Synthesis and biological evaluations of novel pyrazinoic acid derivatives as anticancer agents

Shiva Akhlaghi,Hadi Kalantar,Azar Mostoufi,Masood Fereidoonnezhad

doi:10.1007/s00044-022-02858-2

Shiva Akhlaghi, Hadi Kalantar + Show 2 more

Open Access

https://doi.org/10.1007/s00044-022-02858-2

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Abstract

Pyrazinoic acid or pyrazine-2-carboxylic acid (PA), due to its nitrogenous heteroaromatic ring, can be explored as an anticancer agent. Here, a series of twenty novels PA derivatives have been synthesized and characterized using IR, NMR, and mass spectrums. Their cytotoxic activity was evaluated against three different cancer cell lines, including lung (A549), breast (MCF-7), and colon (HT-29). P16, the most potent compound, showed moderate cytotoxicity with IC50 of 6.11, 10.64, and 14.92 μM, against the A549, MCF-7, and HT-29 cell lines, respectively. Furthermore, the effect of this compound against MRC5 as a non-tumoral lung cell line, exhibited a selectivity index of 9.02. The apoptotic induction activity of P16 was also performed on the A549 cell line. The results showed that as the concentration of the compound increases (from 3 to 6 μM), the percentage of induction of apoptosis increases from 8.54% to 72.4%. Electrophoretic gel mobility shift assays showed that P16 was able to reactive oxygen species (ROS) induce DNA cleavage in the presents of H2O2 (1.0 mM) in high doses. Molecular docking was also applied to anticipate the binding locations and the binding of the synthesized compound with Bcl-2 apoptosis regulator and DNA as their proposed targets.

Highlights

The raising number of cancer patients throughout the world encourages medicinal chemists to seek novel anticancer agents
A series of twenty novels pyrazine-2-carboxylic acid (PA) derivatives have been synthesized and characterized using IR, NMR, and mass spectrums. Their cytotoxic activity was evaluated against three different cancer cell lines, including lung (A549), breast (MCF-7), and colon (HT-29)
The compounds were entirely characterized by (IR, 1HNMR, 13CNMR, Mass) spectrums. These PA derivatives were evaluated for cytotoxic activity against three different cell lines, including lung (A549), breast (MCF-7), and colon (HT-29) and one normal human lung cell line (MRC5)

Summary

Introduction

The raising number of cancer patients throughout the world encourages medicinal chemists to seek novel anticancer agents. An estimated 28.4 million new cases of cancer are predicted in 2040, a 47 percent raise over the corresponding 19.3 million cases in 2020, assuming local rates remain stable in 2020 [1]. DNA contains all genetic information, including cell replication and transcription [2]. DNA is a significant target for anticancer therapies. Studies have been directed at the interaction of chemicals with this target, causing DNA damage by stopping cancer cells from rapidly dividing. Development of new anticancer agents for apoptosis reactivation methods, which can be used to treat a variety of cancers [6]. Nuclear DNA fragmentation are common biochemical markers of apoptosis [7]

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