Novel Anthra[1,2-c][1,2,5]Thiadiazole-6,11-Diones as Promising Anticancer Lead Compounds: Biological Evaluation, Characterization & Molecular Targets Determination.
Novel Anthra[1,2-c][1,2,5]Thiadiazole-6,11-Diones as Promising Anticancer Lead Compounds: Biological Evaluation, Characterization & Molecular Targets Determination.
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DOI：
10.1371/journal.pone.0154278
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Huang HS
中科院分区：
文献类型：
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作者：
Ali AA;Lee YR;Chen TC;Chen CL;Lee CC;Shiau CY;Chiang CH;Huang HS
我们实验室开发的新化合物 NSC745885 和 NSC757963 在美国国家癌症研究所的一组 60 种癌细胞系和日本癌症研究基金会的一组 39 种癌细胞系中进行了测试。两种化合物都表现出选择性独特的多对数差异活性模式，针对癌细胞而非正常心肌细胞的 GI50 值在亚微摩尔范围内。 NSC757963 对白血病子组表现出高选择性。两种化合物的活性与 NFKB1 和 CSNK2B 基因的表达密切相关，这意味着它们可能抑制 NF-κB 通路。 OVCAR-3 细胞的免疫细胞化学显微镜显示治疗后 NF-κB p65 亚基在胞质中明显积聚。蛋白质印迹显示 NF-κB p65 亚基的核表达受到剂量依赖性抑制，并在治疗后随后在细胞质中积累。对接实验表明，两种化合物均与 NF-κB 激活剂 IKKβ 亚基结合，防止其易位至细胞核。总的来说，这些结果证实了我们的化合物抑制 OVCAR-3 细胞组成型活性 NF-κB 通路的能力。此外，COMPARE分析表明NSC757963的活性与抗结核药物利福霉素SV相似，这一点通过测试NSC757963对结核分枝杆菌的抗分枝杆菌活性得到证实，结果显示其具有强大的活性，适合在临床实践中使用。分子特性和 Lipinski 参数预测了可接受的生物利用度特性，没有任何致突变性、致瘤性、过敏性和生殖影响的迹象。使用人类 Caco-2 模型进行的口服吸收实验显示，NSC745885 通过被动转运机制实现高肠道吸收，无肠道外排或主动转运机制。独特的分子特征以及图示的抗癌活性谱和生物利用度特性保证了我们的化合物的进一步开发，并为临床前研究奠定了基础，以便在临床实践中实施此类化合物。
The novel compounds NSC745885 and NSC757963 developed at our laboratory were tested against a panel of 60 cancer cell lines at the National Cancer Institute, USA, and a panel of 39 cancer cell lines at the Japanese Foundation of Cancer Research. Both compounds demonstrated selective unique multi-log differential patterns of activity, with GI50 values in the sub-micro molar range against cancer cells rather than normal cardiac cells. NSC757963 showed high selectivity towards the leukemia subpanel. Activities of both compounds strongly correlated to expression of NFKB1 and CSNK2B genes, implying that they may inhibit the NF-κB pathway. Immunocytochemical microscopy of OVCAR-3 cells showed clear cytosolic accumulation of the NF-κB p65 subunit following treatment. Western blotting showed dose dependent inhibition of the nuclear expression of the NF-κB p65 subunit with subsequent accumulation in the cytosol following treatment. Docking experiments showed binding of both compounds to the NF-κB activator IKKβ subunit preventing its translocation to the nucleus. Collectively, these results confirm the ability of our compounds to inhibit the constitutively active NF-κB pathway of OVCAR-3 cells. Furthermore, COMPARE analysis indicated that the activity of NSC757963 is similar to the antituberculosis agent rifamycin SV, this was confirmed by testing the antimycobacterial activity of NSC757963 against Mycobacterium tuberculosis, results revealed potent activity suitable for use in clinical practice. Molecular properties and Lipinski’s parameters predicted acceptable bioavailability properties with no indication of mutagenicity, tumorigenicity, irritability and reproductive effects. Oral absorption experiments using the human Caco-2 model showed high intestinal absorption of NSC745885 by passive transport mechanism with no intestinal efflux or active transport mechanisms. The unique molecular characterization as well as the illustrated anticancer spectra of activity and bioavailability properties warrant further development of our compounds and present a foundation brick in the pre-clinical investigations to implement such compounds in clinical practice.