Moreira Joana, Silva Patrícia M A, Barros Matilde, Saraiva Lucília, Pinto Madalena, Bousbaa Hassan, Cidade Honorina
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.
Pharmaceuticals (Basel). 2023 Jun 14;16(6):879. doi: 10.3390/ph16060879.
In this work, the design and synthesis of a new chalcone-trimethoxycinnamide hybrid () based on the combination of subunits of two promising antiproliferative compounds ( () and ()), previously obtained by our research group, are reported. In order to expand the structure-activity relationship (SAR) knowledge, a new series of -analogues was also designed and synthetized. All the compounds were evaluated for their antitumor activity against melanoma (A375-C5), breast adenocarcinoma (MCF-7), and colorectal carcinoma (HCT116) cell lines, as well as non-tumor HPAEpiC cells. Three of the newly synthesized compounds (, , and ) exhibited potent antiproliferative activity, mainly on colorectal tumor cells (GI = 2.66-3.26 μM), showing hybrid selectivity for tumor cells. We performed molecular mechanism studies to evaluate the potential interference of compounds with the p53 pathway, namely, p53-MDM2 interaction and mitosis in HCT116 cells. The antiproliferative activities of compounds were shown to be p53-independent. Compound emerged as an antimitotic agent by inducing the mitotic arrest of colorectal tumor cells, and subsequently, cell death.
在本研究中，我们报道了基于我们研究小组先前获得的两种有前景的抗增殖化合物（化合物（）和化合物（））的亚基组合，设计并合成了一种新型查尔酮 - 三甲氧基肉桂酰胺杂合物（）。为了扩展构效关系（SAR）知识，还设计并合成了一系列新的 - 类似物。评估了所有化合物对黑色素瘤（A375 - C5）、乳腺腺癌（MCF - 7）和结肠直肠癌（HCT116）细胞系以及非肿瘤HPAEpiC细胞的抗肿瘤活性。三种新合成的化合物（、和）表现出强大的抗增殖活性，主要针对结肠直肠肿瘤细胞（GI = 2.66 - 3.26 μM），显示出杂合物对肿瘤细胞的选择性。我们进行了分子机制研究，以评估化合物对p53途径的潜在干扰，即HCT116细胞中的p53 - MDM2相互作用和有丝分裂。结果表明，化合物的抗增殖活性与p53无关。化合物通过诱导结肠直肠肿瘤细胞的有丝分裂停滞并随后导致细胞死亡，成为一种抗有丝分裂剂。
