Ozcan-Sezer Senem, Ince Elif, Akdemir Atilla, Ceylan Özlem Öztürk, Suzen Sibel, Gurer-Orhan Hande
a Faculty of Pharmacy, Department of Pharmaceutical Toxicology , Ege University , Izmir , Turkey.
b Computer-Aided Drug Discovery Laboratory, Faculty of Pharmacy, Department of Pharmacology , Bezmialem Vakif University , Istanbul , Turkey.
Xenobiotica. 2019 May;49(5):549-556. doi: 10.1080/00498254.2018.1482029. Epub 2018 Sep 12.
A causal association is reported between prolonged exposures to elevated levels of estrogen and breast cancer. Therefore inhibiting aromatase (CYP19A), which catalyses the conversion of androgens to estrogens, is an important approach in prevention and treatment of estrogen receptor positive (ER+) breast cancer. Melatonin, a natural indolic hormone, is reported to prevent free radical induced carcinogenesis and block local estrogen synthesis in breast tissue via aromatase inhibition. However several features of melatonin limit its therapeutic use. In the present study aromatase inhibiting potential of 2-methyl indole hydrazones are investigated, and compared with melatonin, by two in vitro models; a cell-free assay using a fluorescence substrate and a cell-based assay where cell proliferation was determined in ER + human breast cancer cells (MCF-7 BUS) in the absence of estrogen and the presence of testosterone. Aromatase inhibitory effect is also explored by molecular modelling studies. In biological activity assays monochloro substituted indole hydrazones were found to have stronger aromatase inhibitory activity among all tested derivatives and were more active than melatonin. This finding is further confirmed by molecular modelling. These results may be useful in the design and synthesis of novel melatonin analogues with higher inhibitory potency against aromatase.
据报道，长期暴露于高水平雌激素与乳腺癌之间存在因果关联。因此，抑制催化雄激素转化为雌激素的芳香化酶（CYP19A）是预防和治疗雌激素受体阳性（ER+）乳腺癌的重要方法。褪黑素是一种天然吲哚类激素，据报道它可预防自由基诱导的致癌作用，并通过抑制芳香化酶来阻断乳腺组织中的局部雌激素合成。然而，褪黑素的一些特性限制了其治疗用途。在本研究中，通过两种体外模型研究了2-甲基吲哚腙的芳香化酶抑制潜力，并与褪黑素进行了比较；一种是使用荧光底物的无细胞测定法，另一种是基于细胞的测定法，即在无雌激素和有睾酮存在的情况下，在ER+人乳腺癌细胞（MCF-7 BUS）中测定细胞增殖。还通过分子模拟研究探索了芳香化酶抑制作用。在生物活性测定中，发现单氯取代的吲哚腙在所有测试衍生物中具有更强的芳香化酶抑制活性，并且比褪黑素更具活性。这一发现通过分子模拟得到进一步证实。这些结果可能有助于设计和合成对芳香化酶具有更高抑制效力的新型褪黑素类似物。
