Elsevier

European Journal of Medicinal Chemistry

Volume 145, 10 February 2018, Pages 315-327
European Journal of Medicinal Chemistry

Research paper
Synthesis and bioevaluation and doking study of 1H-pyrrolo[2,3-b]pyridine derivatives bearing aromatic hydrazone moiety as c-Met inhibitors

https://doi.org/10.1016/j.ejmech.2017.12.078Get rights and content

Highlights

  • Two series of 1H-pyrrolo[2,3-b]pyridine derivatives bearing aromatic hydrazone moiety were designed and synthesized.

  • Most of the synthesized compounds showed moderate to significant antitumor activity.

  • 7c arrest efficiently the cell cycle progression in G2/M phase of A549 cells.

  • Docking study was investigated to explore the binding modes of compounds with c-Met.

Abstract

Two series of aromatic hydrazone derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (7ar, 8ai, 12ab, 13ac, 16ad and 17ae) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, HepG2, MCF-7and PC-3). Two selected compounds (7c and 17e) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2 and EGFR kinases. The data indicated that targets compounds were selective for c-Met kinase. And the most promising compound 7c was further studied in terms of dose-dependent, time-dependent and cell apoptosis. Most of the compounds showed excellent cytotoxicity activity, especially the most promising compound 7c with the IC50 values of 0.82 ± 0.08 μM, 1.00 ± 0.11 μM, 0.93 ± 0.28 μM and 0.92 ± 0.17 μM against A549, HepG2, MCF-7 and PC-3 cell lines and 0.506 μM against c-Met kinase. Structure–activity relationships (SARs) and docking studies indicated that the activities of the phenyl hydrazone derivatives (7ar and 8ai) were superior to that of the heterocyclic hydrazone series (12ab, 13ac, 16ad and 17ae). What's more, the further studies indicated that the target compounds can induce apoptosis of A549 cells and arrest efficiently the cell cycle progression in G2/M phase of A549 cells.

Graphical abstract

Image 1
  1. Download : Download high-res image (157KB)
  2. Download : Download full-size image
Two series of aromatic hydrazone derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (7ar, 8ai, 12ab, 13ac, 16ad and 17ae) were designed. What's more, enzyme-based selectivity, cell cycle, cell apoptosis and molecules docking study were also carried out in this paper.

Introduction

Cancer is a disease that seriously endangers human life and health [1,2]. According to the World Health Organization (WHO) statistics, 8.8 million patients died of cancer in 2015 [3]. Therefore, it is urgent to find effective and less toxic side effects of cancer treatment [4]. Because c-Met kinase is located at the intersection of many tumor signaling pathways and is a key node protein, which can interact with other kinases and receptors, therefore, the small molecule inhibitors targeting c-Met become the hotspot of research [5].

Foretinib [6], the first small molecule oral inhibitor to enter clinical trials, is in clinical stage II currently, whose inhibitory effect against c-Met kinase is 0.4 nM. Cabozantinib [7] also belongs to this class of inhibitors and was approved by FDA for the treatment of patients with progressive metastatic medullary thyroid cancer on November 29, 2012. And many other kinds of c-Met inhibitor were also reported [8,9]. In our previous study, we also reported a series of quinoline derivatives and a series of 1H-pyrrolo[2,3-b]pyridine derivatives as potential c-Met inhibitors [[10], [11], [12]] (the structures are shown in Fig. 1). In addition, it was found that this class inhibitor exhibited the best antitumor activity when the 5 atoms were connected between A and B, which was characterized by the illustrated “5 atoms regulation” [10]. The design of the compounds in this article is based on this conclusion.

In this study, further modifications were carried out on 1H-pyrrolo[2,3-b]pyridine derivatives that reported in our previous study. It has been found that N-acylhydrazones and its analogs containing multiple hydrogen bond donors and receptors were with different biological activity and strong coordination ability [13]. Therefore, they were used as a component of anticancer agents, such as PAC-1 [14] and compounds I [15] and II [16] (the structures are shown in Fig. 2). Thus, the N-acylhydrazone was introduced into the compounds according to the principle of flattening and replaced the phenylpicolinamide scaffold and the phenylpyrimidine moiety to obtain the target compounds 7ar and 8ai. In addition, it was found that a reasonable modification of the phenyl group could modulate the π-stacking effect with the corresponding receptor and enhance the inhibitory potency of the compounds. Therefore, we replaced the phenyl group with pyrrole (five-membered heterocycle) and introduced the small molecule amine on the N atom to increase the water solubility to design the target compounds 12ab, 13ac, 16ad and 17ae bearing the heterocyclic hydrazone structure. The design strategy are shown in Fig. 3.

Herein, the synthesis and antitumor activity against A549, HepG2, MCF-7 and PC-3cancer cell lines, and c-Met, Flt-3, VEGFR-2 and EGFR kinases of the target compounds were disclosed. Moreover, docking studies were presented in this paper as well.

Section snippets

Chemistry

The preparation of target compounds 7ar and 8ai is described in Scheme 1.

Compounds 3a, 3b, 4a and 4b were synthesized according to the reported procedures [11,12].

Compounds 5a and 5b was synthesized by amide 4a or 4b and phenyl chloroformate via substitution in 1,4-dioxane. Then the key intermediates 6a and 6b were obtained via hydrazinolysis of 5a and 5b with 80% hydrazine hydrate in 1,4-dioxane [17]. The mixture of 6a or 6b, substituted benzaldehyde and catalytic amounts of acetic acid were

Antiproliferative assay in vitro

Taking c-Met inhibitor Foretinib as reference compound, the target compounds (12ab, 13ac, 16ad and17ae) were evaluated for the cytotoxicity against four cancer cell lines A549 (human lung cancer), PC-3 (human prostatic cancer), MCF-7(human breast cancer) and HepG2 (Human liver cancer) by 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay. In addition, two selected (7c and 17e) were evaluated for the IC50 values against c-Met kinase in vitro by the

Conclusions

In summary, we designed and synthesized two series of aromatic hydrazone derivatives bearing1H-pyrrolo[2,3-b]pyridine nucleus and evaluated for the IC50 values against four cancer cell lines and c-Met, Flt-3, VEGFR-2 and EGFR kinases. Most of them exhibited moderate to excellent cytotoxic activity against four cancer cell lines. Especially, the most promising compound 7c showed superior activity to Foretinib, with the IC50 values of 0.82 ± 0.08 μM, 1.00 ± 0.11 μM, 0.93 ± 0.28 μM and

Chemistry

All melting points were obtained on a Büchi Melting Point B-540 apparatus (Büchi Labor technik, Flawil, Switzerland) and were 4 uncorrected. NMR spectra were performed using Bruker 400 MHz spectrometers(Bruker Bioscience, Billerica, MA, USA) with TMS as an internal standard. Mass spectra (MS) were taken in ESI mode on Agilent 1100 LCMS (Agilent, Palo Alto, CA, USA). TLC analysis was carried out on silica gel plates GF254 (Qindao Haiyang Chemical, China). All the materials were obtained from

Acknowledgments

We gratefully acknowledge the generous support provided by The National Natural Science Funds (No. 21162014), Natural Science Funds for Distinguished Young Scholar of Jiangxi Province, China (20171BCB23078); Key projects of the youth fund, Natural Science Funds of Jiangxi Province (20171ACB21052); The Project Supported by Natural Science Foundation of Jiangxi, China (20161BAB215216); Department Education Science and Technology Research Project of Jiangxi, China (GJJ 160787); Jiangxi Provincial

References (21)

There are more references available in the full text version of this article.

Cited by (19)

  • Synthesis of pyridine derivatives for diverse biological activity profiles: A review

    2022, Recent Developments in the Synthesis and Applications of Pyridines
  • Structure–activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy

    2020, European Journal of Medicinal Chemistry
    Citation Excerpt :

    Another good example of class II inhibitor BMS-777607 (4), a pyridine-based selective MET inhibitor which primarily targets MET and several MET family members, including AXL, RON, and Tyro 3, is currently undergoing phase II clinical trials for various cancers [20]. Hence, the increasing FDA-approved drugs and clinical trial drug candidates targeting MET kinase push the development of small-molecule MET inhibitors to a hotspot [21–31]. In our previous research, we reported the discovery of diverse naphthyridine derivatives as kinase inhibitors [32–38].

  • Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction

    2020, European Journal of Medicinal Chemistry
    Citation Excerpt :

    Up to now, many strategies have applied to regulate the abnormal activation of c-Met/HGF signaling pathway and small molecule c-Met kinase inhibitors as one of the most promising approaches has been attracted more and more attention [18–24]. The advantage of small molecule inhibitors via the intracellular kinase domain is that they can effectively block both ligand-dependent and independent activation of c-Met [25–31]. Although the development of small-molecule c-Met tyrosine kinase inhibitors (TKIs) started much later than other strategies, significant progress has been made recently with a considerable number of compounds entering clinical trials or being approved as anticancer drugs (Fig. 1).

View all citing articles on Scopus
1

These authors contribute equally to this work.

View full text