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.
- 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: [email protected].
- 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.
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.