Novel imidazole derivatives as heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2) inhibitors and their cytotoxic activity in human-derived cancer cell lines
Novel imidazole derivatives as heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2) inhibitors and their cytotoxic activity in human-derived cancer cell lines
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DOI：
10.1016/j.ejmech.2015.04.003
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发表时间：
2015-05-26
影响因子：
6.7
通讯作者：
Greish, Khaled
中科院分区：
文献类型：
--
作者：
Salerno, Loredana;Pittala, Valeria;Greish, Khaled
血红素加氧酶（HO）是一种细胞保护酶，可在某些病理条件下过度表达，包括某些癌症。本论文设计并合成了一类新型咪唑类化合物作为血红素加氧酶-1（HO-1）和血红素加氧酶-2（HO-2）的抑制剂。在这些化合物中，对活性至关重要的咪唑环通过不同长度的烷基或硫代烷基链连接到由芳氧基、苯并噻唑或苯并恶唑部分表示的疏水基团。许多测试的化合物对HO的两种亚型之一是有效的和/或选择性的。此外，大多数戊基衍生物显示出HO-2相对于HO-1更好的抑制剂，揭示了烷基链在区分两种同工酶中的关键作用。选择显示出更好的HO抑制特性的化合物并进行测试以评估它们在前列腺癌和乳腺癌细胞系（DU-145、PC 3、LnCap、MDA-MB-231和MCF-7）中的细胞毒性性质。在这些测定中，芳氧基烷基衍生物比苯并噻唑硫代烷基衍生物产生更大的细胞毒性;特别是化合物31对所有测试的细胞系都有活性，证实了HO抑制剂的抗增殖特性及其在治疗特定癌症中的潜在用途。(C)2015年Elsevier Masson SAS。All rights reserved.
Heme oxygenase (HO) is a cytoprotective enzyme that can be overexpressed in some pathological conditions, including certain cancers. In this work, novel imidazole derivatives were designed and synthesized as inhibitors of heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2). In these compounds the imidazole ring, crucial for the activity, is connected to a hydrophobic group, represented by aryloxy, benzothiazole, or benzoxazole moieties, by means of alkyl or thioalkyl chains of different length. Many of the tested compounds were potent and/or selective against one of the two isoforms of HO. Furthermore, most of the pentyl derivatives showed to be better inhibitors of HO-2 with respect to HO-1, revealing a critical role of the alkyl chain in discriminating between the two isoenzymes. Compounds which showed the better profile of HO inhibition were selected and tested to evaluate their cytotoxic properties in prostate and breast cancer cell lines (DU-145, PC3, LnCap, MDA-MB-231, and MCF-7). In these assays, aryloxyalkyl derivatives resulted more cytotoxic than benzothiazolethioalkyl ones; in particular compound 31 was active against all the cell lines tested, confirming the anti-proliferative properties of HO inhibitors and their potential use in the treatment of specific cancers. (C) 2015 Elsevier Masson SAS. All rights reserved.