The Antiproliferative and Apoptotic Effect of a Novel Synthesized S-Triazine Dipeptide Series, and Toxicity Screening in Zebrafish Embryos.

Azizah M Malebari,Mohammad A M Wadaan,Muhammad Farooq,Anamika Sharma,Beatriz G De La Torre,Fernando Albericio,Zainab Almarhoon,Ayman El-Faham,Rakia Abd Alhameed

doi:10.3390/molecules26041170

Abstract

Several derivatives containing morpholine/piperidine, anilines, and dipeptides as pending moieties were prepared using s-triazine as a scaffold. These compounds were evaluated for their anticancer activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231), a colon cancer cell line (HCT-116), and a non-tumorigenic cell line (HEK 293). Tamoxifen was used as a reference. Animal toxicity tests were carried out in zebrafish embryos. Most of these compounds showed a higher activity against breast cancer than colon cancer. Compound 3a—which contains morpholine, aniline, and glycylglycinate methyl ester—showed a high level of cytotoxicity against MCF-7 cells with IC50 values of less than 1 µM. This compound showed a much lower level of toxicity against the non-tumorigenic HEK-293 cell line, and in the in vivo studies using zebrafish embryos. Furthermore, it induced cell cycle arrest at the G2/M phase, and apoptosis in MCF-7 cells. On the basis of our results, 3a emerges as a potential candidate for further development as a therapeutic drug to treat hormone receptor-positive breast cancer.

Highlights

Cancer is one of the most threatening diseases for human health
Given the above data and our ongoing efforts in the design and synthesis of novel antitumor agents using the s-triazine scaffold [11,14,15,16,23], here we have focused on the preparation of different s-triazine dipeptide (IV) derivatives (Figure 2) as modulators of biological activity
The secondary amine (1.1 eq.) was added in the presence of N,N-diisopropylethylamine (DIEA), and the mixture was refluxed in tetrahydrofuran (THF) for 24 h in order to render 1 in high purity and yield

Summary

Introduction

Cancer is one of the most threatening diseases for human health. The identification of efficient therapeutic agents to treat this condition is a major objective in medicinal chemistry. New anticancer therapeutic agents should be selective for cancer cells while exerting a lesser or no effect on normal cells [2,3,4]. In order to evaluate the medicinal value of any new compound, it is crucial to determine its biological activity before it can be considered further as a potential drug. Testing the safety of newly-synthesized compounds in suitable animal models before clinical trials is an essential step to save time and money. In this regard, zebrafish models have emerged in recent decades for such preclinical testing [6]. Given the reproducibility of the results, zebrafish models are expected to play a key role in speeding up the development of precision medicine [6,7,8,9]

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Results

Conclusion