TY - JOUR
T1 - Synthesis and biological evaluation of C1-O-substituted-3-(3-butylamino-2-hydroxy-propoxy)-xanthen-9-one as topoisomerase IIα catalytic inhibitors
AU - Park, Seojeong
AU - Hong, Eunji
AU - Kwak, Soo Yeon
AU - Jun, Kyu Yeon
AU - Lee, Eung Seok
AU - Kwon, Youngjoo
AU - Na, Younghwa
N1 - Funding Information:
This study was supported by grants from The Ministry of Science, ICT & Future Planning, Korea ( NRF-2015R1A2A2A01006513 to YNa).
Publisher Copyright:
© 2016 Elsevier Masson SAS
PY - 2016
Y1 - 2016
N2 - Topoisomerase II poison blocks the transitorily generated DNA double-strand breaks (DSBs) from religation, thereby causes severe DNA damage and gene toxicity. While topoisomerase II catalytic inhibitor does not form cleavable DNA-enzyme complex because its function attributes to inhibition of the catalytic steps of the enzyme such as before generating DNA DSBs or in the last step of the catalytic cycle after religation. It has been reported that the stabilizing effect of etoposide on transient cleavable DNA-topoisomerase IIβ complex attributes to its secondary malignancy. Therefore, topoisomerase IIα has been considered as more attractive target than topoisomerase IIβ for the development of chemotherapeutic agents. In the previous work, we reported compounds I and II as novel topoisomerase IIα catalytic inhibitors targeting for ATP binding site of human topoisomerase IIα ATP-binding domain. As a continuous work, we have designed and synthesized 43 compounds of C1-O-alkyl and arylalkyl substitiuted compounds with or without methoxy group on ring A. In the topoisomerase IIα inhibitory test, among the tested C1-O-4-chlorophenethyl substituted compounds 37 and 47 were more active than others, and compound 37 showed strongest topoisomerase IIα inhibitory activity with 94.4% and 23.0% inhibition, respectively, at 100 and 20 μM. Compounds 37 and 47 have also showed much enhanced cytotoxic activity against T47D cells; IC50(μM): 0.63 ± 0.01 and 0.19 ± 0.02, respectively, which are stronger than reference drugs. Band depletion assay and cleavage complex assay results showed compounds 37 and 47 were potential topoisomerase IIα catalytic inhibitor with low DNA damage.
AB - Topoisomerase II poison blocks the transitorily generated DNA double-strand breaks (DSBs) from religation, thereby causes severe DNA damage and gene toxicity. While topoisomerase II catalytic inhibitor does not form cleavable DNA-enzyme complex because its function attributes to inhibition of the catalytic steps of the enzyme such as before generating DNA DSBs or in the last step of the catalytic cycle after religation. It has been reported that the stabilizing effect of etoposide on transient cleavable DNA-topoisomerase IIβ complex attributes to its secondary malignancy. Therefore, topoisomerase IIα has been considered as more attractive target than topoisomerase IIβ for the development of chemotherapeutic agents. In the previous work, we reported compounds I and II as novel topoisomerase IIα catalytic inhibitors targeting for ATP binding site of human topoisomerase IIα ATP-binding domain. As a continuous work, we have designed and synthesized 43 compounds of C1-O-alkyl and arylalkyl substitiuted compounds with or without methoxy group on ring A. In the topoisomerase IIα inhibitory test, among the tested C1-O-4-chlorophenethyl substituted compounds 37 and 47 were more active than others, and compound 37 showed strongest topoisomerase IIα inhibitory activity with 94.4% and 23.0% inhibition, respectively, at 100 and 20 μM. Compounds 37 and 47 have also showed much enhanced cytotoxic activity against T47D cells; IC50(μM): 0.63 ± 0.01 and 0.19 ± 0.02, respectively, which are stronger than reference drugs. Band depletion assay and cleavage complex assay results showed compounds 37 and 47 were potential topoisomerase IIα catalytic inhibitor with low DNA damage.
KW - Anticancer agents
KW - C1-alkyl and arylalkyl substituted xanthones
KW - Topoisomerase IIα catalytic inhibitor
UR - http://www.scopus.com/inward/record.url?scp=84979911460&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2016.07.046
DO - 10.1016/j.ejmech.2016.07.046
M3 - Article
C2 - 27484510
AN - SCOPUS:84979911460
SN - 0223-5234
VL - 123
SP - 211
EP - 225
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -