Using Cyclic Ketones to Synthesize New 3,5,6,7,8,9-Hexahydro-pyrazolo[1,5-a]quinoline Derivatives with Antiproliferative Activities: Morphological Studies.

IF 2.3 4区 医学 Q3 ONCOLOGY
Rafat M Mohareb, Marwa S Gamaan, Nadia Y Megally Abdo, Ibram R Mikhail
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引用次数: 0

Abstract

Background: Quinoline derivatives, often incorporating other heterocyclic structures, have shown a wide range of therapeutic potential, especially in the treatment of cancer. These compounds have demonstrated significant anticancer activity against various cell lines, including HeLa (human cervical cancer) and MDA-MB-435 (melanoma), exhibiting strong inhibitory effects.

Objective: In this study, arylhydrazonopyrazole derivatives (3a-c) were employed in a series of multicomponent reactions to synthesize 3,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinoline and pyran derivatives. Pyrazolo[1,5-a]quinoline derivatives, due to their structural properties, are considered valuable scaffolds for the development of novel drugs targeting similar biological pathways, with the potential for improved therapeutic efficacy. This study aimed to demonstrate the use of simple arylhydrazonopyrazole derivatives in multicomponent reactions with cyclic ketones and aromatic aldehydes. The resulting compounds were then assessed for their cytotoxic and antiproliferative activities. Following these reactions, further heterocyclization processes were conducted, incorporating the quinoline moiety into the final structures. These findings underscore the potential of pyrazolo [1,5-a]quinoline derivatives as promising candidates for drug discovery, offering new avenues for targeting diseases with related molecular mechanisms.

Methods: The key starting compound in this study was 3,5-dimethyl-4-(2-phenylhydrazono)-4H-pyrazole, which has been utilized in numerous heterocyclization reactions. These reactions, involving various reagents, such as cyclic ketones and diketones in the presence of aromatic aldehydes, led to the formation of fused tetracyclic compounds. Arylhydrazonopyrazole derivatives (5a-c) were employed in multicomponent reactions to synthesize 3,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinoline and pyran derivatives. The reactions were carried out using both conventional catalysts and ionic liquid-immobilized catalysts. Notably, the use of ionic liquid-immobilized catalysts resulted in higher yields of the desired compounds.

Results: In this study, new compounds were synthesized, characterized, and evaluated for their cytotoxicity against six cancer cell lines: A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460. Additionally, the cytotoxic effects of the synthesized compounds were assessed against hepatocellular carcinoma (HepG2) and cervical carcinoma (HeLa) cell lines. Morphological studies of selected compounds were also conducted to further understand their effects on the cancer cells. Moreover, the cytotoxicity of the selected compounds was tested against seventeen different cancer cell lines, categorized by disease type. Morphological analyses of these selected compounds were also performed to gain deeper insights into their potential as anticancer agents.

Conclusion: The inhibition assays of the tested compounds demonstrated significant activity against c-Met enzymatic activity, with IC50 values ranging from 0.25 to 10.30 nM. Additionally, potent inhibition was observed in the prostate PC-3 cell line, with IC50 values ranging from 0.19 to 8.62 μM. These promising results highlight the potential of these compounds and encourage further research to explore their therapeutic applications in the future.

环酮合成具有抗增殖活性的新型3,5,6,7,8,9-六氢吡唑啉[1,5-a]喹啉衍生物的形态学研究
背景:喹啉衍生物通常包含其他杂环结构,已显示出广泛的治疗潜力,特别是在治疗癌症方面。这些化合物已显示出对多种细胞系的显著抗癌活性,包括HeLa(人宫颈癌)和MDA-MB-435(黑色素瘤),表现出强烈的抑制作用。目的:本研究以芳酰腙吡唑衍生物(3a-c)为原料,通过一系列多组分反应合成3,5,6,7,8,9-六氢吡唑啉[1,5-a]喹啉和吡喃衍生物。Pyrazolo[1,5-a]喹啉衍生物由于其结构特性,被认为是开发针对类似生物途径的新型药物的有价值的支架,具有提高治疗效果的潜力。本研究旨在证明简单芳酰腙吡唑衍生物在与环酮和芳香醛的多组分反应中的应用。然后评估所得化合物的细胞毒性和抗增殖活性。在这些反应之后,进行了进一步的杂环化过程,将喹啉部分纳入最终结构。这些发现强调了吡唑啉[1,5-a]喹啉衍生物作为药物发现的有希望的候选物的潜力,为靶向具有相关分子机制的疾病提供了新的途径。方法:以3,5-二甲基-4-(2-苯基腙)- 4h -吡唑为主要起始化合物,该化合物已被广泛应用于杂环化反应中。这些反应,涉及各种试剂,如环酮和二酮在芳香醛的存在,导致形成融合的四环化合物。以芳酰腙吡唑衍生物(5a-c)为原料,通过多组分反应合成了3,5,6,7,8,9-六氢吡唑[1,5-a]喹啉和吡喃衍生物。采用常规催化剂和离子液体固定化催化剂进行反应。值得注意的是,离子液体固定化催化剂的使用提高了所需化合物的产率。结果:本研究合成了新的化合物,并对其对A549、HT-29、MKN-45、U87MG、SMMC-7721和H460 6种癌细胞的细胞毒性进行了表征和评价。此外,还评估了合成的化合物对肝细胞癌(HepG2)和宫颈癌(HeLa)细胞系的细胞毒性作用。我们还对所选化合物进行了形态学研究,以进一步了解它们对癌细胞的影响。此外,选定的化合物对17种不同的癌细胞系的细胞毒性进行了测试,按疾病类型分类。这些选定的化合物的形态分析也进行了更深入的了解,以获得其潜在的抗癌剂。结论:化合物对c-Met酶活性的抑制作用显著,IC50值在0.25 ~ 10.30 nM范围内。此外,在前列腺PC-3细胞系中观察到有效的抑制作用,IC50值为0.19 ~ 8.62 μM。这些有希望的结果突出了这些化合物的潜力,并鼓励进一步研究以探索它们在未来的治疗应用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Current cancer drug targets
Current cancer drug targets 医学-肿瘤学
CiteScore
5.40
自引率
0.00%
发文量
105
审稿时长
1 months
期刊介绍: Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes and genes. Current Cancer Drug Targets publishes original research articles, letters, reviews / mini-reviews, drug clinical trial studies and guest edited thematic issues written by leaders in the field covering a range of current topics on drug targets involved in cancer. As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.
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