2. Academic Validation
  3. Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives

Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives

  • Eur J Med Chem. 2018 Jan 1:143:1553-1562. doi: 10.1016/j.ejmech.2017.10.055.
Georgy Y Nadysev 1,  Alexander S Tikhomirov 1,  Ming-Hung Lin 2,  Ya-Ting Yang 3,  Lyubov G Dezhenkova 4,  Huei-Yu Chen 3,  Dmitry N Kaluzhny 5,  Dominique Schols 6,  Alexander A Shtil 7,  Andrey E Shchekotikhin 8,  Pin Ju Chueh 9
Affiliations

Affiliations

  • 1 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia.
  • 2 Division of Urology, Department of Surgery, Tainan Municipal An-Nan Hospital-China Medical University, Tainan 70965, Taiwan; Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defence Medical Center, Taipei 11490, Taiwan.
  • 3 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.
  • 4 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
  • 5 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
  • 6 Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
  • 7 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia; ITMO University, 49 Kronverksky Avenue, 197101 St. Petersburg, Russia.
  • 8 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia. Electronic address: shchekotikhin@mail.ru.
  • 9 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan; Graduate Institute of Basic Medicine, China Medical University, Taichung, 40402, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, 40402, Taiwan; Department of Biotechnology, Asia University, Taichung, 41354, Taiwan. Electronic address: https://dragon.nchu.edu.tw.
PMID: 29137865 DOI: 10.1016/j.ejmech.2017.10.055
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.

Keywords

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

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