کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10582668 | 981085 | 2011 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Synthesis and antiproliferative activity of novel 2-aryl-4-benzoyl-imidazole derivatives targeting tubulin polymerization
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کلمات کلیدی
MRPTMStetramethylsilaneBcrpPGPABIMDRSARP-glycoprotein - P-گلیکوپروتئینMelanoma - خال سرطانی یا ملانوماStructure–activity relationships - روابط ساختاری-فعالیتProstate cancer - سرطان پروستاتCancer drug resistance - مقاومت در برابر سرطانMultidrug resistance - مقاومت چند داروییSMART - هوشمندانهbreast cancer resistance protein - پروتئین مقاومت به سرطان سینهmultidrug resistance-associated proteins - پروتئین های مرتبط با مقاومت چند دارویی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
We previously reported the discovery of 2-aryl-4-benzoyl-imidazoles (ABI-I) as potent antiproliferative agents for melanoma. To further understand the structural requirements for the potency of ABI analogs, gain insight in the structure-activity relationships (SAR), and investigate metabolic stability for these compounds, we report extensive SAR studies on the ABI-I scaffold. Compared with the previous set of ABI-I analogs, the newly synthesized ABI-II analogs have lower potency in general, but some of the new analogs have comparable potency to the most active compounds in the previous set when tested in two melanoma and four prostate cancer cell lines. These SAR studies indicated that the antiproliferative activity was very sensitive to subtle changes in the ligand. Tested compounds 3ab and 8a are equally active against highly paclitaxel resistant cancer cell lines and their parental cell lines, indicating that drugs developed based on ABI-I analogs may have therapeutic advantages over paclitaxel in treating resistant tumors. Metabolic stability studies of compound 3ab revealed that N-methyl imidazole failed to extend stability as literature reported because de-methylation was found as the major metabolic pathway in rat and mouse liver microsomes. However, this sheds light on the possibility for many modifications on imidazole ring for further lead optimization since the modification on imidazole, such as compound 3ab, did not impact the potency.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 16, 15 August 2011, Pages 4782-4795
Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 16, 15 August 2011, Pages 4782-4795
نویسندگان
Jianjun Chen, Chien-Ming Li, Jin Wang, Sunjoo Ahn, Zhao Wang, Yan Lu, James T. Dalton, Duane D. Miller, Wei Li,