Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation.
Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation.
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基于咪唑的新化合物对血红素加氧酶-1（HO-1）抑制剂的新结构见解： 生化和体外抗癌活性评估。
DOI：
10.3390/molecules23051209
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发表时间：
2018-05-18
期刊：
影响因子：
--
通讯作者：
Pittalà V
中科院分区：
文献类型：
--
作者：
Greish KF;Salerno L;Al Zahrani R;Amata E;Modica MN;Romeo G;Marrazzo A;Prezzavento O;Sorrenti V;Rescifina A;Floresta G;Intagliata S;Pittalà V
本文以化合物1为先导化合物，通过乙醇间隔基将咪唑基团连接到疏水基团上，设计合成了一种新型的唑类HO-1抑制剂，并进行了分子模拟。测试的化合物显示出良好的抑制剂活性，并且具有微摩尔范围内的IC 50值。这些结果是通过靶向疏水的西部区域获得的。分子模拟研究证实了一种巩固的结合模式，其中咪唑基部分的氮与血红素亚铁配位，同时疏水性基团位于HO-1结合口袋的西部区域。此外，对新化合物进行了计算机ADME-Tox特性筛选，以预测药物样行为，结果令人信服。最后，研究了化合物1在不同癌细胞系中的体外抗肿瘤活性特征，并合成了纳米胶束制剂，目的是改善化合物1的水溶性。最后，在黑素瘤细胞中测试化合物1与多柔比星的组合，显示出令人感兴趣的协同活性。
In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound 1 as a lead compound, in which an imidazole moiety is linked to a hydrophobic group by means of an ethanolic spacer. The tested compounds showed a good inhibitor activity and possessed IC50 values in the micromolar range. These results were obtained by targeting the hydrophobic western region. Molecular modeling studies confirmed a consolidated binding mode in which the nitrogen of the imidazolyl moiety coordinated the heme ferrous iron, meanwhile the hydrophobic groups were located in the western region of HO-1 binding pocket. Moreover, the new compounds were screened for in silico ADME-Tox properties to predict drug-like behavior with convincing results. Finally, the in vitro antitumor activity profile of compound 1 was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound’s 1 water solubility. Finally, compound 1 was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.
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S2RSLDB：Sigma-2受体选择性配体的全面手动策划的，可访问的Internet可访问数据库。
影响因子：
8.6
作者：
Nastasi G;Miceli C;Pittalà V;Modica MN;Prezzavento O;Romeo G;Rescifina A;Marrazzo A;Amata E
通讯作者：
Amata E
影响因子：
3.8
作者：
Lee, Wen-Ying;Chen, Yen-Chou;Lin, Cheng-Wei
通讯作者：
Lin, Cheng-Wei
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P
影响因子：
1.2
作者：
Amata E;Marrazzo A;Dichiara M;Modica MN;Salerno L;Prezzavento O;Nastasi G;Rescifina A;Romeo G;Pittalà V
通讯作者：
Pittalà V
影响因子：
3.5
作者：
Forte, Giuseppe;Fortuna, Cosimo Gianluca;Pittala, Valeria
通讯作者：
Pittala, Valeria