Design, Synthesis, and Biological Evaluation of Tetrahydro‐β‐carboline Derivatives as Selective Sub‐Nanomolar Gelatinase Inhibitors,ChemMedChem

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Design, Synthesis, and Biological Evaluation of Tetrahydro‐β‐carboline Derivatives as Selective Sub‐Nanomolar Gelatinase Inhibitors
ChemMedChem ( IF 3.6 ) Pub Date : 2018-06-12 , DOI: 10.1002/cmdc.201800237
Giuseppe Felice Mangiatordi _{1,

2} , Tatiana Guzzo ₃ , Eugenio Claudio Rossano ₃ , Daniela Trisciuzzi ₁ , Domenico Alberga ₁ , Giovanni Fasciglione ₄ , Massimiliano Coletta ₄ , Alessandra Topai ₃ , Orazio Nicolotti ₁

Affiliation

Targeting matrix metalloproteinases (MMPs) is a pursued strategy for treating several pathological conditions, such as multiple sclerosis and cancer. Herein, a series of novel tetrahydro‐β‐carboline derivatives with outstanding inhibitory activity toward MMPs are present. In particular, compounds 9 f, 9 g, 9 h and 9 i show sub‐nanomolar IC₅₀ values. Interestingly, compounds 9 g and 9 i also provide remarkable selectivity toward gelatinases; IC₅₀=0.15 nm for both toward MMP‐2 and IC₅₀=0.63 and 0.58 nm, respectively, toward MMP‐9. Molecular docking simulations, performed by employing quantum mechanics based partial charges, shed light on the rationale behind binding involving specific interactions with key residues of S1′ and S3′ domains. Taken together, these studies indicate that tetrahydro‐β‐carboline represents a promising scaffold for the design of novel inhibitors able to target MMPs and selectively bias gelatinases, over the desirable range of the pharmacokinetics spectrum.

中文翻译：

四氢-β-咔啉衍生物作为选择性亚纳米摩尔明胶酶抑制剂的设计，合成和生物学评估

靶向基质金属蛋白酶（MMPs）是一种用于治疗多种病理状况（例如多发性硬化症和癌症）的策略。本文介绍了一系列对MMP具有出色抑制活性的新型四氢-β-咔啉衍生物。特别是化合物9 f，9 g，9 h和9 i表现出亚纳摩尔级的IC ₅₀值。有趣的是，化合物9 g和9 i还提供了对明胶酶的显着选择性。对于MMP-2而言，IC ₅₀ = 0.15 n m，对于IC ₅₀ = 0.63和0.58 n m分别朝向MMP-9。通过使用基于量子力学的部分电荷进行的分子对接模拟，阐明了结合背后的基本原理，其中涉及与S1'和S3'域的关键残基的特异性相互作用。综上所述，这些研究表明四氢-β-咔啉代表了一种有希望的支架，可用于设计能够在药代动力学谱的理想范围内靶向MMPs和选择性偏向明胶酶的新型抑制剂。

更新日期：2018-06-12

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