Chemistry Department (Biochemistry Branch), Faculty of Science, Cairo University, Giza, Egypt.
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt.
Curr Cancer Drug Targets. 2018;18(4):372-381. doi: 10.2174/1568009617666170630143311.
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.
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.
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.
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.
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.
最近有报道称，含有嘧啶并喹啉部分的杂环化合物具有广泛的药用和药理特性，包括抗癌、抗微生物、抗炎活性、镇痛和抗病毒活性。此外，含螺环吲哚的化合物代表了一类具有广泛生物活性的重要化合物。不对称手性螺碳被认为是生物活性的主要标准。螺吲哚结构是各种生物碱和重要药物化合物的主要骨架。其中，天然存在的吡咯烷并螺吲哚生物碱霍西芬iline 对人脑癌细胞系具有抗癌活性。
本研究的目的是合成新型嘧啶并[4,5-b]喹啉双螺环 2-氧吲哚衍生物，并评估新化合物的协同抗癌活性。不同的遗传工具被用于试图了解该化合物对乳腺癌的作用机制。
采用 6-氨基尿嘧啶、双异亚氨酸和二甲基酮一锅法高效合成嘧啶并[4,5-b]喹啉-4,6-二酮的双螺环 2-氧吲哚衍生物。评估了对不同人癌细胞系 MCF7、HCT116 和 A549 的细胞毒性作用。发现该系列中最有希望的化合物是 6a，因此选择它进行针对 MCF7 的分子研究。
我们的数据表明，化合物 6a 是乳腺癌的一个有吸引力的靶点，因为它抑制肿瘤细胞的增殖、细胞周期进程并诱导其凋亡。这种抑制是通过基因组 DNA 的片段化、[caspase-3、肿瘤抑制基因 p53 和促凋亡基因 BAX]的上调以及抗凋亡基因 BCL2 的下调介导的。此外，它还导致细胞周期停滞在 S 期。这项工作为新化合物 6a 的强大作用提供了证据，并有助于癌症新治疗药物的进展。
我们开发了一种高效的方法来合成新型生物活性双螺环 2-氧吲哚衍生物，其中包含嘧啶并[4,5-b]喹啉衍生物。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，特别是化合物 6a，它在这个系列中对 MCF7、HCT116 和 A549 细胞系最有效且最有前途。
