Anticancer Cytotoxic Activity of Bispidine Derivatives Associated with the Increasing Catabolism of Polyamines
Ekaterina V. Neborak,
Altynay B. Kaldybayeva,
Lylia Bey,
Aigul Y. Malmakova,
Anna S. Tveritinova,
Abdullah Hilal,
Valentina K. Yu,
Maria V. Ploskonos,
Marina V. Komarova,
Enzo Agostinelli,
Dmitry D. Zhdanov
Affiliations
Ekaterina V. Neborak
Department of Biochemistry, Peoples’ Friendship University of Russia (RUDN University), 8 Miklukho-Maklaya St., Moscow 117198, Russia
Altynay B. Kaldybayeva
Laboratory of Chemistry of Synthetic and Natural Medicinal Substances, A.B. Bekturov Institute of Chemical Sciences, 59 Tole bi St., Almaty 050000, Kazakhstan
Lylia Bey
Department of Biochemistry, Peoples’ Friendship University of Russia (RUDN University), 8 Miklukho-Maklaya St., Moscow 117198, Russia
Aigul Y. Malmakova
Laboratory of Chemistry of Synthetic and Natural Medicinal Substances, A.B. Bekturov Institute of Chemical Sciences, 59 Tole bi St., Almaty 050000, Kazakhstan
Anna S. Tveritinova
Department of Biochemistry, Peoples’ Friendship University of Russia (RUDN University), 8 Miklukho-Maklaya St., Moscow 117198, Russia
Abdullah Hilal
Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, 10/8 Pogodinskaya St., Moscow 119121, Russia
Valentina K. Yu
Laboratory of Chemistry of Synthetic and Natural Medicinal Substances, A.B. Bekturov Institute of Chemical Sciences, 59 Tole bi St., Almaty 050000, Kazakhstan
Maria V. Ploskonos
Department of Chemistry, Astrakhan State Medical University, Astrakhan 414000, Russia
Marina V. Komarova
Department of Laser and Biotechnical Systems, Samara University, 34 Moskovskoye Shosse, Samara 443086, Russia
Enzo Agostinelli
Department of Sensory Organs, Faculty of Medicine and Dentistry, Sapienza University of Rome, University Hospital Policlinico Umberto I, I-00161 Rome, Italy
Dmitry D. Zhdanov
Department of Biochemistry, Peoples’ Friendship University of Russia (RUDN University), 8 Miklukho-Maklaya St., Moscow 117198, Russia
Polyamine (PA) catabolism is often reduced in cancer cells. The activation of this metabolic pathway produces cytotoxic substances that might cause apoptosis in cancer cells. Chemical compounds able to restore the level of PA catabolism in tumors could become potential antineoplastic agents. The search for activators of PA catabolism among bicyclononan-9-ones is a promising strategy for drug development. The aim of the study was to evaluate the biological activity of new 3,7-diazabicyclo[3.3.1]nonan-9-one derivatives that have antiproliferative properties by accelerating PA catabolism. Eight bispidine derivatives were synthetized and demonstrated the ability to activate PA catabolism in regenerating rat liver homogenates. However, only three of them demonstrated a potent ability to decrease the viability of cancer cells in the MTT assay. Compounds 4c and 4e could induce apoptosis more effectively in cancer HepG2 cells rather than in normal WI-38 fibroblasts. The lead compound 4e could significantly enhance cancer cell death, but not the death of normal cells if PAs were added to the cell culture media. Thus, the bispidine derivative 4e 3-(3-methoxypropyl)-7-[3-(1H-piperazin-1-yl)ethyl]-3,7-diazabicyclo[3.3.1]nonane could become a potential anticancer drug substance whose mechanism relies on the induction of PA catabolism in cancer cells.
