Objective: Derivatives of 3,7-diazabicyclo[3.3.1]nonan-9-one attract considerable attention from pharmacists for the treatment of a wide rangeof diseases. According to this interest, the novel derivatives of 3-cyclopropanmethyl-7-alkoxyalkyl-3,7-diazabicyclo[3.3.1]nonan-9-one withisopropoxypropyl and ethoxypropyl substituents in the position 7 had been synthesized to study their biological activity and toxicity. The practicalsignificance of the work is in the accumulation and development of scientific representations about diazabicyclic compounds, methods for theirsynthesis, structure, and properties, which can subsequently be used in a targeted design and identification of even more complex systems, as wellas in the development of further research in the field of 3,7-diazabicyclo[3.3.1]nonanes. For this purpose, complexes of the synthesized compoundswith β-cyclodextrin are obtained and their biological activity is investigated at the Department of Pharmacology of S.D. Asfendiyarov Kazakh NationalMedical University with the aid of the pharmacological tests.Methods: An experimental study of local anesthetic activity on the models of infiltration, conduction anesthesia, and acute toxicity of synthesizedmolecules was carried out using primary screening methods.Results: As a result of pharmacological screening, it has been found that the compounds exhibit local anesthetic activity and low toxicity and wasrecommended for in-depth study of their pharmacological properties.Conclusion: It turned out that a nature of the N-alkoxyalkyl radical does not affect the toxicity of cyclopropanmethyl- substituted bispidines. In theseries of O-benzoyloximes of bispidinones, the isopropoxypropyl- substituted analog is 1.3 times less toxic than ethoxypropyl- one.
We report the syntheses and characterization of novel 3,7-bicycl[3.3.1]bispidines possessing an imidazolpropyl group attached to N-3, and at N-7 a Boc group, as well as a benzoylated-oximated group at C-9. These compounds were complexed with β-cyclodextrin [β-CD] and evaluated as seed protectors of selected wheat seedlings. Using strong acid, condensations of N-substituted piperidones with the appropriate imidazolpropyl groups at N-3 and N-7 led to bispidinones 6 and 7. These intermediates were reduced to the corresponding 3,7-diazabicyclo[3.3.1]nonane targets. The oxime at C-9 was benzoylated to yield 13. Heating these 3,7-diazabicyclo[3.3.1]nonanes in ethanol with β-CD generated the complexes required. We investigated the ability of such complexes as coatings on seedlings to protect and stimulate growth of three varieties of wheat, namely Kazakhstanskaya-10, Severyanka, and Miras. The complex of 3-[3-(1H-imidazol-1-yl)propyl]-7-(3-methoxypropyl)-3,7-diazabicyclo[3.3.1]nonane (2) promoted growth in the root systems of all three wheat varieties by more than 30% in Kazakhstanskaya-10, 30% in Severyanka and 8.5% in Miras. A complex of 3-Boc-7-[3-(1H-imidazol-1-yl)propyl]-3,7-diazabicyclo[3.3.1]nonane (9) increased both shoot and root length in only the Severyanka variety. The complex of 3-(3-butoxypropyl)-7-[3-(1H-imidazol-1-yl)propyl]-3,7-diazabicyclo[3.3.1]nonane (11) stimulated both shoot growth (0.8%, 12.3%, 13.5%) and root growth (12.3%, 9.4%, 21.7%) in all three varieties of wheat, respectively. The nature of substituents on the bispidine affect the activity. Solid complexes (1:1) were generated as powders which melted above 240 °C (dec) and were characterized via elemental analyses as 1:1 complexes.
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.
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