کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1395304 1501204 2009 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: Synthesis, structure–activity relationship, and action mechanism studies
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: Synthesis, structure–activity relationship, and action mechanism studies
چکیده انگلیسی

Bis-8-hydroxyquinoline substituted benzylamines have been synthesized and screened for their antitumor activity on KB3 cell line model. Synthesis of this series of new analogues was accomplished using a one pot specific methodology which allows the synthesis of both bis- and mono-8-hydroxyquinoline substituted benzylamines. Among the synthesized compounds two compounds (4a and 5a), respectively, named JLK 1472 and JLK 1486, were particularly potent on KB3 cell line. Their CC50 values being, respectively, 2.6 and 1.3 nM. Screened on a panel of cell lines showing various phenotype alterations, both compounds were found inactive on some cell lines such as PC3 (prostate cell line) and SF268 (neuroblastoma cell line) while highly active on other different cell lines. Mechanistic studies reveal that these two analogues did not affect tubulin and microtubules neither they exert a proteasomal inhibition effect. In contrast 4a and 5a activate specifically caspase 3/7 and not caspase 8 and 9, suggesting that their biological target should be located upstream from caspase 3/7. Moreover their cytotoxic effect is potentiated by the pro-apoptotic effects of TRAIL.

Compounds 4a and 5a exhibited potent antitumor activities on KB3 cell line with CC50 values of, respectively, 2.3 and 1.6 nM. These compounds which do not interfere with proteasome or α, β tubulin seems to activate caspase apoptotic pathway, specifically caspase 3/7, suggesting that the biological target should be upstream caspase 3/7 pathway.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Medicinal Chemistry - Volume 44, Issue 2, February 2009, Pages 558–567
نویسندگان
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