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標題: Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives
作者: Nadysev, Georgy Y
Tikhomirov, Alexander S
Lin, Ming-Hung
Yang, Ya-Ting
Dezhenkova, Lyubov G
Chen, Huei-Yu
Kaluzhny, Dmitry N
Schols, Dominique
Shtil, Alexander A
Shchekotikhin, Andrey E
Chueh, Pin Ju
關鍵字: Anticancer agents;Apoptosis;DNA;Heliomycin;Mannich aminomethylation;ROS;Resistomycin;Antineoplastic Agents;Apoptosis;Cell Line, Tumor;Cell Proliferation;Dose-Response Relationship, Drug;Drug Screening Assays, Antitumor;Humans;Methylation;Molecular Structure;Polycyclic Compounds;Structure-Activity Relationship
Project: European journal of medicinal chemistry, Volume 143, Page(s) 1553-1562.
A series of 4-aminomethyl derivatives of heliomycin 1 was prepared using the Mannich reaction. The modification significantly improved aqueous solubility of the initially poorly soluble antibiotic. Testing the antiproliferative efficacy revealed a potent activity of heliomycin as well as its new derivatives on a panel of mammalian tumor cells including drug resistant variants. In contrast to 1 the new derivatives 7a, 7l, 7p generated a high level of ROS associated with induction of apoptosis in T24 bladder cancer cells. Introduction of 4-aminomethyl moiety increased the affinity to DNA and the ability to inhibit topoisomerase 1 making 7p the most promising candidate for further preclinical evaluation. Thus, aminomethylation is the first-in-class successful transformation of the antibiotic 1 resulting in an improved water solubility of derivatives and promising properties in search of novel anticancer drug candidates.
DOI: 10.1016/j.ejmech.2017.10.055
Appears in Collections:生物醫學研究所

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