{"title":"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。","authors":"Ezgi Pehlivanlar, Deniz Arca Çakir, Sonia Sanajou, Hülya Tezel Yalçin, Terken Baydar, Pınar Erkekoğlu, Hanife Avci, Rahime Şimşek","doi":"10.55730/1300-0527.3686","DOIUrl":null,"url":null,"abstract":"<p><p>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, <sup>1</sup>H NMR, <sup>13</sup>C 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 <b>3e</b> provided the most significant decrease in this cytokine. Moreover, <b>3e</b> increased both C3 and C9 levels. Molecular modeling studies also showed that <b>3e</b> 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 <b>3e</b> 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 <b>3e</b>.</p>","PeriodicalId":23367,"journal":{"name":"Turkish Journal of Chemistry","volume":"48 4","pages":"659-675"},"PeriodicalIF":1.3000,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11407359/pdf/","citationCount":"0","resultStr":"{\"title\":\"Synthesis and characterization of new hexahydroquinoline derivatives and evaluation of their cytotoxicity, intracellular ROS production, and inhibitory effects on inflammatory mediators.\",\"authors\":\"Ezgi Pehlivanlar, Deniz Arca Çakir, Sonia Sanajou, Hülya Tezel Yalçin, Terken Baydar, Pınar Erkekoğlu, Hanife Avci, Rahime Şimşek\",\"doi\":\"10.55730/1300-0527.3686\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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, <sup>1</sup>H NMR, <sup>13</sup>C 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 <b>3e</b> provided the most significant decrease in this cytokine. Moreover, <b>3e</b> increased both C3 and C9 levels. Molecular modeling studies also showed that <b>3e</b> 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 <b>3e</b> 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 <b>3e</b>.</p>\",\"PeriodicalId\":23367,\"journal\":{\"name\":\"Turkish Journal of Chemistry\",\"volume\":\"48 4\",\"pages\":\"659-675\"},\"PeriodicalIF\":1.3000,\"publicationDate\":\"2024-07-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11407359/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Turkish Journal of Chemistry\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.55730/1300-0527.3686\",\"RegionNum\":4,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Turkish Journal of Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.55730/1300-0527.3686","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Synthesis and characterization of new hexahydroquinoline derivatives and evaluation of their cytotoxicity, intracellular ROS production, and inhibitory effects on inflammatory mediators.
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.
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.