الفهرس 
Abstract
Cell cycleOnly 14 pages are availabe for public view
 |  | from | 311 |  |  |
| | | from | 311 | | |
Abstract
antiproliferative agents against different types of cancer. The new 3,4-diarylpyrazole-1-carboxamide derivatives 9a-r, 10a-r, 20a-i, and 21a-i (54 final compounds), 1,3,4-triarylpyrazole compounds 24a-h, 25a-h, 26a-h, and 27a-h (32 final compounds), and pyrrolo[3,2-c]pyridine derivatives 34a-i, 35a-k, 39a-h, and 40a-h (36 final compounds) were synthesized in moderate to good yields, adapting variable and efficient synthetic and purification protocols. All the target compounds were tested for antiproliferative activity against A375P human melanoma cell line. Many target compounds showed high potency with IC50 as low as 7 nM in case of the pyrrolo[3,2-c]pyridine compound 35d. In addition, many promising compounds with high potency against A375P were tested over NIH3T3 fibroblasts in order to examine their selectivity towards melanoma cells over fibroblasts. Among the tested compounds, 40b was 454.90 times more selective for melanoma cells over normal cells. The structures of all the target compounds were submitted to the National Cancer Institute (NCI), Bethesda, Maryland, USA, and a group of compounds was selected for in vitro anticancer testing over a panel of 60 cancer cell lines of 9 different cancer types. Different compounds showed high potency and broad spectrum anticancer activity. And compound 10o was more selective for melanoma. In order to investigate the possible mechanism(s) of antiproliferative activity of our target compounds, the pyrazole compounds 9a, 10o, 27e, and 27g, as representative examples, were tested for ERK kinase inhibition. All of them showed good inhibitory activity, inhibited ERK kinase activity in a dosedependent manner. Furthermore, compounds 34g and 40e were tested against a panel of kinases. 34g demonstrated multiple-kinase inhibition, while 40e was selective against FMS kinase. A molecular modeling study was carried out by docking compounds 10b, 21a, and 27e into the domain of V600E-B-RAF kinase in order to investigate the possible binding interactions.