2. Academic Validation
  3. 2-Anilinoquinoline based arylamides as broad spectrum anticancer agents with B-RAFV600E/C-RAF kinase inhibitory effects: Design, synthesis, in vitro cell-based and oncogenic kinase assessments

2-Anilinoquinoline based arylamides as broad spectrum anticancer agents with B-RAFV600E/C-RAF kinase inhibitory effects: Design, synthesis, in vitro cell-based and oncogenic kinase assessments

  • Eur J Med Chem. 2020 Dec 15;208:112756. doi: 10.1016/j.ejmech.2020.112756.
Ashraf K El-Damasy 1,  Md Mamunul Haque 2,  Jung Woo Park 3,  Sang Chul Shin 4,  Jun-Seok Lee 5,  Eunice EunKyeong Kim 4,  Gyochang Keum 6
Affiliations

Affiliations

  • 1 Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address: ashraf.el-damasy@kist.re.kr.
  • 2 Molecular Recognition Research Center, KIST, Seoul, 02792, Republic of Korea.
  • 3 Center for Supercomputing Applications, Div. of National Supercomputing R&D, Korea Institute of Science and Technology Information, 245, Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
  • 4 Biomedical Research Institute, KIST, Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea.
  • 5 Molecular Recognition Research Center, KIST, Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul, 02792, Republic of Korea.
  • 6 Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul, 02792, Republic of Korea. Electronic address: gkeum@kist.re.kr.
PMID: 32942186 DOI: 10.1016/j.ejmech.2020.112756
Abstract

Prompted by the urgent demand for identification of new Anticancer agents with improved potency and efficacy, a new series of arylamides incorporating the privileged 2-anilinoquinoline scaffold has been designed, synthesized, and biologically assessed. Aiming at extensive evaluation of the target compounds' potency and spectrum, a panel of 60 clinically important Cancer cell lines representing nine Cancer types has been used. Compounds 9a and 9c, with piperazine substituted phenyl ring, emerged as the most active members surpassing the Anticancer potencies of the FDA-approved drug imatinib. They elicited sub-micromolar or one-digit micromolar GI50 values over the majority of tested Cancer cells including multidrug resistant (MDR) cells like colon HCT-15, renal TK-10 and UO-31, and ovarian NCI/ADR-RES. In vitro mechanistic study showed that compounds 9a and 9c could trigger morphological changes, Apoptosis and cell cycle arrest in HCT-116 colon Cancer cells. Besides, compound 9c altered microtubule polymerization pattern in a similar fashion to paclitaxel. Kinase screening of 9c disclosed its inhibitory activity over B-RAFV600E and c-Raf kinases with IC50 values of 0.888 μM and 0.229 μM, respectively. Taken together, the current report presents compounds 9a and 9c as promising broad-spectrum potent Anticancer candidates, which could be considered for further development of new Anticancer drugs.

Keywords

2-Anilinoquinoline; Anticancer activity; Apoptosis; Arylamides; B-RAF(V600E); C-RAF kinase; Cell cycle arrest; Tubulin polymerization.

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