Laboratory of the Chemistry of Heterocyclic Compounds, Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, 13 Surganov Str., 220072, Minsk, Belarus.
Brain Centre, Institute of Physiology, National Academy of Sciences of Belarus, 28 Akademicheskaya Str., 220072, Minsk, Belarus.
Sci Rep. 2023 Aug 21;13(1):13624. doi: 10.1038/s41598-023-40094-9.
Chemotherapy is one of the main treatment options for cancer, but it is usually accompanied with negative side effects. The classical drugs combination with synergistic adjuvants can be the solution to this problem, allowing reducing therapeutic dose. Elucidating the mechanism of adjuvant action is of key importance for the selection of the optimal agent. Here we examine the system drug-adjuvant to explain the observed effect in practice. We used the first line drug cisplatin. Morpholinium and 4-methylpiperazinium 4,5-dichloro isothiazol-3-carboxylates were selected as adjuvants. The study of the cisplatin-adjuvant system was carried out by quantum chemical modeling using DFT. It turned out that adjuvants form conjugates with cisplatin that lead to the relocation of frontier molecular orbitals as well as increase of conjugate's dipole moment. It resulted in change of the interaction character with DNA and increase of the bioactivity of the system. The data obtained are the basis for expanding the studies to include other drugs and adjuvants. Oncologists will have opportunity to use "classical" chemotherapy drugs in combination with synergists for those patients who have not been previously recommended to such a treatment because of pronounced toxic side effects.
化疗是癌症的主要治疗方法之一，但通常伴随着负面副作用。具有协同增效剂的经典药物组合可以解决这个问题，允许减少治疗剂量。阐明辅助剂作用的机制对于选择最佳药物至关重要。在这里，我们检查药物-辅助剂系统以解释在实践中观察到的效果。我们使用一线药物顺铂。选择吗啉和 4-甲基哌嗪 4,5-二氯异噻唑-3-羧酸酯作为佐剂。通过使用 DFT 的量子化学建模研究了顺铂-佐剂系统。结果表明，佐剂与顺铂形成缀合物，导致前线分子轨道的重定位以及共轭物的偶极矩的增加。这导致与 DNA 的相互作用特性发生变化，并增加了系统的生物活性。获得的数据为扩展研究包括其他药物和佐剂提供了依据。肿瘤学家将有机会为那些由于明显的毒性副作用而以前不建议接受这种治疗的患者使用“经典”化疗药物与增效剂联合使用。
