Inhibition of mouse double minute 2 homolog (MDM2)-p53 interaction and reactivation of p53 signaling have been explored as effective anticancer therapeutic strategy. The potent and specific antitumor activity shown by Nutlins, first class of MDM2-p53 inhibitors discovered, has made these compounds potential antitumor candidates. To this end, we synthesized Nutlin-1 and Nutlin-2 analogs through molecular simplification and selected the compound with the most efficient antitumoral activity. Cytotoxicity of Nutlin-2 analog LQFM126 on B16F10 melanoma cells induced intense cytoplasmic vacuolization, reduction of cell size, chromatin condensation, cytoplasmic degeneration and nuclear fragmentation. LQFM126 antiproliferative effects mediated cell cycle retention in G0/G1 phase and increased the levels of cell cycle regulatory proteins p21 and p27. This Nutlin analog increased mitochondrial membrane potential, activated caspase-8, -9 and -3/7 and reduced VEGF levels in B16F10 cells. Therefore, LQFM126 promoted alterations suggestive of apoptosis, G0/G1 cell cycle arrest and suppression of angiogenesis through modulation of VEGF expression in B16F10 cells. Additionally, LQFM126 was classified as UN GHS category 4 (LD50 > 300-2000 mg/kg), suggesting it has low acute systemic toxicity. LQFM126 can be a promising prototype for anticancer therapy.

中文翻译：

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LQFM126原型针对B16F10黑色素瘤细胞的抗血管生成和抗肿瘤活性。

已经研究了抑制小鼠双分钟2同源物（MDM2）-p53相互作用和p53信号传导的重新激活作为有效的抗癌治疗策略。Nutlins是发现的第一类MDM2-p53抑制剂，显示出有效的抗肿瘤活性，这些化合物已成为潜在的抗肿瘤候选药物。为此，我们通过分子简化合成了Nutlin-1和Nutlin-2类似物，并选择了具有最有效抗肿瘤活性的化合物。Nutlin-2类似物LQFM126对B16F10黑色素瘤细胞的细胞毒性诱导了强烈的细胞质空泡，细胞大小减少，染色质浓缩，细胞质变性和核碎裂。LQFM126的抗增殖作用介导了细胞周期停留在G0 / G1期，并增加了细胞周期调节蛋白p21和p27的水平。这种Nutlin类似物可增加线粒体膜电位，激活caspase-8，-9和-3/7并降低B16F10细胞中的VEGF水平。因此，LQFM126通过调节B16F10细胞中VEGF的表达来促进细胞凋亡，G0 / G1细胞周期阻滞和血管生成抑制的改变。此外，LQFM126被列为联合国GHS类别4（LD50> 300-2000 mg / kg），表明其急性全身毒性较低。LQFM126可能是抗癌治疗的有希望的原型。LQFM126被列为联合国GHS类别4（LD50> 300-2000 mg / kg），表明它的急性全身毒性较低。LQFM126可能是抗癌治疗的有希望的原型。LQFM126被列为联合国GHS类别4（LD50> 300-2000 mg / kg），表明它的急性全身毒性较低。LQFM126可能是抗癌治疗的有希望的原型。