TY - JOUR
T1 - Discovery of a 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amine derivative as a novel DNA intercalating topoisomerase IIα poison
AU - Kunwar, Surendra
AU - Hwang, Soo Yeon
AU - Katila, Pramila
AU - Park, Seojeong
AU - Jeon, Kyung Hwa
AU - Kim, Daeun
AU - Kadayat, Tara Man
AU - Kwon, Youngjoo
AU - Lee, Eung Seok
N1 - Publisher Copyright:
© 2021 Elsevier Masson SAS
PY - 2021/12/15
Y1 - 2021/12/15
N2 - Several anticancer agents have been developed and innovative approaches have been made toward cancer type-specific medicines for cancer treatment. As a continuous effort to develop potential chemotherapeutic agents, a novel series of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines containing amino groups, hydroxyphenyl and fluorine functionalities were designed and synthesized. The compounds were evaluated for topo IIα inhibitory and cytotoxicity against HCT15, and HeLa human cancer cell lines. Among synthesized thirty compounds, the majority exhibited strong topo IIα inhibition and anti-proliferation against HCT15 colorectal adenocarcinoma cell line. The structure-activity relationship study revealed that compounds with –CF3 and –OCF3 substituents at 4- position and 3′ or 4′-hydroxyphenyl at 2-position attached to the central pyridine ring displayed potent topo IIα and anti-proliferative activity in colorectal and cervix cancer cell line. In vitro studies provided the evidence that compounds 16, 19, 22, and 28 possess excellent topo IIα inhibition and antiproliferative activity. For a better understanding, topo IIα cleavage complex, EtBr displacement, KI quenching assays and molecular docking of compound 19 was performed and the results revealed the mode of action as a DNA intercalative topo IIα poison inhibitor. The results obtained from this study provide insight into the DNA binding mechanism of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines and alteration in topo IIα inhibitory and antiproliferative activity with modifications in the rigid structure.
AB - Several anticancer agents have been developed and innovative approaches have been made toward cancer type-specific medicines for cancer treatment. As a continuous effort to develop potential chemotherapeutic agents, a novel series of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines containing amino groups, hydroxyphenyl and fluorine functionalities were designed and synthesized. The compounds were evaluated for topo IIα inhibitory and cytotoxicity against HCT15, and HeLa human cancer cell lines. Among synthesized thirty compounds, the majority exhibited strong topo IIα inhibition and anti-proliferation against HCT15 colorectal adenocarcinoma cell line. The structure-activity relationship study revealed that compounds with –CF3 and –OCF3 substituents at 4- position and 3′ or 4′-hydroxyphenyl at 2-position attached to the central pyridine ring displayed potent topo IIα and anti-proliferative activity in colorectal and cervix cancer cell line. In vitro studies provided the evidence that compounds 16, 19, 22, and 28 possess excellent topo IIα inhibition and antiproliferative activity. For a better understanding, topo IIα cleavage complex, EtBr displacement, KI quenching assays and molecular docking of compound 19 was performed and the results revealed the mode of action as a DNA intercalative topo IIα poison inhibitor. The results obtained from this study provide insight into the DNA binding mechanism of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines and alteration in topo IIα inhibitory and antiproliferative activity with modifications in the rigid structure.
KW - 2,4,6-Triarylyridines
KW - 5,6-Dihydrobenzo(h)Quinolin-8-amine
KW - Antiproliferative activity
KW - Structure-activity relationship
KW - Topo IIα poison inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85115937876&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2021.113860
DO - 10.1016/j.ejmech.2021.113860
M3 - Article
C2 - 34597897
AN - SCOPUS:85115937876
SN - 0223-5234
VL - 226
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 113860
ER -