Department of Organic Chemistry, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland.
Department of Basic Chemical Sciences, Wroclaw Medical University, Borowska 211a, 50-556 Wrocław, Poland.
Int J Mol Sci. 2024 Oct 13;25(20):11011. doi: 10.3390/ijms252011011.
Pyrimidine derivatives exhibit a wide range of biological activities, including anti-inflammatory properties. The aim of this study was to investigate the effects of tested pyrimidine derivatives on the activity of cyclooxygenase isoenzymes (COX-1 and COX-2), antioxidant properties, and their ability to inhibit the growth of inflammatory cells. In vitro tests were conducted to assess the ability of pyrimidine derivatives L1-L4 to inhibit COX-1 and COX-2 activity using the TMPD oxidation assay (N,N,N',N'-tetramethyl-p-phenylenediamine). The compounds' ability to inhibit the growth of lipopolysaccharide (LPS)-stimulated THP-1 (human leukemia monocytic) monocyte cells and their impact on reactive oxygen species (ROS) levels in an inflammatory model were also evaluated. The binding properties of human serum albumin (HSA) were assessed using UV-Vis spectroscopy, circular dichroism (CD), and isothermal titration calorimetry (ITC). Among the tested pyrimidine derivatives, L1 and L2 showed high selectivity towards COX-2, outperforming piroxicam and achieving results comparable to meloxicam. In the sulforhodamine B (SRB) assay, L1 and L2 demonstrated dose-dependent inhibition of LPS-stimulated THP-1 cell growth. Additionally, ROS assays indicated that these compounds reduced free radical levels, confirming their antioxidant properties. Binding studies with albumin revealed that L1 and L2 formed stable complexes with HSA. These results suggest that these compounds could serve as a basis for further research into anti-inflammatory and anticancer drugs with reduced toxicity.
嘧啶衍生物具有广泛的生物活性，包括抗炎特性。本研究旨在研究测试的嘧啶衍生物对环氧化酶同工酶（COX-1 和 COX-2）活性、抗氧化特性以及抑制炎症细胞生长能力的影响。进行了体外试验，以使用 TMPD 氧化测定法（N，N，N'，N'-四甲基-p-苯二胺）评估嘧啶衍生物 L1-L4 抑制 COX-1 和 COX-2 活性的能力。还评估了这些化合物抑制脂多糖（LPS）刺激的 THP-1（人白血病单核细胞）单核细胞生长的能力及其对炎症模型中活性氧（ROS）水平的影响。使用紫外-可见光谱法、圆二色性（CD）和等温热力学滴定法（ITC）评估了人血清白蛋白（HSA）的结合特性。在测试的嘧啶衍生物中，L1 和 L2 对 COX-2 具有高选择性，优于吡罗昔康，并且与美洛昔康的结果相当。在磺基罗丹明 B（SRB）测定中，L1 和 L2 表现出对 LPS 刺激的 THP-1 细胞生长的剂量依赖性抑制。此外，ROS 测定表明这些化合物降低了自由基水平，证实了它们的抗氧化特性。与白蛋白的结合研究表明，L1 和 L2 与 HSA 形成稳定的复合物。这些结果表明，这些化合物可以作为进一步研究具有降低毒性的抗炎和抗癌药物的基础。
