title: Synthesis and biological evaluation of C1-O-substituted-3-(3-butylamino-2-hydroxy-propoxy)-xanthen-9-one as topoisomerase IIα catalytic inhibitors.
abstract: 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.
authors.affiliation: College of Pharmacy & Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 120-750, South Korea.
authors.forename: Seojeong
authors.initials: S
authors.lastname: Park
authors.affiliation: College of Pharmacy, CHA University, Pocheon, 487-010, South Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Hong
authors.affiliation: College of Pharmacy, CHA University, Pocheon, 487-010, South Korea.
authors.forename: Soo Yeon
authors.initials: SY
authors.lastname: Kwak
authors.affiliation: College of Pharmacy & Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 120-750, South Korea.
authors.forename: Kyu-Yeon
authors.initials: KY
authors.lastname: Jun
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, 712-749, South Korea.
authors.forename: Eung-Seok
authors.initials: ES
authors.lastname: Lee
authors.affiliation: College of Pharmacy & Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 120-750, South Korea. Electronic address: ykwon@ewha.ac.kr.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: College of Pharmacy, CHA University, Pocheon, 487-010, South Korea. Electronic address: yna7315@cha.ac.kr.
authors.forename: Younghwa
authors.initials: Y
authors.lastname: Na
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D055162:Biocatalysis / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D044004:Xanthones / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: C000614244:3-(3-butylamino-2-hydroxypropoxy)-1-(4-chlorophenethoxy)-9H-xanthen-9-one; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D059005:Topoisomerase II Inhibitors; D044004:Xanthones; D000255:Adenosine Triphosphate; D004250:DNA Topoisomerases, Type II
keywords: Anticancer agents; C1-alkyl and arylalkyl substituted xanthones; Topoisomerase IIα catalytic inhibitor