title: 3-(3-Butylamino-2-hydroxy-propoxy)-1-hydroxy-xanthen-9-one acts as a topoisomerase IIα catalytic inhibitor with low DNA damage.
abstract: As a continuous study we prepared several alkylamine (n = 3-6) and evaluated for the pharmacological activity and mode of action. In the topoisomerase IIα (topo IIα) inhibition test, compound 4 showed strongest inhibitory activity among the compounds at 10 μM. Inhibitory activities of the compounds are in the order of 4 (n = 4) > 1 (n = 3) >> 5 (n = 5) ≈ 6 (n = 6); 8 (n = 4) >> 7 (n = 3) ≈ 9 (n = 5) ≈ 10 (n = 6) where n is the number of carbon in the aliphatic side chain in ring C and compounds 7-10 have additional methoxy group in ring A compared to compounds 1, 4-6. Compound 4 showed efficient cytotoxicities against T47D (IC₅₀: 0.93 ± 0.04 μM) and HCT15 (IC50: 0.78 ± 0.01 μM) cells, which are higher than etoposide. Compound 4 was also an ATP-competitive human topo IIα catalytic inhibitor with partially blocking human topo IIα-catalyzed ATP hydrolysis and intercalating into DNA. Compound 4 induced much less DNA damage than etoposide in HCT15 human colorectal carcinoma cells. Overall, compound 4 can be a potential anticancer agent acting as topo IIα catalytic inhibitor with low DNA damage.
authors.affiliation: College of Pharmacy & Ewha Global Top5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: So-Eun
authors.initials: SE
authors.lastname: Park
authors.forename: In-Hye
authors.initials: IH
authors.lastname: Chang
authors.forename: Kyu-Yeon
authors.initials: KY
authors.lastname: Jun
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Lee
authors.forename: Eung-Seok
authors.initials: ES
authors.lastname: Lee
authors.forename: Younghwa
authors.initials: Y
authors.lastname: Na
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055162:Biocatalysis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044004:Xanthones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000589296:3-(3-butylamino-2-hydroxypropoxy)-1-hydroxyxanthen-9-one; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D059005:Topoisomerase II Inhibitors; D044004:Xanthones; D004250:DNA Topoisomerases, Type II
keywords: ATP-competitive inhibitor; Anticancer agents; DNA intercalator; Topoisomerase IIα catalytic inhibitor; Xanthones