氰基吡啶、吡啶并吡唑嘧啶和吡啶并吡唑并三嗪的设计、合成及生物评价作为潜在的抗癌剂。

Design, Synthesis and Biological Evaluation of Cyanopyridines, Pyridopyrazolopyrimidines and Pyridopyrazolotriazines as Potential Anticancer Agents.

机构信息

Department of Chemistry, Faculty of Science, Damanhour University, Damanhour 22511, Egypt.

出版信息

Curr Org Synth. 2021;18(5):483-492. doi: 10.2174/1570179417666201229163045.

DOI:10.2174/1570179417666201229163045

PMID:33372879

Abstract

BACKGROUND

The continuous need for new anticancer drugs is never-ending task due to cancer resistance to the existing drugs.

OBJECTIVE

This article aimed to design, synthesis, characterization, and anticancer evaluation of cyanopyridines, pyridopyrazolopyrimidines and pyridopyrazolotriazines.

METHODS

Anticancer activity of the synthesized compounds was determined using MTT assay against three cancer cell lines, namely liver cancer cell line (HepG-2), pancreatic cancer cell line (PANC-1), non-small lung cancer cell line (A-549) and normal fibroblast.

RESULTS AND DISCUSSION

A series of 3-cyanopyridines (2a,b, 4, 5, 9), pyridopyrimidine (10), pyridopyrazolopyrimidines (11a-c, 12a,b, 18), pyrazolopyridine salt (13) and pyridopyrazolotriazines (16a,b) were synthesized from 3-cyano-4,6-dimethyl-2-pyridone. The synthesized compounds were evaluated in vitro for their anticancer activity and their chemical structures were determined by elemental analysis and spectroscopic data.

CONCLUSION

Some of the synthesized compounds showed remarkable anticancer activities, especially 11a exhibited superior potency to the reference drug cisplatin against A-549 (IC50 = 9.24 μg mL-1 compared to 11.76 μg mL-1 for reference drug) and was found to be safe (IC50 = 66 μg mL-1) for normal fibroblast. Furthermore, compound 16a displayed the highest activity among the tested compounds against HepG-2 (IC50 = 6.45 μg mL-1 equipotent to cisplatin) with the highest safety profile for normal fibroblast (IC50=113.97 μg mL-1).

摘要

背景

由于癌症对现有药物的耐药性，对新抗癌药物的持续需求是一项永无止境的任务。

目的

本研究旨在设计、合成、表征氰基吡啶、吡啶并吡唑嘧啶和吡啶并吡唑三嗪，并评估其抗癌活性。

方法

采用 MTT 法测定合成化合物对三种癌细胞系（肝癌细胞系 HepG-2、胰腺癌细胞系 PANC-1、非小细胞肺癌细胞系 A-549）和正常成纤维细胞的抗癌活性。

结果与讨论

以 3-氰基-4,6-二甲基-2-吡啶酮为原料，合成了一系列 3-氰基吡啶（2a,b, 4, 5, 9）、吡啶并嘧啶（10）、吡啶并吡唑嘧啶（11a-c, 12a,b, 18）、吡唑吡啶盐（13）和吡啶并吡唑三嗪（16a,b）。通过元素分析和光谱数据确定了化合物的化学结构，并对其进行了体外抗癌活性评价。

结论

部分合成化合物表现出显著的抗癌活性，特别是化合物 11a 对 A-549 的活性优于阳性对照药顺铂（IC50=9.24 μg mL-1，而阳性对照药为 11.76 μg mL-1），对正常成纤维细胞的安全性也较高（IC50=66 μg mL-1）。此外，化合物 16a 对 HepG-2 的活性最高（IC50=6.45 μg mL-1，与顺铂相当），对正常成纤维细胞的安全性也最高（IC50=113.97 μg mL-1）。