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

Georgy Y Nadysev; Alexander S Tikhomirov; Ming-Hung Lin; Ya-Ting Yang; Lyubov G Dezhenkova; Huei-Yu Chen; Dmitry N Kaluzhny; Dominique Schols; Alexander A Shtil; Andrey E Shchekotikhin; Pin Ju Chueh

doi:10.1016/j.ejmech.2017.10.055

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. Epub 2017 Oct 19.

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Methylation
Molecular Structure
Polycyclic Compounds / chemical synthesis
Polycyclic Compounds / chemistry
Polycyclic Compounds / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Polycyclic Compounds
heliomycin