title: Synthesis, in vitro Antiproliferative and Antiinflammatory Activities, and Kinase Inhibitory effects of New 1,3,4-triarylpyrazole Derivatives.
abstract: BACKGROUND
  Pyrazole derivatives have been reported as both anticancer and antiinflammatory agents.
  
  
  OBJECTIVE
  This study was conducted to develop new pyrazole derivatives as potential anticancer and/or antiinflammatory agents. Their molecular mechanisms of action have been investigated.
  
  
  METHODS
  a series of new triarylpyrazole derivatives were synthesized. Their in vitro anticancer activity was tested against NCI-58 cancer cell line panel of nine cancer types. The most active compound 1a was tested against sixteen kinases, many of them are known to be over-expressed in leukemia and breast cancer. The most sensitive kinases were V600E-B-RAF, C-RAF, FLT3, and P38α/MAPK14. Compound 1a was further tested for caspase-3/7 activity and LDH release assay as measures of its apoptotic and necrotic activities against RPMI-8226. Moreover, the ability of compounds 1a, 1b, and 1g to inhibit nitric oxide and prostaglandin Eproduction in LPS-induced RAW 264.7 macrophages was also examined.
  
  
  RESULTS
  Compounds 1a, 1c, and 1g showed the highest activities against the cancer cell line panel, with more inhibitory effects against leukemia and breast cancer subpanels. The highest activity was exerted by compound 1a. Its IC50 values against RPMI-8226, K-562 leukemia cell lines, and MDA-MB-468 breast cancer cell line were 1.71 μM, 3.42 μM, and 6.70 μM, respectively. The IC50 of compound 1a against P38α/MAPK14 kinase was 0.515 μM. The caspase activity was increased by 72% and 170% at 1.23 μM and 3.70 μM concentrations of compound 1a, respectively. Furthermore, compound 1b inhibited 80.26% and 95.31% of NO and PGE2 productions, respectively, at 50 μM concentration in the LPS-induced RAW 264.7 macrophages.
  
  
  CONCLUSIONS
  Compound 1a could kill the cells through induction of apoptosis rather than necrosis. Compound 1a was more selective against cancer cells than non-cancerous cells. In addition, the hydroxyl analogue 1b was the most active as antiinflammatory agent.
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: El-Gamal
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Abdel-Maksoud
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Gamal El-Din
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Shin
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Yoo
authors.affiliation: Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea. Korea, Republic of.
authors.forename: Chang-Hyun
authors.initials: CH
authors.lastname: Oh
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles