Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects

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.

Unmasking the Warburg Effect: Unleashing the Power of Enzyme Inhibitors for Cancer Therapy

“…This multifunctionality enabled T1084 to concurrently exert two distinct pharmacological actions, anti-angiogenesis and hypoxia-oriented cytotoxicity, that could potentially enhance its anti-tumor effects. The methodology employed in this study potentially allowed for the possibility of developing additional multifunctional anti-tumor compounds with diverse molecular mechanisms of action [105].…”

Preclinical studies of NOS inhibitor T1059 vasopressor activity on the models of acute hemorrhagic shock in rats and dogs

“…So, some time ago, while screening linear and cyclic isothioureas, we identified and synthesized a large group of isothiourea derivatives (Figure 1A) that are competitive inhibitors of NOS (Proskuryakov et al, 2002(Proskuryakov et al, , 2005Proskuryakov et al, 2010;Filimonova et al, 2012a). Further, we found that some compounds of this group (such as T1023, T1082, T1084) are promising for further pharmacological development-as hypoxic radioprotectors that provide effective prevention of hematopoietic and gastrointestinal acute radiation syndromes, and radiotherapy complications (Filimonova et al, 2020b(Filimonova et al, , 2021(Filimonova et al, , 2022bSaburova et al, 2020), as well as antitumor, antiangiogenic agents (Filimonova et al, 2019a;2019b;2022a).…”