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Organotin compound as an inhibitor of nitric oxide formation

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Abstract

The effect of antitumor and antimetastatic agent, triphenyltin (3,5-di-tert-butyl-4-hydroxyphenyl)thiolate (Me-5), on the in vitro activity of inducible nitric oxide synthase (iNOS) as a relevant biological target was studied. The compound Me-5 (the half-maximal inhibitory concentration IC50 = 0.47 µmol L−1) induced a significant inhibition of NO formation by macrophages, exceeding that of dexamethasone used as the reference compound (IC50 = 1.55 µmol L−1). Estimation of the morphology of macrophages after incubation with Me-5 in 10 µmol L−1 concentration revealed signs of the pronounced cytotoxicity: destruction of cell membranes, reduction of cell volume, chromatin condensation, and nuclear shrinkage. It was found that the organotin compound substantially inhibits the anti-inflammatory response and viability of macrophages, especially the functions of lysosomes. Molecular docking of Me-5 into the iNOS structure was carried out. According to calculations, the molecule is located at the entrance of the active site cavity, above the plane of the heme moiety, and hinders the substrate penetration into the active site, which may attest to a plausible mechanism of antitumor and antimetastatic action of Me-5.

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Authors and Affiliations

  1. Department of Chemistry, Lomonosov Moscow State University, Build. 3, 1 Leninskie Gory, 119991, Moscow, Russian Federation

    E. R. Milaeva, D. B. Shpakovsky, E. V. Radchenko & V. A. Palyulin

  2. Volgograd State Medical University, 1 pl. Pavshikh Bortsov, 400131, Volgograd, Russian Federation

    D. A. Babkov, A. V. Borisov & A. A. Spasov

  3. Rostov State Medical University, Ministry of Health Care of the Russian Federation, 29 per. Nakhichevanskii, 344022, Rostov-on-Don, Russian Federation

    M. A. Dodokhova, A. V. Safronenko & I. M. Kotieva

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  1. E. R. Milaeva
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  2. D. B. Shpakovsky
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  3. E. V. Radchenko
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Corresponding author

Correspondence to E. R. Milaeva.

Additional information

Based on the materials of the V Russian Conference on Medicinal Chemistry with international participation “MedChem-Russia 2021” (May 16–19, 2022, Volgograd, Russia).

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2605–2611, December, 2022.

This work was financially supported by the Russian Science Foundation (Project No. 22-63-00016).

All procedures with animals were performed in accordance with generally accepted ethical standards for animal handling. The housing of animals complied with the Rules of Laboratory Practice for Conducting Preclinical Studies in the Russian Federation (GOST 351.000.3-96 and 51000.4-96), the Order of the Ministry of Health and Social Development of the Russian Federation No. 708n, dated August 23, 2010, “On approval of the Rules of Laboratory Practice”, and were in line with the Directives 2010/63/EU of the European Parliament and of the Council of September 22, 2010, on the protection of animals used for scientific purposes. The experimental protocols were approved by the Commission on Biomedical Ethics of the Volgograd State Medical University IRB 00005839 IORG 0004900, OHRP, Certificate No. 2021/056 dated June, 15, 2021.

The authors declare no competing interests.

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Milaeva, E.R., Shpakovsky, D.B., Radchenko, E.V. et al. Organotin compound as an inhibitor of nitric oxide formation. Russ Chem Bull 71, 2605–2611 (2022). https://doi.org/10.1007/s11172-022-3689-6

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  • DOI: https://doi.org/10.1007/s11172-022-3689-6

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