新型苯并三唑 N-酰基芳腙杂合体的设计、合成及抗癌活性、对细胞周期谱的影响、caspase-3 介导的细胞凋亡和 FAK 抑制作用。
Novel benzotriazole N-acylarylhydrazone hybrids: Design, synthesis, anticancer activity, effects on cell cycle profile, caspase-3 mediated apoptosis and FAK inhibition.
机构信息
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
出版信息
Bioorg Chem. 2018 Oct;80:531-544. doi: 10.1016/j.bioorg.2018.07.008. Epub 2018 Jul 10.
A series of novel benzotriazole N-acylarylhydrazone hybrids was synthesized according fragment-based design strategy. All the synthesized compounds were evaluated for their anticancer activity against 60 human tumor cell lines by NCI (USA). Five compounds: 3d, 3e, 3f, 3o and 3q exhibited significant to potent anticancer activity at low concentrations. Compound 3q showed the most prominent broad-spectrum anticancer activity against 34 tumor cell lines, with mean growth inhibition percent of 45.80%. It exerted the highest potency against colon HT-29 cell line, with cell growth inhibition 86.86%. All leukemia cell lines were highly sensitive to compound 3q. Additionally, compound 3q demonstrated lethal activity to MDA-MB-435 belonging melanoma. Compound 3e exhibited the highest anticancer activity against leukemic CCRF-CEM and HL-60(TB) cell lines, with cell growth inhibition 86.69% and 86.42%, respectively. Moreover, it exerted marked potency against ovarian OVCAR-3 cancer cell line, with cell growth inhibition 78.24%. Four compounds: 3d, 3e, 3f and 3q were further studied through determination of IC values against the most sensitive cancer cell lines. The four compounds exhibited highly potent anticancer activity against ovarian cancer OVCAR-3 and leukemia HL-60 (TB) cell lines, with IC values in nano-molar range between 25 and 130 nM. They showed 18-2.3 folds more potent anticancer activity than doxorubicin. The most prominent compound was 3e, (IC values 29 and 25 nM against OVCAR-3 and HL-60 (TB) cell lines, respectively), representing 10 and 18 folds more potency than doxorubicin. The anti-proliferative activity of these four compounds appeared to correlate well with their ability to inhibit FAK at nano-molar range between 44.6 and 80.75 nM. Compound 3e was a potent, inhibitor of FAK and Pyk2 activity with IC values of 44.6 and 70.19 nM, respectively. It was 1.6 fold less potent for Pyk2 than FAK. Additionally, it displayed inhibition in cell based assay measuring phosphorylated-FAK (IC = 32.72 nM). Inhibition of FAK enzyme led to a significant increase in the level of active caspase-3, compared to control (11.35 folds), accumulation of cells in pre-G1 phase and annexin-V and propidium iodide staining in addition to cell cycle arrest at G2/M phase indicating that cell death proceeded through an apoptotic mechanism.
根据基于片段的设计策略，合成了一系列新型苯并三唑 N-酰基芳腙杂合化合物。所有合成的化合物均通过美国国立癌症研究所（NCI）对 60 个人类肿瘤细胞系进行了抗癌活性评估。五种化合物：3d、3e、3f、3o 和 3q 在低浓度下表现出显著的抗癌活性。化合物 3q 对 34 种肿瘤细胞系表现出最显著的广谱抗癌活性，平均生长抑制率为 45.80%。它对结肠 HT-29 细胞系的抑制作用最强，细胞生长抑制率为 86.86%。所有白血病细胞系对化合物 3q 高度敏感。此外，化合物 3q 对属于黑色素瘤的 MDA-MB-435 具有致命活性。化合物 3e 对白血病 CCRF-CEM 和 HL-60（TB）细胞系表现出最高的抗癌活性，细胞生长抑制率分别为 86.69%和 86.42%。此外，它对卵巢癌 OVCAR-3 癌细胞系具有显著的效力，细胞生长抑制率为 78.24%。四种化合物：3d、3e、3f 和 3q 进一步通过测定对最敏感的癌细胞系的 IC 值来研究。四种化合物对卵巢癌 OVCAR-3 和白血病 HL-60（TB）细胞系表现出高度有效的抗癌活性，IC 值在纳摩尔范围内为 25 至 130 nM。它们的抗癌活性比阿霉素强 18-2.3 倍。最突出的化合物是 3e（对 OVCAR-3 和 HL-60（TB）细胞系的 IC 值分别为 29 和 25 nM），其效力比阿霉素强 10 倍和 18 倍。这些化合物的抗增殖活性似乎与其在纳摩尔范围内抑制 FAK 的能力密切相关，范围在 44.6 至 80.75 nM 之间。化合物 3e 是一种有效的 FAK 和 Pyk2 活性抑制剂，IC 值分别为 44.6 和 70.19 nM，对 Pyk2 的抑制作用比 FAK 弱 1.6 倍。此外，它在测量磷酸化-FAK 的细胞基础测定中显示出抑制作用（IC=32.72 nM）。抑制 FAK 酶会导致活性 caspase-3 的水平显著增加，与对照相比（11.35 倍），细胞在 G1 期前积累，并用 Annexin-V 和碘化丙啶染色，此外，细胞周期在 G2/M 期被阻断，表明细胞死亡通过凋亡机制进行。
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