Two new series of -aryl acetamides and benzyloxy benzylidenes based 2-oxoindole derivatives were designed as potent antiproliferative multiple kinase inhibitors. The results of one-dose NCI antiproliferative screening for compounds and elucidated that the most promising antiproliferative scaffolds were and , which underwent five-dose testing. Notably, the amido congener was the most potent derivative towards pancreatic ductal adenocarcinoma MDA-PATC53 and PL45 cell lines (IC = 1.73 µM and 2.40 µM, respectively), and the benzyloxy derivative was the next potent one with IC values of 2.85 µM and 2.96 µM, respectively. Both compounds and demonstrated a favorable safety profile when tested against normal prostate epithelial cells (RWPE-1). Additionally, compound displayed exceptional selectivity as a multiple kinase inhibitor, particularly targeting PDGFRα, PDGFRβ, and VEGFR-2 kinases, with IC values of 7.41 nM, 6.18 nM, and 7.49 nM, respectively. In contrast, the reference compound Sunitinib exhibited IC values of 43.88 nM, 2.13 nM, and 78.46 nM against the same kinases. The derivative followed closely, with IC values of 9.9 nM, 6.62 nM, and 22.21 nM for the respective kinases. Both and disrupt the G2/M cell cycle transition by upregulating p21 and reducing CDK1 and cyclin B1 mRNA levels. The interplay between targeted kinases and these cell cycle regulators underpins the G2/M cell cycle arrest induced by our compounds. Also, compounds and fundamentally resulted in entering MDA-PATC53 cells into the early stage of apoptosis with good percentages compared to the positive control Sunitinib. The molecular-docking outcomes of scaffolds and in VEGFR-2, PDGFRα, and PDGFRβ active sites depicted their ability to adopt essential binding interactions like the reference Sunitinib. Our designed analogs, specifically and , possess promising antiproliferative and kinase inhibitory properties, making them potential candidates for further therapeutic development.

中文翻译：

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新型 2-氧代吲哚衍生物作为多种 PDGFRα/ß 和 VEGFR-2 酪氨酸激酶抑制剂

两个新系列的基于 2-氧代吲哚衍生物的 β-芳基乙酰胺和苯甲氧基亚苄基衍生物被设计为有效的抗增殖多激酶抑制剂。 NCI 化合物的一剂量抗增殖筛选结果表明，最有希望的抗增殖支架是 和 ，并进行了五剂量测试。值得注意的是，酰胺同系物是对胰腺导管腺癌 MDA-PATC53 和 PL45 细胞系最有效的衍生物（IC50 分别为 1.73 µM 和 2.40 µM），而苄氧基衍生物是下一个有效的衍生物，IC50 值为 2.85 µM 和 2.96分别为μM。当针对正常前列腺上皮细胞 (RWPE-1) 进行测试时，这两种化合物均表现出良好的安全性。此外，该化合物作为多激酶抑制剂表现出卓越的选择性，特别是针对 PDGFRα、PDGFRβ 和 VEGFR-2 激酶，IC 值分别为 7.41 nM、6.18 nM 和 7.49 nM。相比之下，参考化合物舒尼替尼对相同激酶的 IC 值分别为 43.88 nM、2.13 nM 和 78.46 nM。衍生物紧随其后，各个激酶的 IC 值为 9.9 nM、6.62 nM 和 22.21 nM。两者均通过上调 p21 并降低 CDK1 和细胞周期蛋白 B1 mRNA 水平来破坏 G2/M 细胞周期转变。靶向激酶和这些细胞周期调节剂之间的相互作用支撑着我们的化合物诱导的 G2/M 细胞周期停滞。此外，与阳性对照舒尼替尼相比，化合物从根本上导致 MDA-PATC53 细胞进入细胞凋亡的早期阶段，百分比较高。支架以及 VEGFR-2、PDGFRα 和 PDGFRβ 活性位点的分子对接结果表明它们具有像参考舒尼替尼一样采用基本结合相互作用的能力。我们设计的类似物，特别是 和 ，具有有前途的抗增殖和激酶抑制特性，使它们成为进一步治疗开发的潜在候选者。