2. Academic Validation
  3. Design, synthesis, broad-spectrum antiproliferative activity, and kinase inhibitory effect of triarylpyrazole derivatives possessing arylamides or arylureas moieties

Design, synthesis, broad-spectrum antiproliferative activity, and kinase inhibitory effect of triarylpyrazole derivatives possessing arylamides or arylureas moieties

  • Eur J Med Chem. 2016 Aug 25:119:122-31. doi: 10.1016/j.ejmech.2016.04.048.
Mahmoud M Gamal El-Din 1,  Mohammed I El-Gamal 2,  Mohammed S Abdel-Maksoud 1,  Kyung Ho Yoo 3,  Chang-Hyun Oh 4
Affiliations

Affiliations

  • 1 Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Biomolecular Science, University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea; Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki-Giza 12622, Egypt.
  • 2 Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt.
  • 3 Chemical Kinomics Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
  • 4 Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Biomolecular Science, University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea. Electronic address: [email protected].
PMID: 27155467 DOI: 10.1016/j.ejmech.2016.04.048
Abstract

A novel series of 1,3,4-triarylpyrazole derivatives possessing terminal arylamide or arylurea terminal moieties has been designed and synthesized. Their in vitro antiproliferative activities were investigated against a panel of 58 cell lines of nine different Cancer types at the NCI, USA. The urea analogues 2b, 2c, and 2f as well as the amide derivatives 3e and 3f exerted the highest mean % inhibition values over the 58 cell line panel at 10 μM, and thus were further tested in 5-dose testing mode to determine their GI50, TGI, and LC50 values. The above mentioned compounds have shown stronger antiproliferative activities in terms of potency and efficacy upon comparing their results with Sorafenib as a reference compound. Among them, compounds 2c and 2f possessing 3,4-dichlorophenylurea terminal moiety showed the highest mean %inhibition value of about 99.85 and 104.15% respectively over the 58-cell line panel at 10 μM concentration. Also compounds 2b, 3e, and 3f exhibited mean % inhibition over 80% at 10 μM concentration. The GI50 value of compound 3e over K-562 Cancer cell line was 0.75 μM. Accordingly, compound 2f was screened over seven kinases at a single-dose concentration of 10 μM to profile its kinase inhibitory activity. Interestingly, the compound showed highly inhibitory activities (90.44% and 87.71%) against BRAF (V600E) and RAF1 kinases, respectively. Its IC50 value against BRAF (V600E) was 0.77 μM. Compounds 2b, 2c, 2f, 3e, and 3f exerted high selectivity towards Cancer cell lines than L132 normal lung cells.

Keywords

1,3,4-Triarylpyrazole; Antiproliferative activity; Arylamides; Arylureas; Kinase inhibition.

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