TY - JOUR
T1 - Di-indenopyridines as topoisomerase II-selective anticancer agents
T2 - Design, synthesis, and structure–activity relationships
AU - Shrestha, Aarajana
AU - Hwang, Soo Yeon
AU - Kunwar, Surendra
AU - Man Kadayat, Tara
AU - Park, Seojeong
AU - Liu, Yi
AU - Jo, Hyunji
AU - Sheen, Naeun
AU - Seo, Minjung
AU - Lee, Eung Seok
AU - Kwon, Youngjoo
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/8/15
Y1 - 2023/8/15
N2 - Topoisomerases are key molecular enzymes responsible for altering DNA topology, thus they have long been considered as attractive targets for novel chemotherapeutic agents. Topoisomerase type II (Topo II) catalytic inhibitors embrace a fresh perspective meant to get beyond drawbacks caused by topo II poisons, such as cardiotoxicity and secondary malignancies. Based on previously reported 5H-indeno[1,2-b]pyridines, here we presented new twenty-three hybrid di-indenopyridines along with their topo I/IIα inhibitory and antiproliferative activity. Most of the prepared 11-phenyl-diindenopyridines showed negligible topo I inhibitory activity, showing selectivity over topo II. Among the series, we finally selected compound 17, which displayed 100 % topo IIα inhibition at 20 μM concentration and comparable antiproliferative activity against the tested cell lines. Through competitive EtBr displacement assay, cleavable complex assay, and comet assay, compound 17 was finally determined as a non-intercalative catalytic topo IIα inhibitor. The findings in this study highlight the significance of phenolic, halophenyl, thienyl, and furyl groups at the 4-position of the indane ring in the design and synthesis of di-indenopyridines as potent catalytic topo IIα inhibitors with remarkable anticancer effects.
AB - Topoisomerases are key molecular enzymes responsible for altering DNA topology, thus they have long been considered as attractive targets for novel chemotherapeutic agents. Topoisomerase type II (Topo II) catalytic inhibitors embrace a fresh perspective meant to get beyond drawbacks caused by topo II poisons, such as cardiotoxicity and secondary malignancies. Based on previously reported 5H-indeno[1,2-b]pyridines, here we presented new twenty-three hybrid di-indenopyridines along with their topo I/IIα inhibitory and antiproliferative activity. Most of the prepared 11-phenyl-diindenopyridines showed negligible topo I inhibitory activity, showing selectivity over topo II. Among the series, we finally selected compound 17, which displayed 100 % topo IIα inhibition at 20 μM concentration and comparable antiproliferative activity against the tested cell lines. Through competitive EtBr displacement assay, cleavable complex assay, and comet assay, compound 17 was finally determined as a non-intercalative catalytic topo IIα inhibitor. The findings in this study highlight the significance of phenolic, halophenyl, thienyl, and furyl groups at the 4-position of the indane ring in the design and synthesis of di-indenopyridines as potent catalytic topo IIα inhibitors with remarkable anticancer effects.
KW - Antiproliferative activity
KW - Di-indenopyridines
KW - Structure-activity relationships
KW - Topoisomerase
KW - Topoisomerase inhibition
UR - http://www.scopus.com/inward/record.url?scp=85164337594&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2023.117403
DO - 10.1016/j.bmc.2023.117403
M3 - Article
C2 - 37418826
AN - SCOPUS:85164337594
SN - 0968-0896
VL - 91
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
M1 - 117403
ER -