Design and synthesis of new indole containing biaryl derivatives as potent antiproliferative agents

https://doi.org/10.1016/j.bioorg.2021.104821Get rights and content

Highlights

  • Novel indole containing biaryl derivatives were designed and synthesized in a metal-free manner.

  • Compound 23 effectively inhibited growth of MGC-803 cells (IC50 = 8.28 µM).

  • Compound 23 induced the expression of c-Myc and glycolysis related proteins.

  • Compound 23 induced apoptosis through the activation of AMPK and p53 signalling pathways.

Abstract

A new series of indole containing biaryl derivatives were designed and synthesized, and further biological evaluations of their antiproliferative activity against cancer cell lines (MGC-803 and TE-1 cells) were also conducted. Of these synthesized biaryls, compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) performed as the most potent antiproliferative agent that inhibited cell viability of MGC-803 cells with an IC50 value of 8.28 µM. In addition, investigation of mechanism exhibited that the compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) could inhibit the expression of c-Myc and glycolysis related proteins, decrease the ATP and lactate production, and further induce apoptosis by activating the AMP-activated protein kinase (AMPK) and p53 signaling pathways.

Introduction

Gastrointestinal cancer, one of the leading causes of cancer death in world, is more prevalent in East Asian countries [1]. Early gastrointestinal cancer can be treated by surgery or gastroscope, while chemotherapy and radiotherapy are employed as the main treatments for advanced gastrointestinal cancer. However, in clinical application, the use of chemotherapeutic drugs is usually limited by adverse effects and drug resistance. To the best of our knowledge, glycolysis is an important energy metabolism pathway in cancer cells, and inhibition of it could trigger potent anti-tumor effect [2]. The c-Myc oncogene, a dominating regulator of cellular growth and metabolism, could almost always lead to metabolic changes in many tumor cells by overexpression [3]. Due to the importance of c-Myc in regulation of oncogenesis, many efforts have been made in the field of employing c-Myc as a therapeutic target for oncotherapy. Moreover, some studies showed that many genes involved in glucose metabolism, including hexokinase 2 (HK2), M2 splice isoform of pyruvate kinase (PKM2) and lactate dehydrogenase A (LDHA), were directly regulated by c-Myc [4], [5]. In addition, the essential energy sensor AMP-activated protein kinase (AMPK) could be activated through increasing the ratios of AMP/ATP or ADP/ATP [6]. Studies have shown that autophagy induced by AMPK activation may be related to glycolysis, and apoptosis induced by AMPK activation is regulated by several proteins including p53, p21 and caspase family proteins [7]. Moreover, AMPK signaling pathway also plays a crucial role in cell metabolism and mitochondrial function [8]. Therefore, targeting glycolysis and AMPK signaling pathway is becoming an important therapeutic strategy to develop more effective and less toxic drugs for the treatment of gastrointestinal cancer.

Biaryl skeletons are widespread in many natural products and pharmaceutical molecules, especially indole-pyrimidine biaryl scaffolds have been reported to show diverse and potent biological activities, such as osimertinib (3rd generation epidermal growth factor receptor inhibitor for the treatment of non-small-cell lung carcinomas), meridianin D (with potential antibiofilm activity against methicillin-resistant Staphylococcus aureus) and AZ20 (potent and selective inhibitor of ataxia telangiectasia and Rad3-related protein) (Fig. 1) [9], [10], [11]. Due to the potent biological activity of these unique biaryl fragments, considerable efforts have been made to develop novel indole-pyrimidine biaryl derivatives for drug discovery over the past few years [12], [13].

In an ongoing effort towards designing and developing more effective novel anticancer agents [14], [15], [16], [17], we established an in-house biaryl fragment library [18] and screened their antitumor activity against MGC-803 cells and TE-1 cells using the MTT assay. Delightfully, we found that compounds containing 7-(indolyl)-[1], [2], [4]triazolo[1,5-a]pyrimidine biaryl scaffold exhibited potential anti-tumor activity against MGC-803 cell lines. In addition, the fused [1], [2], [4]triazolo-[1,5-a]pyrimidine fragment has recently become a recognized and privileged pharmacophore due to its diverse biological activities such as antitumor, anti-inflammatory and antimicrobial [19], [20], [21]. Therefore, we speculate that the 7-(indolyl)-[1], [2], [4]triazolo[1,5-a]pyrimidine biaryl skeleton could be employed as a valuable building block for developing new antitumor agents. In this report, we constructively designed and synthesized a series of 7-(indolyl)-[1], [2], [4]triazolo[1,5-a]pyrimidine biaryl derivatives as potent antiproliferative agents and investigated their underlying mechanism of inducing cell apoptosis.

Section snippets

Chemistry

The general synthetic method of desired indole-pyrimidine biaryls was presented in Scheme 1. Commercially available (4H)-1,2,4-triazol-3-amine 1 was subjected to [3+3] cycloaddition reaction with ethyl acetoacetate in refluxing acetic acid (AcOH) to afford intermediate 2, which then reacted with phosphorus oxychloride to give chlorinated product 3. The target analogues 4-43 were easily obtained in good yields with the mature reaction conditions developed by our group.

Antiproliferative activity

All final biaryl compounds

Conclusions

In summary, a new series of 7-(indolyl)-[1], [2], [4]triazolo[1,5-a]pyrimidine biaryl derivatives were designed and synthesized and further evaluated for their antiproliferative activity. It should be noted all the biaryl compounds were synthesized in a novel metal-free manner, which will be exploited to synthesize various biaryl containing fragments. Among these biaryl compounds, compound 23 showed the most potent inhibitory activity against the examined tumor cells (MGC-803 and TE-1 cells).

General

Reagents and solvents were purchased from commercial sources and were used without further purification. Melting points were determined on an X-5 micromelting apparatus and are uncorrected. 1H NMR and 13C NMR spectra were recorded on a Bruker 400 MHz and 100 MHz spectrometer respectively. High resolution mass spectra (HRMS) were recorded on a Waters Micromass Q-T of Micromass spectrometer by electrospray ionization (ESI).

General procedure for the synthesis of compound 2

To an oven dried round flask was added 1H-1,2,4-triazol-5-amine 1 (8.41 g,

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

This work was supported by the National Natural Science Foundation of China (No. 81773562 and 81973177), Program for Science & Technology Innovation Talents in Universities of Henan Province (No. 21HASTIT045), China Postdoctoral Science Foundation (No. 2018M630840 and 2019T120641), Scientific and Technological Projects of Henan Province (No. 212102310311) and Henan Scientific Innovation Talent Team, Department of Education (No. 19IRTSTHN001).

References (26)

  • E. Jameel et al.

    Rational design, synthesis and biological screening of triazine-triazolopyrimidine hybrids as multitarget anti-Alzheimer agents

    Eur. J. Med. Chem.

    (2017)
  • N. Murphy et al.

    Adiposity and gastrointestinal cancers: epidemiology, mechanisms and future directions

    Nat. Rev. Gastroenterol. Hepatol.

    (2018)
  • K.S. Gill et al.

    Glycolysis inhibition as a cancer treatment and its role in an anti-tumour immune response

    Biochim. Biophys. Acta

    (1866)
  • Cited by (4)

    • Synthesis and biological activity of new indole based derivatives as potent anticancer, antioxidant and antimicrobial agents

      2022, Journal of Molecular Structure
      Citation Excerpt :

      Moreover, both intrinsic and extrinsic pathways are involved for the induction of apoptosis due to modulation of apoptosis-related proteins Bax, Bcl-2, caspase-3, caspas-8 and caspase-9. In accordance with the present results, many studies reported that novel indole derivatives caused cancer cell death by inducing apoptosis [38–40]. The total glutathione S-transferases (GST) enzyme activity was determined in the HepG2 cell line, throughout this study (Fig. 6).

    1

    Shuo Yuan and Si-Qi Feng contributed equally to this work.

    View full text