Synthesis and characterization of new hexahydroquinoline derivatives and evaluation of their cytotoxicity, intracellular ROS production, and inhibitory effects on inflammatory mediators.

IF 1.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Turkish Journal of Chemistry Pub Date : 2024-07-23 eCollection Date: 2024-01-01 DOI:10.55730/1300-0527.3686
Ezgi Pehlivanlar, Deniz Arca Çakir, Sonia Sanajou, Hülya Tezel Yalçin, Terken Baydar, Pınar Erkekoğlu, Hanife Avci, Rahime Şimşek
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引用次数: 0

Abstract

Inflammation is a response to injury and infection in an organism. It can be categorized as acute or chronic. Chronic inflammation is the underlying cause of many diseases such as Alzheimer disease, diabetes, rheumatoid arthritis, atherosclerosis, and cardiovascular diseases. Recent studies have proven the antiinflammatory properties of 1,4-dihydropyridines (1,4-DHPs) and their derivatives, which have many biological activities including the blocking of calcium channels. In this study, 15 compounds that are condensed derivatives of 1,4-DHPs, with the general structure of hexahydroquinoline-3-carboxylate, were synthesized. These compounds, expected to show inhibitory activity against inflammatory mediators, were obtained by the reaction of 4-(difluoromethoxy)benzaldehyde, substituted/nonsubstituted 1,3-cyclohexanedione derivatives, and appropriate alkyl acetoacetate compounds in the presence of ammonium acetate as a nitrogen source according to the Hantzsch synthesis method. The structures of the synthesized compounds were elucidated by IR, 1H NMR, 13C NMR, and HRMS methods. The cytotoxic properties of the compounds were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method in the 3T3 cell line. Among the 15 compounds, the three compounds with the lowest levels of cytotoxic effects were selected for further experiments. Inflammation was induced by lipoxygenase and the effects of the selected compounds on the levels of reactive oxygen species, cytokines, and complement C3 and C9 regulatory proteins were investigated. It was found that the three selected compounds decreased the levels of transforming growth factor-beta 1 (TGF-β1). Among these compounds, compound 3e provided the most significant decrease in this cytokine. Moreover, 3e increased both C3 and C9 levels. Molecular modeling studies also showed that 3e had better affinity for TGF-β1. When the binding modes of these compounds in the active site of TGF-β1 were analyzed, it was found that compound 3e had hydrophobic interactions with amino acids Leu142, Tyr84, and Ile13; halogen bond interactions with Asp92; and hydrogen bond interactions with Ser89, Gly88, and Gly14 in the active binding site. Further in vitro and in vivo studies are needed to show the possible mechanism of action of compound 3e.

新型六氢喹啉衍生物的合成和表征,以及对其细胞毒性、细胞内 ROS 生成和炎症介质抑制作用的评估。
炎症是机体对损伤和感染的一种反应。炎症可分为急性和慢性两种。慢性炎症是许多疾病的根本原因,如老年痴呆症、糖尿病、类风湿性关节炎、动脉粥样硬化和心血管疾病。最近的研究证明了 1,4-二氢吡啶(1,4-DHPs)及其衍生物的抗炎特性,它们具有多种生物活性,包括阻断钙通道。本研究合成了 15 种 1,4-DHPs 的缩合衍生物,其一般结构为六氢喹啉-3-羧酸酯。这些化合物是由 4-(二氟甲氧基)苯甲醛、取代/未取代的 1,3-Cyclohexanedione 衍生物和适当的乙酰乙酸烷基化合物在醋酸铵作为氮源的条件下,按照汉茨合成法反应得到的,预计对炎症介质具有抑制活性。通过红外光谱、1H NMR、13C NMR 和 HRMS 方法阐明了合成化合物的结构。用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑(MTT)法测定了这些化合物在 3T3 细胞系中的细胞毒性。在这 15 种化合物中,选取了细胞毒性作用最低的三种化合物进行进一步实验。通过脂氧合酶诱导炎症,研究了所选化合物对活性氧、细胞因子、补体 C3 和 C9 调节蛋白水平的影响。研究发现,所选的三种化合物降低了转化生长因子-β1(TGF-β1)的水平。在这些化合物中,化合物 3e 对该细胞因子的降低作用最为显著。此外,3e 还能提高 C3 和 C9 的水平。分子建模研究还表明,3e 对 TGF-β1 具有更好的亲和力。在分析这些化合物在 TGF-β1 活性部位的结合模式时,发现化合物 3e 与氨基酸 Leu142、Tyr84 和 Ile13 有疏水相互作用;与 Asp92 有卤键相互作用;与活性结合部位的 Ser89、Gly88 和 Gly14 有氢键相互作用。还需要进一步的体外和体内研究来显示化合物 3e 的可能作用机制。
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来源期刊
Turkish Journal of Chemistry
Turkish Journal of Chemistry 化学-工程:化工
CiteScore
2.40
自引率
7.10%
发文量
87
审稿时长
3 months
期刊介绍: The Turkish Journal of Chemistry is a bimonthly multidisciplinary journal published by the Scientific and Technological Research Council of Turkey (TÜBİTAK). The journal is dedicated to dissemination of knowledge in all disciplines of chemistry (organic, inorganic, physical, polymeric, technical, theoretical and analytical chemistry) as well as research at the interface with other sciences especially in chemical engineering where molecular aspects are key to the findings. The journal accepts English-language original manuscripts and contribution is open to researchers of all nationalities. The journal publishes refereed original papers, reviews, letters to editor and issues devoted to special fields. All manuscripts are peer-reviewed and electronic processing ensures accurate reproduction of text and data, plus publication times as short as possible.
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