Synthesis and Biological Evaluation of Benzo [4,5]- and Naphtho[2′,1′:4,5]imidazo[1,2-c]pyrimidinone Derivatives

Azacarbazoles have attracted significant interest due to their valuable properties, such as anti-pathogenic and antitumor activity. In this study, a series of structurally related tricyclic benzo[4,5]- and tertacyclic naphtho[2′,1′:4,5]imidazo[1,2-c]pyrimidinone derivatives with one or two positively charged tethers were synthesized and evaluated for anti-proliferative activity. Lead tetracyclic derivative 5b with two amino-bearing arms inhibited the metabolic activity of A549 lung adenocarcinoma cells with a CC50 value of 3.6 μM, with remarkable selectivity (SI = 17.3) over VA13 immortalized fibroblasts. Cell-cycle assays revealed that 5b triggers G2/M arrest without signs of apoptosis. A study of its interaction with various DNA G4s and duplexes followed by dual luciferase and intercalator displacement assays suggests that intercalation, rather than the modulation of G4-regulated oncogene expression, might contribute to the observed activity. Finally, a water-soluble salt of 5b was shown to cause no acute toxic effects, changes in mice behavior, or any decrease in body weight after a 72 h treatment at concentrations up to 20 mg/kg. Thus, 5b is a promising candidate for studies in vivo; however, further investigations are needed to elucidate its molecular target(s).

Authors
Kamzeeva Polina1 , Dagaev Nikolai2 , Lizunova Sofia3 , Khodarovich Yuri 1, 4 , Sogomonyan Anna1 , Kolchanova Anastasia2 , Pokrovsky Vadim 5, 6 , Alferova Vera1 , Chistov Alexey1 , Eshtukov-Shcheglov Artur1 , Eshtukova-Shcheglova Elizaveta7 , Belyaev Evgeny8 , Skvortsov Dmitry2 , Varizhuk Anna3, 9, 10 , Aralov Andrey1, 3, 10
Journal
Publisher
MDPI AG
Number of issue
11
Language
English
Pages
1669
Status
Published
Volume
13
Year
2023
Organizations
  • 1 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
  • 2 Department of Chemistry and Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia
  • 3 Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
  • 4 Research and Educational Resource Center for Cellular Technologies, The Peoples’ Friendship University of Russia, 117198 Moscow, Russia
  • 5 N.N. Blokhin Cancer Research Center, 115478 Moscow, Russia
  • 6 Research Institute of Molecular and Cellular Medicine, RUDN University, 117198 Moscow, Russia
  • 7 Lomonosov Institute of Fine Chemical Technology, MIREA-Russian Technological University, 119571 Moscow, Russia
  • 8 Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, 119071 Moscow, Russia
  • 9 Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
  • 10 G4_Interact, USERN, University of Pavia, 27100 Pavia, Italy
Date of creation
25.01.2024
Date of change
25.01.2024
Short link
https://repository.rudn.ru/en/records/article/record/106142/
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