TY - JOUR
T1 - 2-Anilinoquinoline based arylamides as broad spectrum anticancer agents with B-RAFV600E/C-RAF kinase inhibitory effects
T2 - Design, synthesis, in vitro cell-based and oncogenic kinase assessments
AU - El-Damasy, Ashraf K.
AU - Haque, Md Mamunul
AU - Park, Jung Woo
AU - Shin, Sang Chul
AU - Lee, Jun Seok
AU - EunKyeong Kim, Eunice
AU - Keum, Gyochang
N1 - Funding Information:
This research was supported by Bio & Medical Technology Development Program (NRF-2019M3E5D4066905) and Korea Research Fellowship Program (NRF-2019H1D3A1A01070882 and 2018H1D3A1A02074556) of the National Research Foundation (NRF) funded by the Korean government (MSIT), and by the Korea Institute of Science and Technology (KIST) Institutional Programs (Grant No. 2E30180 and 2Z05800). This research was also supported by the Korea Institute of Science and Technology Information (KISTI) Institutional Program. We would like to express our sincere gratitude to the National Cancer Institute (NCI, Bethesda, Maryland, USA) for conducting the in vitro anticancer evaluation of the new compounds.
Funding Information:
This research was supported by Bio & Medical Technology Development Program ( NRF-2019M3E5D4066905 ) and Korea Research Fellowship Program ( NRF-2019H1D3A1A01070882 and 2018H1D3A1A02074556 ) of the National Research Foundation (NRF) funded by the Korean government (MSIT) , and by the Korea Institute of Science and Technology (KIST) Institutional Programs (Grant No. 2E30180 and 2Z05800 ). This research was also supported by the Korea Institute of Science and Technology Information (KISTI) Institutional Program. We would like to express our sincere gratitude to the National Cancer Institute (NCI, Bethesda, Maryland, USA) for conducting the in vitro anticancer evaluation of the new compounds.
Publisher Copyright:
© 2020
PY - 2020/12/15
Y1 - 2020/12/15
N2 - 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.
AB - 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.
KW - 2-Anilinoquinoline
KW - Anticancer activity
KW - Apoptosis
KW - Arylamides
KW - B-RAF
KW - C-RAF kinase
KW - Cell cycle arrest
KW - Tubulin polymerization
UR - http://www.scopus.com/inward/record.url?scp=85090743583&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2020.112756
DO - 10.1016/j.ejmech.2020.112756
M3 - Article
C2 - 32942186
AN - SCOPUS:85090743583
VL - 208
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 112756
ER -