Filimonova Marina, Shitova Anna, Soldatova Olga, Shevchenko Ljudmila, Saburova Alina, Podosinnikova Tatjana, Surinova Valentina, Shegay Petr, Kaprin Andrey, Ivanov Sergey, Filimonov Alexander
Personalized Medicine Centre, Almazov National Medical Research Centre, 197341 Saint Petersburg, Russia.
A. Tsyb Medical Radiological Research Center-Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia.
Int J Mol Sci. 2022 Jan 10;23(2):730. doi: 10.3390/ijms23020730.
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.
我们之前已证明一氧化氮合酶（NOS）抑制剂T1023（1 - 异丁酰基 - 2 - 异丙基异硫脲氢溴酸盐）具有很高的抗肿瘤潜力：在多种动物肿瘤模型中具有抗肿瘤抗血管生成活性，并且能够协同增强贝伐单抗、环磷酰胺和γ射线的抗肿瘤作用。同时，经常观察到实验性肿瘤对T1023治疗的适应性相当迅速。我们试图通过用能够产生缺氧导向毒性作用的PDK抑制片段二氯乙酸（DCA）补充其分子结构来增强这种NOS抑制剂的抗肿瘤活性。我们合成了化合物T1084（1 - 异丁酰基 - 2 - 异丙基异硫脲二氯乙酸盐）。与T1023和Na - DCA相比，研究了其体内毒性特性、NOS抑制和PDK抑制活性以及对小鼠艾氏癌模型（SEC）的抗肿瘤活性。我们发现成盐酸从HBr变为DCA并不会增加1 - 异丁酰基 - 2 - 异丙基异硫脲盐的毒性，但会显著扩展其生化和抗肿瘤活性。新化合物T1084在体内实现了NOS抑制和PDK抑制活性，在数量上与之前的化合物T1023和Na - DCA相当。在关于SEC模型的两项独立实验中，与等摩尔剂量的T1023和Na - DCA相比，观察到T1084具有明显的协同抗肿瘤作用。没有迹象表明SEC对T1084治疗产生适应性，而实验性肿瘤对T1023和Na - DCA的单独治疗迅速产生脱敏。所获得的数据总体表明，抗血管生成和缺氧导向毒性作用的组合（在这种情况下，在活性物质的分子结构内）可以增加抗肿瘤作用并抑制肿瘤缺氧抗性的发展。总体而言，所提出的方法可用于设计新的抗癌药物。
