Czeleń Przemysław, Jeliński Tomasz, Skotnicka Agnieszka, Szefler Beata, Szupryczyński Kamil
Department of Physical Chemistry, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Kurpinskiego 5, 85-096 Bydgoszcz, Poland.
Faculty of Chemical Technology and Engineering, Bydgoszcz University of Science and Technology, Seminaryjna 3, 85-326 Bydgoszcz, Poland.
Biomedicines. 2023 Nov 10;11(11):3019. doi: 10.3390/biomedicines11113019.
The development of new substances with the ability to interact with a biological target is only the first stage in the process of the creation of new drugs. The 5-nitroisatin derivatives considered in this study are new inhibitors of cyclin-dependent kinase 2 (CDK2) intended for anticancer therapy. The research, carried out based on the ADMET (absorption, distribution, metabolism, excretion, toxicity) methods, allowed a basic assessment of the physicochemical parameters of the tested drugs to be made. The collected data clearly showed the good oral absorption, membrane permeability, and bioavailability of the tested substances. The analysis of the metabolite activity and toxicity of the tested drugs did not show any critical hazards in terms of the toxicity of the tested substances. The substances' low solubility in water meant that extended studies tested compounds were required, which helped to select solvents with a high dissolving capacity of the examined substances, such as DMSO or NMP. The use of aqueous binary mixtures based on these two solvents allowed a relatively high solubility with significantly reduced toxicity and environmental index compared to pure solvents to be maintained, which is important in the context of the search for green solvents for pharmaceutical use.
开发具有与生物靶点相互作用能力的新物质只是新药创制过程的第一阶段。本研究中所考虑的5-硝基异吲哚酮衍生物是用于抗癌治疗的细胞周期蛋白依赖性激酶2(CDK2)新型抑制剂。基于ADMET(吸收、分布、代谢、排泄、毒性)方法开展的研究,使得对受试药物的理化参数进行了基本评估。收集的数据清楚地表明受试物质具有良好的口服吸收、膜通透性和生物利用度。对受试药物的代谢物活性和毒性分析未显示受试物质在毒性方面存在任何重大危害。这些物质在水中的低溶解度意味着需要对受试化合物进行进一步研究,这有助于选择对受试物质具有高溶解能力的溶剂,如二甲基亚砜(DMSO)或N-甲基吡咯烷酮(NMP)。与纯溶剂相比,使用基于这两种溶剂的二元水性混合物可保持相对较高的溶解度,同时显著降低毒性和环境指数,这在寻找药用绿色溶剂的背景下很重要。