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首页> 外文期刊>Molecular and Cellular Biochemistry: An International Journal for Chemical Biology >Novel tetrahydroacridine derivatives with iodobenzoic moieties induce G0/G1 cell cycle arrest and apoptosis in A549 non-small lung cancer and HT-29 colorectal cancer cells
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Novel tetrahydroacridine derivatives with iodobenzoic moieties induce G0/G1 cell cycle arrest and apoptosis in A549 non-small lung cancer and HT-29 colorectal cancer cells

机译：具有碘苯甲酸的新型四氢吖啶衍生物诱导A549非小肺癌和HT-29结直肠癌细胞的G0 / G1细胞循环骤停和细胞凋亡

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摘要

A series of nine tetrahydroacridine derivatives with iodobenzoic moiety were synthesized and evaluated for their cytotoxic activity against cancer cell lines-A549 (human lung adenocarcinoma), HT-29 (human colorectal adenocarcinoma) and somatic cell line-EA.hy926 (human umbilical vein cell line). All compounds displayed high cytotoxicity activity against A549 (IC50 59.12-14.87 mu M) and HT-29 (IC50 17.32-5.90 mu M) cell lines, higher than control agents-etoposide and 5-fluorouracil. Structure-activity relationship showed that the position of iodine in the substituent in the para position and longer linker most strongly enhanced the cytotoxic effect. Among derivatives, 1i turned out to be the most cytotoxic and displayed IC50 values of 14.87 mu M against A549 and 5.90 mu M against HT-29 cell lines. In hyaluronidase inhibition assay, all compounds presented anti-inflammatory activity, however, slightly lower than reference compound. ADMET prediction showed that almost all compounds had good pharmacokinetic profiles. 1b, 1c and 1f compounds turned out to act against chemoresistance in cisplatin-resistant 253J B-V cells. Compounds intercalated into DNA and inhibited cell cycle in G0/G1 phase-the strongest inhibition was observed for 1i in A549 and 1c in HT-29. Among compounds, the highest apoptotic effect in both cell lines was observed after treatment with 1i. Compounds caused DNA damage and H2AX phosphorylation, which was detected in A549 and HT-29 cells. All research confirmed anticancer properties of novel tetrahydroacridine derivatives and explained a few pathways of their mechanism of cytotoxic action.
机译：合成含有碘苯甲酸的一系列九种四氢吖啶衍生物，并评估其对癌细胞系-A549（人肺腺癌），HT-29（人结肠腺癌）和体细胞系 - EA.HY926（人脐带细胞）的细胞毒性活性线）。所有化合物均针对A549（IC50 59.12-14.87 mu m）和HT-29（IC5017.32-5.90 mu m）细胞系，高于对照剂 - 依托泊苷和5-氟尿嘧啶，所有化合物显示出高的细胞毒性活性。结构 - 活性关系表明，碘在对达位置和更长的接头中的取代基中的位置最强烈地增强了细胞毒性作用。在衍生物中，1I原来是最多的细胞毒性，并针对HT-29细胞系对抗A549和5.90μm的14.87μm的IC50值。在透明质酸酶抑制测定中，所有化合物呈现出抗炎活性，然而，略低于参考化合物。呼叫预测显示，几乎所有化合物都具有良好的药代动力学谱。 1B，1C和1F化合物原因在顺铂抗性253JB-V细胞中反对化学化。在HT-29中，在A549和1C中观察到在G0 / G1相中嵌入到DNA中并抑制细胞周期的化合物在HT-29中的1I中。在化合物中，用1I处理后观察到两种细胞系中的最高凋亡效应。化合物导致DNA损伤和H2AX磷酸化，其在A549和HT-29细胞中检测到。所有研究确认了新型四氢吖啶衍生物的抗癌特性，并解释了它们对其细胞毒性作用机制的几种途径。

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