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Development of 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and their salts as potent cytotoxic agents and topoisomerase I/II alpha inhibitors

Authors
Arepalli, Sateesh KumarLee, ChaerimSim, SeongrakLee, KihoJo, HyunjiJun, Kyu-YeonKwon, YoungjooKang, Jong-SoonJung, Jae-KyungLee, Heesoon
Issue Date
1-10월-2018
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Keywords
13H-Benzo[f]chromeno[4,3-b][1,7]naphthyridines; Dual human Topoisomerase I and II alpha inhibition; Cytotoxicity; Molecular docking; Imino Diels-Alder reaction
Citation
BIOORGANIC & MEDICINAL CHEMISTRY, v.26, no.18, pp.5181 - 5193
Indexed
SCIE
SCOPUS
Journal Title
BIOORGANIC & MEDICINAL CHEMISTRY
Volume
26
Number
18
Start Page
5181
End Page
5193
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/72534
DOI
10.1016/j.bmc.2018.09.019
ISSN
0968-0896
Abstract
A novel series of 35 angularly fused pentacyclic 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridin-5-ium chlorides were designed and synthesized. Their cytotoxic activities were investigated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Among all screened compounds; 28, 30, 34, 35, 46, 48, 52, and 53 compounds exhibited potent cytotoxic activities against all tested human cancer cell lines. Further, these potent lead cytotoxic agents were evaluated against human Topoisomerase I and II alpha inhibition. Among them, the compound 48 exhibited dual Topoisomerase I and II alpha inhibition especially at 20 mu M concentrations the compound 48 exhibited 1.25 times more potent Topoisomerase II alpha inhibitory activity (38.3%) than the reference drug etoposide (30.6%). The compound 52 also exhibited excellent (88.4%) topoisomerase I inhibition than the reference drug camptothecin (66.7%) at 100 mu M concentrations. Molecular docking studies of the compounds 48 and 52 with topo I discovered that they both intercalated into the DNA single-strand cleavage site where the compound 48 have van der Waals interactions with residues Arg364, Pro431, and Asn722 whilst the compound 52 have with Arg364, Thr718, and Asn722 residues. Both the compounds 48 and 52 have pi-pi stacking interactions with the stacked DNA bases. The docking studies of the compound 48 with topo IIa explored that it was bound to the topo II alpha DNA cleavage site where etoposide was situated. The benzo[f]chromeno[4,3-b][1,7]naphthyridine ring of the compound 48 was stacked between the DNA bases of the cleavage site with pi-pi stacking interactions and there were no hydrogen bond interactions with topo II alpha.
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