Özdemir Ahmet, Gökbulut Sevtem, Sever Belgin, Çiftçi Gülşen A, Altıntop Mehlika D
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey.
Department of Biochemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey.
Anticancer Agents Med Chem. 2018;18(10):1394-1404. doi: 10.2174/1871520618666171206111923.
Arylidene indanones have attracted a great deal of interest due to their outstanding therapeutic applications. In particular, considerable research has pointed out the importance of arylidene indanones in the field of cancer research.
The aim of the current work was to design and synthesize arylidene indanone-based anticancer agents.
New arylidene indanones were obtained via the Claisen-Schmidt condensation of 5-chloro-6-methoxy- 2,3-dihydro-1H-inden-1-one with p-substituted benzaldehyde derivatives. MTT assay was performed to evaluate their cytotoxic effects on MCF-7 human breast adenocarcinoma, HeLa human cervix carcinoma and NIH/3T3 mouse embryonic fibroblast cell lines. The most effective derivatives were evaluated for their DNA synthesis inhibitory and apoptotic effects. The most apoptotic compounds were also investigated for their effects on caspase-3 activation in HeLa cells. The binding interactions of the most effective caspase-3 activator at the active site of caspase-3 were confirmed through molecular docking studies using Schrodinger's Maestro molecular modeling package.
Compounds 2, 3, 4, 5, 6 and 7 exhibited selective anticancer activity against HeLa cells, whilst compounds 7 and 10 showed selective anticancer activity against MCF-7 cells. Compound 10 caused significant DNA synthesis inhibition on MCF-7 cells, whereas compound 3 caused significant DNA synthesis inhibition on HeLa cells. Compounds 2 and 3 were determined as the most apoptotic agents against HeLa cells, whereas compounds 7 and 10 showed apoptotic activity against MCF-7 cells. Besides, compound 2 was identified as the most effective compound on caspase-3 activation in HeLa cells. Docking studies showed that compound 2 interacted with the residues His121 and Tyr204 forming π-π stacking interactions.
亚芳基茚满二酮因其出色的治疗应用而备受关注。特别是，大量研究指出了亚芳基茚满二酮在癌症研究领域的重要性。
当前工作的目的是设计并合成基于亚芳基茚满二酮的抗癌剂。
通过5-氯-6-甲氧基-2,3-二氢-1H-茚-1-酮与对取代苯甲醛衍生物的克莱森-施密特缩合反应得到新型亚芳基茚满二酮。进行MTT试验以评估它们对MCF-7人乳腺腺癌、HeLa人宫颈癌和NIH/3T3小鼠胚胎成纤维细胞系的细胞毒性作用。对最有效的衍生物进行DNA合成抑制和凋亡作用评估。还研究了最具凋亡活性的化合物对HeLa细胞中半胱天冬酶-3激活的影响。使用薛定谔公司的Maestro分子建模软件包通过分子对接研究证实了最有效的半胱天冬酶-3激活剂在半胱天冬酶-3活性位点的结合相互作用。
化合物2、3、4、5、6和7对HeLa细胞表现出选择性抗癌活性，而化合物7和10对MCF-7细胞表现出选择性抗癌活性。化合物10对MCF-7细胞引起显著的DNA合成抑制，而化合物3对HeLa细胞引起显著的DNA合成抑制。化合物2和3被确定为对HeLa细胞最具凋亡活性的试剂，而化合物7和10对MCF-7细胞表现出凋亡活性。此外，化合物2被确定为对HeLa细胞中半胱天冬酶-3激活最有效的化合物。对接研究表明化合物2与His121和Tyr204残基相互作用形成π-π堆积相互作用。
