设计、合成、抗增殖、抗微生物、抗血管生成活性及新型腙衍生物分析。
Design, Synthesis, Anti-Proliferative, Anti-microbial, Anti-Angiogenic Activity and Analysis of Novel Hydrazone Derivatives.
机构信息
Chemistry Department, Faculty of Science, Eskisehir Technical University, 26470, Eskisehir, Turkey.
Biology Department, Faculty of Science, Eskisehir Technical University, 26470, Eskisehir, Turkey.
出版信息
Anticancer Agents Med Chem. 2019;19(13):1658-1669. doi: 10.2174/1871520619666190318125824.
BACKGROUND
Cancer is the second leading cause of death globally. Hydrazone and hydrazone derivatives have high activity, and for this reason, these compound are greatly used by researchers to synthesize new anti-cancer drug. The aim of this research work is to synthesize novel anticancer agents.
METHODS
New hydrazone derivatives were synthesized a reaction between 3-formylphenyl methyl carbonate and benzhydrazide, 4-methylbenzoic hydrazide, 4--butylbenzoic hydrazide, 4-nitrobenzoic hydrazide and 3- methoxybenzoic hydrazide, and were successfully characterized using elemental analysis, H-NMR, C-NMR, FT-IR and LC-MS techniques. The synthesized compounds were evaluated for their antimicrobial (some grampositive and -negative bacteria, filamentous fungi and yeasts), anti-proliferative (T47D and HCC1428-breast cancer cells) and anti-angiogenic (HUVEC-endothelial cells) activities. The anti-proliferative activities of the hydrazone compounds R1-R5 were studied on these cell lines by MTT assay. The anti-angiogenic potential of the compounds was determined by the endothelial tube formation assay. To identify structural features related to the anti-proliferative activity of these compounds, 2D-QSAR was performed.
RESULT
The results indicated that compound R3 exhibited strong anti-angiogenic and anti-proliferative activity on breast cancer cell lines and healthy cell lines. Also, this compound; possessing a tertiary butyl moiety on the hydrazine, exhibited the highest inhibitory effect against all tested microorganisms; in particular, it inhibited at a lower concentration than ketoconazole. Among the investigated compounds, those bearing methyl, tertiary butyl (compound R2, R3) and methoxy (compound R5) moiety were found to be more successful anticandidal derivatives than standard antifungal antibiotics. The QSAR analysis suggested that the tumor specificity of the hydrazone correlated with their molecular weight, lipophilicity, molar refractivity, water solubility, DipolHybrid:(MOPAC) and ExchangeEnergy:(MOPAC). Absorption, Distribution, Metabolism and Elimination (ADME) analysis of the hydrazone compounds showed that they have favorable pharmacokinetic and drug-likeness properties. The ADME results clarify that R3 is the best compound in terms of pharmacokinetic properties. In contrast to other compounds; target prediction analysis of the compound R3 showed inhibitory activity on estrogen-related receptor alpha transcription factor (ESRRA). The target prediction analysis was supported by molinspiration bioactivity score.
CONCLUSION
The R3 compound is considered to be an important candidate for future studies with its suitability for the Lipinski's rule of five for drug-likeness, and effective and results.
背景
癌症是全球第二大死亡原因。腙及其衍生物活性高，因此，这些化合物被研究人员广泛用于合成新的抗癌药物。本研究工作的目的是合成新型抗癌剂。
方法
通过 3-甲酰基苯基碳酸甲酯与苯甲酰肼、4-甲基苯甲酸酰肼、4-正丁基苯甲酸酰肼、4-硝基苯甲酸酰肼和 3-甲氧基苯甲酸酰肼之间的反应，成功合成了新型腙衍生物，并通过元素分析、H-NMR、C-NMR、FT-IR 和 LC-MS 技术对其进行了表征。对合成化合物进行了抗菌（部分革兰氏阳性和阴性细菌、丝状真菌和酵母）、抗增殖（T47D 和 HCC1428-乳腺癌细胞）和抗血管生成（HUVEC-内皮细胞）活性评价。通过 MTT 测定法研究了 R1-R5 腙化合物对这些细胞系的抗增殖活性。通过内皮管形成测定法确定了化合物的抗血管生成潜力。为了确定与这些化合物抗增殖活性相关的结构特征，进行了 2D-QSAR 研究。
结果
结果表明，化合物 R3 对乳腺癌细胞系和正常细胞系表现出较强的抗血管生成和抗增殖活性。此外，该化合物在肼上具有叔丁基部分，对所有测试的微生物均表现出最高的抑制作用；特别是，它以低于酮康唑的浓度抑制。在所研究的化合物中，那些带有甲基、叔丁基（化合物 R2、R3）和甲氧基（化合物 R5）部分的化合物比标准抗真菌抗生素更成功地成为抗真菌衍生物。QSAR 分析表明，腙的肿瘤特异性与其分子量、亲脂性、摩尔折射率、水溶性、DipolHybrid:（MOPAC）和 ExchangeEnergy:（MOPAC）有关。腙化合物的吸收、分布、代谢和消除（ADME）分析表明，它们具有良好的药代动力学和类药性。ADME 结果表明，R3 化合物在药代动力学特性方面是最好的化合物。与其他化合物相比；R3 化合物的靶标预测分析显示对雌激素相关受体α转录因子（ESRRA）有抑制活性。靶标预测分析得到了 molinspiration 生物活性评分的支持。
结论
R3 化合物被认为是未来研究的重要候选物，因为它符合类药性的利宾斯基五法则，并且具有有效的结果。
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