三丁基锡（IV）配合物的羧酸酯衍生物作为抗癌和抗利什曼原虫药物。
Carboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents.
机构信息
Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
Department of Chemistry, Allama Iqbal Open University, H-8, Islamabad, 44000, Pakistan.
出版信息
Daru. 2017 Apr 4;25(1):8. doi: 10.1186/s40199-017-0174-0.
BACKGROUND
Tributyltin (IV) compounds are promising candidates for drug development. In the current study, we evaluated in-vitro and in-silico profile of carboxylate derivatives of tributyltin (IV) complexes.
METHODS
ADMET and drug-likeliness properties were predicted using MetaPrint2D React, preADMET, SwissADME and Molsoft tools. SwissTargetPrediction predicted molecular targets for compounds. In-vitro bioactivity was evaluated by quantifying cytotoxicity against HepG2, THP-1 cell lines, isolated lymphocytes and leishmania promastigotes as well as measuring protein kinase (PK) inhibition activity.
RESULTS
Results indicate partial compliance of compounds with drug-likeliness rules. Ch-409 complies with WDI and Lipinski rules. ADMET profile prediction shows strong plasma protein binding except for Ch-409, low to high GI absorption and BBB penetration (C/C = 0.942-11; caco-2 cells permeability 20.13-26.75 nm/sec), potential efflux by P-glycoprotein, metabolism by CYP3A4, medium inhibition of hERG, mutagenicity and capacity to be detoxified by glutathionation and glucuronidation. Molecular targets include proteases, enzymes, membrane receptors, transporters and ion channels where Ch-409 targets membrane receptors only. Compounds are significantly (p < 0.05) cytotoxic against HepG2 cell line and leishmania as compared with normal isolated lymphocytes. Ch-459 indicates highest toxicity against leishmania (mortality 97.9 ± 3.99%; LC50 0.323 ± 0.002 μg/mL) whereas Ch-409 possesses maximum cytotoxicity against HepG2 cell line (IC50 0.08 ± 0.001 μg/mL) as well as 97.5 ± 1.98% (LC50 0.954 ± 0.158 μg/mL) mortality of leishmania promastigotes. It was observed that antileishmanial effect was reduced by 16.38%-34.38% and 15-38.2% in the presence of NaN and mannitol respectively. PK inhibition and reactive oxygen species production are possible mechanisms for cytotoxicity.
CONCLUSIONS
Selected carboxylate derivatives of tributyltin (IV) complexes possess significant antileishmanial and cytotoxic potential. These are promising compounds for the development of antileishmanial and anticancer drugs. Graphical Abstract Carboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents.
背景
三丁基锡（IV）化合物是药物开发的有前途的候选物。在本研究中，我们评估了三丁基锡（IV）配合物的羧酸酯衍生物的体外和计算机模拟特性。
方法
使用 MetaPrint2D React、preADMET、SwissADME 和 Molsoft 工具预测 ADMET 和药物相似性特性。SwissTargetPrediction 预测化合物的分子靶标。通过量化对 HepG2、THP-1 细胞系、分离的淋巴细胞和利什曼原虫前鞭毛体的细胞毒性以及测量蛋白激酶（PK）抑制活性来评估体外生物活性。
结果
结果表明，化合物部分符合药物相似性规则。Ch-409 符合 WDI 和 Lipinski 规则。ADMET 谱预测显示除 Ch-409 外，具有较强的血浆蛋白结合，低至高的 GI 吸收和 BBB 穿透性（C/C=0.942-11；caco-2 细胞渗透率 20.13-26.75nm/sec），可能由 P-糖蛋白外排，CYP3A4 代谢，中等 hERG 抑制，致突变性和通过谷胱甘肽化和葡萄糖醛酸化解毒的能力。分子靶标包括蛋白酶、酶、膜受体、转运体和离子通道，其中 Ch-409 仅靶向膜受体。与正常分离的淋巴细胞相比，化合物对 HepG2 细胞系和利什曼原虫具有显著的细胞毒性（p<0.05）。Ch-599 对利什曼原虫表现出最高的毒性（死亡率 97.9±3.99%；LC50 0.323±0.002μg/mL），而 Ch-409 对 HepG2 细胞系具有最大的细胞毒性（IC50 0.08±0.001μg/mL）以及 97.5±1.98%（LC50 0.954±0.158μg/mL）利什曼原虫前鞭毛体的死亡率。观察到在存在NaN 和甘露醇的情况下，抗利什曼原虫作用分别降低了 16.38%-34.38%和 15-38.2%。PK 抑制和活性氧产生可能是细胞毒性的机制。
结论
三丁基锡（IV）配合物的羧酸酯衍生物具有显著的抗利什曼原虫和细胞毒性潜力。这些是开发抗利什曼原虫和抗癌药物的有前途的化合物。
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