Design, synthesis, and anticancer activity of imidazo[2,1-b]oxazole-based RAF kinase inhibitors.

Autor: Abdel-Maksoud MS; Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC (ID: 60014618)), Dokki, Giza 12622, Egypt., Ammar UM; Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu 02792, Republic of Korea; Department of Biomolecular Science, University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza 12566, Egypt; University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea., El-Gamal MI; 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., Gamal El-Din MM; Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC (ID: 60014618)), Dokki, Giza 12622, Egypt., Mersal KI; Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu 02792, Republic of Korea; Department of Biomolecular Science, University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea., Ali EMH; Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu 02792, Republic of Korea; Department of Biomolecular Science, University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea., Yoo KH; Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea., Lee KT; Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea., Oh CH; Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu 02792, Republic of Korea; Department of Biomolecular Science, University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea. Electronic address: choh@kist.re.kr.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2019 Dec; Vol. 93, pp. 103349. Date of Electronic Publication: 2019 Oct 10.
DOI: 10.1016/j.bioorg.2019.103349
Abstrakt: In the present work, a novel series of B-RAF kinase inhibitors having imidazo[2,1-b]oxazole scaffold was designed and synthesized based on the structures of the well-known B-RAF inhibitors. The twenty two final compounds were tested over A375 and SKMEL28 cell lines to determine the primary cytotoxic activity of these compounds, and their activities were compared with that of sorafenib as a standard. Compounds 11c, 11e, 11o, 11q, 11r, and 11u exhibited higher cellular activity compared to sorafenib with IC 50 values of 7.25, 8.03, 9.81, 8.47, 4.70, and 9.04 µM, respectively and 10.38 µM for sorafenib. In addition, the target compounds were screened for their anticancer activity by the NCI-60 cell line assay. Compounds 11v and 11u were the most active compounds with percent inhibition reached 95.99% for 11v and 87.03% for 11u over K562 cell line at 10 µM concentration. Compound 11v was selected for 5-dose test mode. Furthermore, the kinase inhibitory activities of 11a, 11c, 11e, 11i, 11o, 11q, 11r, 11u, and 11v were determined against wild-type B-RAF, V600E-B-RAF, and RAF1. Compound 11o was the most potent against V600E-B-RAF with IC 50 34 nM followed by 11q and 11u with IC 50 92 and 93 nM, respectively.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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