Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Edifício do Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos s/n, 4450-208 Matosinhos, Portugal.
Molecules. 2021 Jun 19;26(12):3737. doi: 10.3390/molecules26123737.
The p53 protein is one of the most important tumor suppressors that are frequently inactivated in cancer cells. This inactivation occurs either because the gene is mutated or deleted, or due to the p53 protein inhibition by endogenous negative regulators, particularly murine double minute (MDM)2. Therefore, the reestablishment of p53 activity has received great attention concerning the discovery of new cancer therapeutics. Chalcones are naturally occurring compounds widely described as potential antitumor agents through several mechanisms, including those involving the p53 pathway. The inhibitory effect of these compounds in the interaction between p53 and MDM2 has also been recognized, with this effect associated with binding to a subsite of the p53 binding cleft of MDM2. In this work, a literature review of natural and synthetic chalcones and their analogues potentially interfering with p53 pathway is presented. Moreover, in silico studies of drug-likeness of chalcones recognized as p53-MDM2 interaction inhibitors were accomplished considering molecular descriptors, biophysiochemical properties, and pharmacokinetic parameters in comparison with those from p53-MDM2 in clinical trials. With this review, we expect to guide the design of new and more effective chalcones targeting the p53 pathway.
p53 蛋白是最重要的肿瘤抑制因子之一，在癌细胞中经常失活。这种失活要么是因为基因发生了突变或缺失，要么是由于内源性负调节剂，特别是鼠双微体 2（MDM）2 的抑制作用。因此，为了发现新的癌症治疗方法，人们非常关注重新建立 p53 活性。查尔酮是一种天然存在的化合物，广泛描述为具有多种机制的潜在抗肿瘤剂，包括涉及 p53 途径的机制。这些化合物在 p53 和 MDM2 之间相互作用的抑制作用也已得到认可，这种作用与结合到 MDM2 的 p53 结合裂隙的亚部位有关。在这项工作中，对天然和合成查尔酮及其类似物潜在干扰 p53 途径的文献进行了综述。此外，还对被认为是 p53-MDM2 相互作用抑制剂的查尔酮进行了药物相似性的计算研究，考虑了分子描述符、生物物理化学性质和药代动力学参数，并与临床试验中的 p53-MDM2 进行了比较。通过这项综述，我们希望为设计针对 p53 途径的新型和更有效的查尔酮提供指导。
