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European journal of medicinal chemistry v.143, 2018년, pp.1553 - 1562   SCI SCIE
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Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives

Nadysev, Georgy Y. (Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia ) ; Tikhomirov, Alexander S. (Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia ) ; Lin, Ming-Hung (Division of Urology, Department of Surgery, Tainan Municipal An-Nan Hospital-China Medical University, Tainan 70965, Taiwan ) ; Yang, Ya-Ting (Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan ) ; Dezhenkova, Lyubov G. (Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia ) ; Chen, Huei-Yu (Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan ) ; Kaluzhny, Dmitry N. (Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia ) ; Schols, Dominique (Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium ) ; Shtil, Alexander A. (Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia ) ; Shchekotikhin, Andrey E. (Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia ) ; Chueh, Pin Ju (Institute of Biomedical Sciences, National Chung Hsing University, ) ;
  • 초록  

    Abstract 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. Highlights The chemical modification of heliomycin via Mannich aminomethylation was developed. 17 new derivatives with improved water solubility were synthesized. Heliomycin and its new derivatives inhibit growth of tumor cell lines including resistant variants. The designed modification modulates the activities towards DNA, Top1, and ROS. Graphical abstract [DISPLAY OMISSION]


  • 주제어

    Heliomycin .   Resistomycin .   Mannich aminomethylation .   Anticancer agents .   DNA .   ROS .   Apoptosis.  

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