摘要
背景:最近,据报道,含有嘧啶并喹啉部分的杂环显示广泛的医药和药理学性质,包括抗癌,抗微生物,抗炎活性,镇痛和抗病毒。此外,含有螺环环氧吲哚的化合物代表了一类重要的具有广泛生物学性质的化合物。不对称手性螺环碳被认为是生物活性的主要标准。螺环氧吲哚结构代表各种生物碱和药学上重要的化合物的主要骨架。其中,天然存在的吡咯烷基吗啉羟吲哚生物碱,horsifiline具有抗人脑癌细胞系的抗癌活性。 目的:本研究的目的是合成新的嘧啶并[4,5-b]喹啉衍生物双螺环2-羟吲哚并评价新化合物的协同抗癌活性。使用不同的遗传工具试图了解该化合物对乳腺癌的作用机制。 方法:已经开发了使用6-氨基尿嘧啶,双靛红和双甲酮有效地一锅法合成嘧啶并[4,5-b]喹啉-4,6-二酮的双螺环2-羟吲哚衍生物。评估针对不同人类细胞系MCF7,HCT116和A549细胞系的细胞毒性作用。衍生物6a被发现是该系列中最令人鼓舞的化合物,并且它被选择用于针对MCF7的分子研究。 结果:我们的数据表明化合物6a是乳腺癌的有吸引力的靶标,因为它抑制肿瘤细胞的增殖,细胞周期进程并诱导细胞凋亡。这种抑制作用是通过基因组DNA的片段化,[半胱天冬酶-3,肿瘤抑制基因p53和促凋亡基因BAX]的上调和抗凋亡BCL2基因的下调介导的。此外,它在S期引起细胞周期停滞。这项工作提供了新化合物6a的有效作用的证据,并有助于新的癌症治疗剂的进展。 结论:我们已经开发出一种有效的方法来合成新的含有嘧啶并[4,5-b]喹啉衍生物的生物活性双螺环2-羟吲哚衍生物。我们的大多数新衍生物比标准药物氟尿嘧啶(5-FU)具有更强的细胞毒性作用,尤其是化合物6a,它是该系列中对MCF7,HCT116和A549细胞系中最有活性和最有希望的化合物。
关键词: 细胞毒作用,双螺环-2-羟吲哚,嘧啶并[4
Current Cancer Drug Targets
Title:DNA Fragmentation, Cell Cycle Arrest, and Docking Study of Novel Bis Spiro-cyclic 2-oxindole of Pyrimido[4,5-b]quinoline-4,6-dione Derivatives Against Breast Carcinoma
Volume: 18 Issue: 4
关键词: 细胞毒作用,双螺环-2-羟吲哚,嘧啶并[4
摘要: Background: Recently, it is reported that heterocycles containing pyrimidoquinoline moiety show a broad spectrum of medicinal and pharmacological properties including anticancer, anti-microbial, anti-inflammatory activities, analgesic and antiviral. In additions, spirocyclicoxindole containing compounds represent an important class of compounds that exhibit wide range of biological properties. The asymmetric chiral spiro carbon is considered to be the main criteria of the bioactivities. Spirooxindole structures represent the main skeleton for various alkaloids and pharmaceutically important compounds. Among them, the naturally occurring pyrrolidinylespirooxindole alkaloid, horsifiline that exhibits anticancer activity against human brain cancer cell lines.
Objective: The objective of this study is the synthesis of novel bis spiro-cyclic 2-oxindole of pyrimido[4,5-b]quinoline derivatives and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in an attempt to know the mechanism of action of this compound against breast cancer.
Method: An efficient one pot synthesis of bis spiro-cyclic 2-oxindole derivatives of pyrimido[4,5- b]quinoline-4,6-dione using 6-aminouracil, bis-isatin and dimedone has been developed. The cytotoxic effect against different human cell lines MCF7, HCT116 and A549 cell lines was evaluated. The derivative 6a, was found the most encouraging compound in this series and it was selected for molecular studies against MCF7.
Results: Our data indicated that compound 6a is an attractive target for breast cancer, as it inhibits proliferation, cell cycle progression and induces apoptosis of tumor cells. This inhibition is mediated by fragmentation of genomic DNA, up-regulation of [caspase-3, tumor suppressor gene p53, and pro-apoptotic gene BAX], and down-regulation of anti-apoptotic BCL2 gene. In additions it caused cell cycle arrest in S phase. This work provides an evidence of the potent effect of the new compound 6a and assists in the progress of new healing agents for cancer.
Conclusion: We have developed an efficient method for the synthesis of novel bioactive bis spirocyclic 2-oxindole derivatives incorporating pyrimido[4,5-b]quinoline derivatives. Most of our new derivatives give potent cytotoxic effect more than the standard drug Fluorouracil (5-FU) especially, compound 6a which was the most active and promising one in this series against MCF7, HCT116, and A549 cell lines.
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DNA Fragmentation, Cell Cycle Arrest, and Docking Study of Novel Bis Spiro-cyclic 2-oxindole of Pyrimido[4,5-b]quinoline-4,6-dione Derivatives Against Breast Carcinoma, Current Cancer Drug Targets 2018; 18 (4) . https://dx.doi.org/10.2174/1568009617666170630143311
DOI https://dx.doi.org/10.2174/1568009617666170630143311 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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