کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1397397 1501160 2012 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
COX inhibitors Indomethacin and Sulindac derivatives as antiproliferative agents: Synthesis, biological evaluation, and mechanism investigation
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
COX inhibitors Indomethacin and Sulindac derivatives as antiproliferative agents: Synthesis, biological evaluation, and mechanism investigation
چکیده انگلیسی

Cyclooxygenase (COX) inhibitors Indomethacin and its structural analogs Sulindac exhibit cell growth inhibition and apoptosis inducing activities in various cancer cell lines via COX independent mechanisms. In this study, the molecular structures of Indomethacin and Sulindac were used as starting scaffolds to design novel analogs and their effects on the proliferation of human cancer cells were evaluated. Compared to Indomethacin and Sulindac inhibiting cancer cell proliferation with IC50s of more than 1 mM, the derivatives displayed significantly increased activities. Especially, one of the Indomethacin analogs inhibited the growth of a series of cancer cell lines with IC50s around 0.5 μM–3 μM. Mechanistic investigation revealed that the new analog was in fact a tubulin inhibitor, although the parental compound Indomethacin did not show any tubulin inhibitory activity. Tubulin polymerization assay indicated this compound inhibited tubulin assembly at high concentrations, but promoted this process at low concentrations which is a very unique mechanism. The binding mode of this compound in tubulin was predicted using the molecular docking simulation.

Figure optionsDownload as PowerPoint slideHighlights
► A series of COX inhibitors Indomethacin and Sulindac derivatives were synthesized.
► Their effects on the proliferation of human cancer cells were evaluated.
► A potent derivative exhibits opposite activities to tubulin assembly at low and high concentrations.
► Two different binding sites in tubulin may be involved for the unique activities of the new analog.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Medicinal Chemistry - Volume 56, October 2012, Pages 17–29
نویسندگان
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