Pyrrole derivatives (PDs) chloro-1-(4-chlorobenzyl)-4-((3-(trifluoromethyl)phenyl)amino)-1H-pyrrole-2,5-dione (MI-1) and 5-amino-4-(1,3-benzothyazol-2-yn)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrole-3-one (D1) were synthesised as inhibitors of several protein kinases including EGFR and VEGFR. The aim of the study was to reveal the exact mechanisms of PDs' action EGFR and VEGFR are involved in. We observed, that both PDs could bind with EGFR and VEGFR and form stable complexes. PDs entered into electrostatic interactions with polar groups of phospholipid heads in cell membrane, and the power of interaction depended on the nature of PD radical substituents (greater for MI-1 and smaller for D1). Partial intercalation of MI-1 into the membrane hydrophobic zone also occurred. PDs concentrations induced apoptosis in malignant cells but normal ones had different sensitivity to those. MI-1 and D1 acted like antioxidants in inflamed colonic tissue, as evidenced by reduce of lipid and protein peroxidation products (by 43-67%) and increase of superoxide dismutase activity (by 40 and 58%) with restoring these values to control ones. MI-1 restored reduced haemoglobin and normalised elevated platelets and monocytes in settings of colorectal cancer, whereas D1 normalised only platelets. Thus, MI-1 and D1 could be used as competitive inhibitors of EGFR and VEGFR and antioxidants, which might contribute to realisation of their anti-inflammatory, proapoptotic and antitumor activity.

中文翻译：

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吡咯衍生物作为潜在的抗癌疗法：合成、作用机制、安全性。

吡咯衍生物 (PD) chloro-1-(4-chlorobenzyl)-4-((3-(trifluoromethyl)phenyl)amino)-1H-pyrrole-2,5-dione (MI-1) 和 5-amino-4- (1,3-苯并噻唑-2-yn)-1-(3-甲氧基苯基)-1,2-二氢-3H-吡咯-3-酮 (D1) 被合成为几种蛋白激酶的抑制剂，包括 EGFR 和 VEGFR。本研究的目的是揭示 EGFR 和 VEGFR 参与的 PD 作用的确切机制。我们观察到，这两种 PD 都可以与 EGFR 和 VEGFR 结合并形成稳定的复合物。PDs与细胞膜中磷脂头部的极性基团发生静电相互作用，相互作用的力量取决于PD自由基取代基的性质（MI-1较大，D1较小）。MI-1 也部分嵌入到膜疏水区中。PDs浓度诱导恶性细胞凋亡，但正常细胞对这些细胞具有不同的敏感性。MI-1 和 D1 在发炎的结肠组织中就像抗氧化剂一样，这可以通过脂质和蛋白质过氧化产物的减少（43-67%）和超氧化物歧化酶活性的增加（40% 和 58%）来证明，并将这些值恢复到对照值. MI-1 在结肠直肠癌的情况下恢复减少的血红蛋白并使升高的血小板和单核细胞正常化，而 D1 仅使血小板正常化。因此，MI-1 和 D1 可作为 EGFR 和 VEGFR 的竞争性抑制剂和抗氧化剂，这可能有助于实现其抗炎、促凋亡和抗肿瘤活性。脂质和蛋白质过氧化产物的减少（43-67%）和超氧化物歧化酶活性的增加（40%和58%）证明了这些值恢复到对照值。MI-1 在结肠直肠癌的情况下恢复减少的血红蛋白并使升高的血小板和单核细胞正常化，而 D1 仅使血小板正常化。因此，MI-1 和 D1 可作为 EGFR 和 VEGFR 的竞争性抑制剂和抗氧化剂，这可能有助于实现其抗炎、促凋亡和抗肿瘤活性。脂质和蛋白质过氧化产物的减少（43-67%）和超氧化物歧化酶活性的增加（40%和58%）证明了这些值恢复到对照值。MI-1 在结肠直肠癌的情况下恢复减少的血红蛋白并使升高的血小板和单核细胞正常化，而 D1 仅使血小板正常化。因此，MI-1 和 D1 可作为 EGFR 和 VEGFR 的竞争性抑制剂和抗氧化剂，这可能有助于实现其抗炎、促凋亡和抗肿瘤活性。