Synthesis, Biological Evaluation and in Silico Studies of Novel Urea/Thiourea Derivatives of Lenalidomide

IF 3.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Fatih Tok, Burçin İrem Abas, Faika Başoğlu, Özge Çevik, Sevgi Karakuş, Abdulilah Ece
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Abstract

Designing new compounds from existing chemotherapeutic drugs to enhance inhibitory effects on tumor cells while overcoming multidrug resistance is one of the important strategies for new drug discovery in medicinal chemistry. A new series of urea and thiourea derivatives based on Lenalidomide as potential anticancer agents have been designed and synthesized. In vitro anticancer activity assay against Caki cancer cells and HUVEC endothelial cells revealed that 1-(4-methylphenyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl]urea (11) exhibited the highest anticancer activity and selectivity in the series with IC50 values of 9.88 and 179.03 µM, respectively. Among the compounds, 11 showed significant HDAC1 inhibiton of 68.02 ± 2.44% at 10 µM concentration. TGF-β, Bax, Bcl-2 protein levels and scratch assay were analyzed in Caki cells. As a result, compound 11 induced apoptosis in Caki cells. In this study, it has been demonstrated that compound 11 can be a lead compound for further detailed investigation in renal cancer treatment. Through molecular docking studies, it was determined that the most active compound, 11, forms stable interactions with key residues in the enzyme's active site, particularly engaging in hydrogen bonds with GLY149 and coordinating with the zinc ion in the HDAC1 active site. These interactions are crucial for the observed inhibitory activity. Molecular dynamics simulation revealed the binding event of the most active compound with class I histone deacetylase and the stability of the complex in a biological environment.

Abstract Image

来那度胺新型脲/硫脲衍生物的合成、生物学评价及硅研究
从现有化疗药物中设计出新的化合物,增强对肿瘤细胞的抑制作用,同时克服多药耐药是药物化学中发现新药的重要策略之一。以来那度胺为潜在的抗癌药物,设计合成了一系列新的脲和硫脲衍生物。体外对Caki癌细胞和HUVEC内皮细胞的抗癌活性实验表明,1-(4-甲基苯基)-3-[2-(2,6-二氧哌替啶-3-基)-1-氧异吲哚-4-基]尿素(11)具有最高的抗癌活性和选择性,IC50值分别为9.88和179.03µM。在10µM浓度下,11个化合物对HDAC1的抑制率为68.02±2.44%。检测Caki细胞中TGF-β、Bax、Bcl-2蛋白水平及划痕法。结果,化合物11诱导Caki细胞凋亡。在本研究中,化合物11可以作为先导化合物在肾癌治疗中进一步深入研究。通过分子对接研究,确定活性最强的化合物11与酶活性位点的关键残基形成稳定的相互作用,特别是与GLY149形成氢键,并与HDAC1活性位点的锌离子配合。这些相互作用对观察到的抑制活性至关重要。分子动力学模拟揭示了最活跃的化合物与I类组蛋白去乙酰化酶的结合事件以及该复合物在生物环境中的稳定性。
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来源期刊
CiteScore
5.80
自引率
2.80%
发文量
277
审稿时长
6-12 weeks
期刊介绍: The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.
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