Abstract—
The reaction of DL-valine hydroxamic acid with triacetonamine proceeds as the N,N'-regioselective condensation to form (±)-1-hydroxy-3-isopropyl-7,7,9,9-tetramethyl-1,4,8-triazaspiro[4,5]decan-2-one. A study of the antimetastatic and antitumor activities of the resulting hydroxamic acid in vivo by the combined therapy with a cytostatic of the alkylation type on a model of experimental transplanted mouse melanoma B16 showed that the compound is capable of increasing the sensitivity of the tumor to the known antitumor drug cyclophosphamide applied at a subtherapeutic dose. The chemosensitizing activity of hydroxamic acid combined with cyclophosphamide led to an almost twofold increase in the antitumor effect of the cytostatic and a marked decrease in the number of metastases, which showed up as an increase in the metastasis inhibition index (MII) to 74%.
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ACKNOWLEDGMENTS
The study was performed using the facilities of the Analytical Center of Collective Use at the Institute of Problems of Chemical Physics, Russian Academy of Sciences.
Funding
The study was supported by the Russian Scientific Foundation (project no. 19-73-10195) and within the framework of State project no. АААА-А19-119071890015-6.
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The article does not contain any studies involving human participants performed by any of the authors.
All manipulations with animals were carried out in accordance with the regulations of the Commissions on Bioethics at the Institute of Problems of Chemical Physics, Russian Academy of Sciences, and the Institute of Physiologically Active Substances, Russian Academy of Sciences.
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Translated by S. Sidorova
Abbreviations: HA, hydroxamic acid; MII, metastasis inhibition index; UEP, unshared electron pair; ILE, increase in life expectancy; DL-AlaHA, DL-alanine hydroxamic acid; DL-ValHA, DL-valine hydroxamic acid; GlyHA, glycine hydroxamic acid; HDACs, histone deacetylases; LD, lethal dose; ТАА, triacetonamine.
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Vystorop, I.V., Shilov, G.V., Chernyak, A.V. et al. Regioselective Synthesis, Structure, and Chemosensitizing Antitumor Activity of Cyclic Hydroxamic Acid Based on DL-Valine. Russ J Bioorg Chem 47, 757–764 (2021). https://doi.org/10.1134/S1068162021030171
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DOI: https://doi.org/10.1134/S1068162021030171