Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.
Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.
Bioorg Chem. 2020 Mar;96:103616. doi: 10.1016/j.bioorg.2020.103616. Epub 2020 Jan 25.
Recently, interest in matrix metalloproteinases (MMPs) -10 and -13 has been revitalized with the growing knowledge on their relevance within the MMPs network and significance of their inhibition for treatment of various diseases like arthritis, cancer, atherosclerosis and Alzheimer. Within this approach, dual MMP-10/13 inhibition was disclosed as new approach for targeted polypharmacology. While several efficient MMP-13 inhibitors are known, very few potent and selective MMP-10 inhibitors were reported. This study describes the design, synthesis and optimization of novel MMP-10/13 inhibitors with enhanced MMP-10 potency and selectivity towards polypharmacology. Starting with a lead fused pyrimidine-based MMP-13 inhibitor with weak MMP-10 inhibition, a structure-based design of pyrimidine and fused pyrimidine scaffolds was rationalized to enhance activity against MMP-10 in parallel with MMP-13. Firstly, a series of 6-methyl pyrimidin-4-one hydrazones 6-10 was synthesized via conventional and ultrasonic-assisted methods, then evaluated for MMP-10/13 inhibition. The most active derivative 9 exhibited acceptable dual potency with 7-fold selectivity for MMP-10 (IC = 53 nM) over MMP-13. Such hydrazones were then cyclized to the corresponding isomeric 1,2,4-triazolo[4,3-a]pyrimidines 12-19. Their MMP-10/13 inhibition assay revealed, in most cases, superior dual activities with general MMP-10 selectivity compared to the corresponding precursors 6-10. In addition, a clear structure activity relationship trend was deduced within the identified regioisomers, where the 5-oxo-1,2,4-triazolo[4,3-a]pyrimidine derivatives 15 and 16 were far more active against MMP-10/13 than their regioisomers 12 and 13. Remarkably, the p-bromophenyl derivative 16 exhibited the highest MMP-10 inhibition (IC = 24 nM), whereas the p-methoxy derivative 18 was the most potent MMP-13 inhibitor (IC = 294 nM). Moreover, 16 exhibited 19-fold selectivity for MMP-10 over MMP-13, 10-fold over MMP-9, and 29-fold over MMP-7. Docking studies were performed to provide reasonable explanation for structure-activity relationships and isoform selectivity. 16 and 18 were then evaluated for their anticancer activities against three human cancers to assess their therapeutic potential at cellular level via MTT assay. Both compounds exhibited superior anticancer activities compared to quercetin. Their in silico ligand efficiency metrics, physicochemical properties and ADME parameters were drug-like. Guided by such findings that point to 16 as the most promising compound in this study, further structure optimization was carried out via photoirradiation-mediated Dimroth rearrangement of the inactive triazolopyrimidine 13 to its potent regioisomer 16.
最近，随着人们对基质金属蛋白酶（MMPs）-10 和 -13 相关性的认识不断深入，以及它们在关节炎、癌症、动脉粥样硬化和阿尔茨海默病等各种疾病治疗中的抑制作用的重要性不断提高，人们对 MMPs-10 和 -13 的兴趣重新燃起。在这种方法中，双重 MMP-10/13 抑制被揭示为靶向多药理学的新方法。虽然已经知道几种有效的 MMP-13 抑制剂，但报道的强效和选择性 MMP-10 抑制剂却很少。本研究描述了新型 MMP-10/13 抑制剂的设计、合成和优化，这些抑制剂具有增强的 MMP-10 活性和对多药理学的选择性。从具有弱 MMP-10 抑制作用的融合嘧啶 MMP-13 抑制剂为先导化合物，基于结构的嘧啶和融合嘧啶骨架设计合理化，以增强对 MMP-10 的活性，同时保持对 MMP-13 的活性。首先，通过常规和超声辅助方法合成了一系列 6-甲基嘧啶-4-酮腙 6-10，然后对其进行 MMP-10/13 抑制评估。最活跃的衍生物 9 表现出可接受的双重活性，对 MMP-10（IC=53nM）的选择性为 MMP-13 的 7 倍。然后将这些腙环化成相应的异构 1,2,4-三唑并[4,3-a]嘧啶 12-19。它们的 MMP-10/13 抑制试验表明，与相应的前体 6-10 相比，大多数情况下，这些化合物具有更好的双重活性和普遍的 MMP-10 选择性。此外，在所确定的区域异构体中推断出了明确的构效关系趋势，其中 5-氧代-1,2,4-三唑并[4,3-a]嘧啶衍生物 15 和 16 对 MMP-10/13 的活性远高于其区域异构体 12 和 13。值得注意的是，对溴苯基衍生物 16 对 MMP-10 的抑制作用最强（IC=24nM），而对甲氧基衍生物 18 是最有效的 MMP-13 抑制剂（IC=294nM）。此外，16 对 MMP-10 的选择性比 MMP-13 高 19 倍，比 MMP-9 高 10 倍，比 MMP-7 高 29 倍。进行了对接研究，以提供合理的结构-活性关系和同工酶选择性解释。然后对 16 和 18 进行了抗癌活性评估，以通过 MTT 测定法在细胞水平上评估它们的治疗潜力。这两种化合物的抗癌活性均优于槲皮素。它们的体内药效学指标、理化性质和 ADME 参数均具有类药性。基于这些研究结果表明 16 是本研究中最有前途的化合物，通过光辐照介导的 Dimroth 重排进一步优化了活性较低的三唑嘧啶 13 至其有效区域异构体 16。
