评估喹啉相关羧酸衍生物作为不同抗增殖、抗氧化和抗炎药物的前景。

IF 3.2 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Shereen Arabiyat, Ahmad Alzoubi, Hala Al-Daghistani, Yusuf Al-Hiari, Violet Kasabri, Rema Alkhateeb
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引用次数: 0

摘要

癌症发病率较高,对副作用小的抗氧化/抗炎化疗化合物的需求尚未得到满足,这一点至关重要。此外,临床试验失败的可能性增大,开发成本不断增加,这可能会减少临床使用新药的选择范围。这就决定了必须通过再利用来寻找新药,因为探索现有药物或不成功药物的新用途所需的时间、精力和资源都更少。在这项研究中,我们考察了 10 种潜在喹啉衍生物的生物活性。在脂多糖(LPS)诱导的 RAW264.7 小鼠巨噬细胞炎症中,根据半最大抑制浓度(IC50 值),所有商用喹啉类化合物和选定的喹啉类化合物(喹啉-4-羧酸和喹啉-3-羧酸)与经典的非甾体抗炎药吲哚美辛相比,在炎症巨噬细胞中都具有令人印象深刻的抗炎亲和力,但没有相关的细胞毒性。相反,与抗坏血酸相比,所有 14 种测试化合物都缺乏清除 DPPH 自由基的抗氧化能力。与市场上的 FQs、吲哚美辛和喹啉衍生物大不相同,吉米沙星在结直肠 SW480、HCT116 和 CACO2、胰腺 PANC1、前列腺 PC3、乳腺 T47D、肺 A375 和黑色素瘤 A549 的粘附单层中使用磺基罗丹明 B 比色法,与抗肿瘤顺铂相比,具有不同的抗增殖能力。在宫颈 HELA 和乳腺 MCF7 细胞的长期肿瘤培养中,所有喹啉衍生物和吉非沙星,但左氧氟沙星、环丙沙星或吲哚美辛,都显示出大幅选择性的活力降低亲和力。尤其是犬尿酸(水合物)、喹啉-2-羧酸、喹啉-4-羧酸、喹啉-3-羧酸和 1,2-二氢-2-氧代-4-喹啉羧酸对乳腺 MCF7 细胞株具有最显著的生长抑制能力,而喹啉-2-羧酸是唯一对宫颈 HELA 癌细胞具有显著细胞毒性的喹啉衍生物。据此推测,通过 COOH 原子和 N 原子相邻的共面性与二价金属发生螯合作用,可能会产生潜在的分子机制,从而实现最佳的再药用前景。总之,这项研究揭示了喹啉衍生物在细胞毒性和抗炎药理方面具有深远的再利用双重性。以活性为导向对现有核支架进行结构修饰,与改善和提高其再利用药理作用有着内在联系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Evaluation of Quinoline-Related Carboxylic Acid Derivatives as Prospective Differentially Antiproliferative, Antioxidative, and Anti-Inflammatory Agents

The higher prevalence of cancer and the unmet need for antioxidant/anti-inflammatory chemotherapeutic compounds with little side effect are of utmost importance. In addition, the increased likelihood of failure in clinical trials along with increasing development costs may have diminished the range of choices among newer drugs for clinical use. This has dictated the necessity to seek out novel medications by repurposing as it needs less time, effort, and resources to explore new uses of a current or unsuccessful medication. In this study, we examined the biological activity of 10 potential quinoline derivatives. Given the half-maximal inhibitory concentration (IC50 value) in lipopolysaccharide (LPS) induced inflammation of RAW264.7 mouse macrophages, all commercial FQs and selected quinolines (quinoline-4-carboxlic and quinoline-3-carboxylic acids) exerted impressively appreciable anti-inflammation affinities versus classical NSAID indomethacin without related cytotoxicities in inflamed macrophages. Conversely, all 14 tested compounds lacked antioxidative DPPH radical scavenging capacities as compared to ascorbic acid. Gemifloxacin, considerably unlike markets FQs, indomethacin and quinoline derivatives, exerted exceptional and differential antiproliferation propensities in colorectum SW480, HCT116, and CACO2, pancreatic PANC1, prostate PC3, mammary T47D, lung A375, and melanoma A549 adherent monolayers using the sulforhodamine B colorimetric method versus antineoplastic cisplatin. All quinoline derivatives and gemifloxacin alike, but not levofloxacin, ciprofloxacin, or indomethacin, displayed substantially selective viability reduction affinities in prolonged tumor incubations of cervical HELA and mammary MCF7 cells. Specifically kynurenic acid (hydrate), quinoline-2-carboxylic acid, quinoline-4-carboxylic acid, quinoline-3-carboxylic acid, and 1,2-dihydro-2-oxo-4-quinoline carboxylic acids possessed the most remarkable growth inhibition capacities against mammary MCF7 cell line, while quinoline-2-carboxylic acid was the only quinoline derivative with significant cytotoxicity on cervical HELA cancer cells. It is highly speculated that chelation with divalent metals via co-planarity with close proximity of the COOH and the N atom could have the potential molecular mechanism for optimally promising repurposed pharmacologies. Conclusively, this study revealed the considerably profound repurposed duality of cytotoxicity and anti-inflammation pharmacologies of quinoline derivatives. Activity-guided structural modifications of the present nuclear scaffolds can be inherently linked to the betterment and enhancement of their repurposed pharmacologies.

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来源期刊
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
期刊介绍: Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.
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