کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1363151 981504 2009 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors
چکیده انگلیسی

Two series of 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles were synthesized through a combinatorial approach. The prepared analogues were evaluated for their in vitro capacity to inhibit PDE3A and the growth of the human HT-29 colon adenocarcinoma tumor cell line. Compound 6-(4-bromophenyl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Id) exhibited the strongest PDE3 inhibition when cGMP but not cAMP is the substrate with a IC50of 27 μM, which indicates a highly selective mechanism of enzyme inhibition. On the other hand, compound 6-(1,3-benzodioxol-5-yl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Ii) was the most active in inhibiting colon tumor cell growth with a IC50 of 3 μM. The electronic effects, steric effects and conformational aspects of Id seem to be the most crucial for the PDE3 inhibition. Meanwhile, steric factors and the H-bonding capability seem to be the most important factors for tumor cell growth inhibitory activity. Conversely, there is no direct correlation between PDE3 inhibition and anticancer activity for the prepared compounds. An in silico docking experiment indicates the potential involvement of other potential molecular targets such as PIM-1 kinase to explain its tumor cell growth inhibitory activity.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 17, Issue 16, 15 August 2009, Pages 5974–5982
نویسندگان
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