ArticleInternational journal of molecular sciences2022
Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects.
Article in International journal of molecular sciences, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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6 citing papers in PubMed, 10 citations in OpenAlex.
- Synthesis, Clastogenic and Cytotoxic Potential, and In Vivo Antitumor Activity of a Novel N-Mustard Based on Indole-3-carboxylic Acid Derivative.Molecules (Basel, Switzerland) · 2025Article
- Polyacrylic Acid-Coated LaBPharmaceutics · 2025Article
- In Vitro and In Vivo Antitumor Activities of Isothiourea and Cinnamic Acid Derivative with NOS/MCT Inhibitory Effect.Bulletin of experimental biology and medicine · 2024Article
- In Vitro Cytotoxic Potential and In Vivo Antitumor Effects of NOS/PDK-Inhibitor T1084.International journal of molecular sciences · 2024Article
- Binary Proton Therapy of Ehrlich Carcinoma Using Targeted Gold Nanoparticles.Doklady. Biochemistry and biophysics · 2024Article
- Preclinical studies of NOS inhibitor T1059 vasopressor activity on the models of acute hemorrhagic shock in rats and dogs.Frontiers in pharmacology · 2022Article
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Authors and funding
11 authors at 2 institutions in 1 country.
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Abstract
We have previously demonstrated a high antitumor potential of NOS inhibitor T1023 (1-isobutanoyl-2-isopropylisothiourea hydrobromide): antitumor antiangiogenic activity in several animal tumor models and its ability to synergistically enhance the antitumor effects of bevacizumab, cyclophosphamide and γ-radiation. At the same time, rather rapid adaptation of experimental neoplasias to T1023 treatment was often observed. We attempted to enhance the antitumor activity of this NOS inhibitor by supplementing its molecular structure with a PDK-inhibiting fragment, dichloroacetate (DCA), which is capable of hypoxia-oriented toxic effects. We synthesized compound T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). Its toxic properties, NOS-inhibiting and PDK-inhibiting activity in vivo, and antitumor activity on the mouse Ehrlich carcinoma model (SEC) were investigated in compare with T1023 and Na-DCA. We found that the change of the salt-forming acid from HBr to DCA does not increase the toxicity of 1-isobutanoyl-2-isopropylisothiourea salts, but significantly expands the biochemical and anti-tumor activity. New compound T1084 realizes in vivo NOS-inhibiting and PDK-inhibiting activity, quantitatively, at the level of the previous compounds, T1023 and Na-DCA. In two independent experiments on SEC model, a pronounced synergistic antitumor effect of T1084 was observed in compare with T1023 and Na-DCA at equimolar doses. There were no signs of SEC adaptation to T1084 treatment, while experimental neoplasia rapidly desensitized to the separate treatment of both T1023 and Na-DCA. The totality of the data obtained indicates that the combination of antiangiogenic and hypoxia-oriented toxic effects (in this case, within the molecular structure of the active substance) can increase the antitumor effect and suppress the development of hypoxic resistance of neoplasias. In general, the proposed approach can be used for the design of new anticancer agents.
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