CatL. The selectivity was achieved by using the combination of a para biphenyl ring at P3, halogenated phenylalanine in P2 and Thr-O-Bz group at P1. Likewise, compounds 7i and 7j showed selective CatB inhibition among the panel of enzymes studied. We have also described a successful example of bioisosteric replacement of the amide bond for a sulfonamide one [7e → 6b], where we observed an increase in affinity and selectivity for CatB while lowering the compound lipophilicity (ilogP). Our knowledge-based design approach and the respective structure–activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cathepsins.



中文翻译:

组织蛋白酶 B 和 L 腈基抑制剂的设计、合成和逐步优化

人组织蛋白酶 B (CatB) 是癌症治疗中的重要生物学靶点。在这项工作中,我们采用了一种基于知识的设计方法,并合成了一组新的 19 种肽样腈基组织蛋白酶抑制剂。针对一组人半胱氨酸蛋白酶对报告的化合物进行了分析:CatB、CatL、CatK 和 CatS。三种化合物(7h7i7j)显示出对 CatB 的纳摩尔抑制以及对 CatK 和 CatL 的选择性。的选择性通过使用的组合来实现对位联苯环在P 3,卤代苯丙氨酸P 2和Thr-O-BZ组在P 1。同样地,化合物7I7J在所研究的酶组中显示出选择性 CatB 抑制作用。我们还描述了一个成功的例子,用生物等排置换磺酰胺 [ 7e  →  6b ]的酰胺键,我们观察到 CatB 的亲和力和选择性增加,同时降低了化合物的亲脂性 (ilogP)。我们基于知识的设计方法和各自的结构-活性关系为治疗相关组织蛋白酶的特定配体-靶标相互作用提供了见解。

更新日期:2020-11-27
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