Elsevier

Bioorganic Chemistry

Volume 57, December 2014, Pages 30-42
Bioorganic Chemistry

Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents

https://doi.org/10.1016/j.bioorg.2014.07.011Get rights and content

Highlights

  • Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives were designed and synthesized.

  • Five compounds were further examined for their c-Met kinase activity.

  • Compound 17 showed an IC50 values of 2.20 nM against c-Met kinase.

Abstract

Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against HT-29, H460, A549, MKN-45, and U87MG cancer cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially trifluoromethyl groups at 2-position on the phenyl ring (moiety B) were more effective. In this study, a promising compound 17 (c-Met IC50 = 2.20 nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50 values of 0.14 μM, 0.18 μM, 0.09 μM, 0.03 μM, and 1.06 μM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.

Graphical abstract

Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were synthesized and evaluated for their cytotoxic activities. Five potent compounds were further examined for their c-Met kinase activity.

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Introduction

c-Met kinase inhibitors have recently become an attractive therapeutic target for cancer therapy and it normally activated by binding its natural ligand hepatocyte growth factor (HGF), also known as scatter factor (SF). The binding of HGF to c-Met induces several complex signaling pathways and results in cell proliferation, motility, migration, and survival [1], [2], [3]. Moreover, c-Met has been found to be overexpressed or mutated in human cancers, especially correlated with advanced disease stage and poor prognosis. As a result, c-Met has attracted considerable attention as a potential target for cancer treatment [4], [5], [6].

Recently, a number of new 6,7-disubstituted-4-phenoxyquinoline derivatives with excellent antitumor activity have been reported. Many of these derivatives are being marketed or under clinical/preclinical studies, such as cabozantinib (1), Foretinib (2) and AM 7 (3) (Fig. 1) [7], [8]. Cabozantinib (XL-184, 1), a typical multikinase inhibitor (c-Met included) bearing quinoline pharmacophore, was approved by U.S. FDA in November 2012 for the treatment of patients with progressive metastatic medullary thyroid cancer (MTC) [9]. Foretinib (XL880, 2), which is currently undergoing phase III studies for different cancer types, is a novel oral multikinase inhibitor targeting c-Met, VEGFR, RON, KDR and Flt-1. As shown in Figure 1, the main modification of these quinoline derivatives was focused on the 5-atom linker containing hydrogen-bond donors or acceptors between moiety A and B, which is known as “5 atoms regulation” in our previous study [10]. In addition, the modifications of the A moiety usually occurred at 7-position of quinoline, while the methoxy group was replaced by a water-soluble fragment, such as 3-morpholinopropoxy group. These structural features indicated that exploring a satisfactory linker was a practicable way of designing new quinoline derivatives. In our previous study, we had introduced 1,4-dihydroquinoline, N-arylidene semicarbazide and quinoline scaffolds as part of the 5-atom linkers, and the resulting derivatives (46, Fig. 1) showed excellent antitumor activity [11], [12], [13].

Compounds containing N-Aryl-pyrazolone-4-imino and 2,4-imidazolinedione framework displayed a multitude of biological activities, including antitumor, antibacterial, antihypertensive, antiplatelet and anti-inflammatory activities [14], [15], [16], [17]. Remarkably, this framework was widely used as a building block in the design of anticancer agents because of its ability to form hydrogen-bonding interactions with drug targets. For example, compound 7 and 8 (Fig. 2), as a potent catalytic inhibitor of human telomerase, was reported as large ribonucleoprotein complex of reverse transcriptase enzyme [18], [19]. It was interested that the N-Aryl-pyrazolone-4-imino and 2,4-imidazolinedione framework conformed to the rule of “5 atoms regulation” and contained both hydrogen-bond donor and acceptor, which indicated that it was a satisfactory linker.

Therefore, we selected N-Aryl-pyrazolone-4-imino and 2,4-imidazolinedione framework as the 5-atom linker to obtains two series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives (I, II Fig. 2). Meanwhile, at the 7-position of quinolines, a three-carbon tether which contained different cyclic tertiary amines were introduced, such as 4-methyl piperidinyl, piperidinyl, 4-methyl piperazinyl and pyrrolidinyl group. Additionally, various substituents (R2) were introduced into the phenyl ring (B moiety) to investigate their effect on activity. In this paper, the synthesis of these quinoline derivatives was reported and their in vitro anticancer activities against five human cancer cell lines included the A549 (human lung adenocarcinoma), H460 (human lung cancer), HT-29 (human colon cancer), MKN-45 (human gastric cancer) and U87MG (human glioblastoma), and c-Met kinase were evaluated, respectively.

Section snippets

Synthesis of 6,7-disubstituted-4-phenoxyquinolines

The key intermediates 6,7-disubstituted-4-phenoxyquinolines 8a–e were synthesized using a convenient eight-step procedure starting from 1-(4-hydroxy-3-methoxyphenyl)ethanone (Scheme 1), which was illustrated in detail in our previous study [11], [20].

Synthesis of the target compounds of pyrazolone-based quinolines

The target compounds 12–32 were synthesized according to the routes outlined in Scheme 2. The side chains 11a–h were prepared from substituted aniline, which was diazotized and subsequent NaHSO3 provide to 9a–h. Cyclization of 9a–h with ethyl

Cytotoxic activities against tumor cells assay

The antiproliferative activities of compounds 12–32 and 37–46 were evaluated against HT-29, H460, A549, MKN-45, and U87MG cell lines by the standard MTT assay in vitro, with foretinib as the positive control. The cancer cell lines were cultured in minimum essential medium (MEM) supplement with 10% fetal bovine serum (FBS). Approximate 4 × 103 cells, suspended in MEM medium, were plated onto each well of a 96-well plate and incubated in 5% CO2 at 37 °C for 24 h. The tested compounds at the indicated

In vitro cytotoxic activities and structure activity relationships

All the target compounds 12–32 and 37–46 were evaluated for their antitumor activities against non-small cell lung cancer cell line (A549), human lung cancer (H460), human colorectal cancer cell line (HT-29), human gastric cancer (MKN-45), and human glioblastoma cell line (U87MG) by using MTT assay with foretinib as the positive control. The results expressed as IC50 values and summarized in Table 1. The IC50 values were the average of at least three independent experiments.

As illustrated in

Conclusion

In summary, two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and their chemical structures as well as the relative stereochemistry were confirmed. The synthesized compounds were evaluated for their biological activity, and most of them showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines. In particular, the most promising compound 17 (c-Met IC50 = 

Experimental

Reagent and General Procedures Unless otherwise specified, all melting points were obtained on a Büchi Melting Point B-540 apparatus (Büchi Labortechnik, Flawil, Switzerland) and were uncorrected. Reactions’ time and purity of the products were monitored by TLC on FLUKA silica gel aluminum cards (0.2 mm thickness) with fluorescent indicator 254 nm. Mass spectra (MS) were taken in ESI mode on Agilent 1100 LC-MS (Agilent, Palo Alto, CA, U.S.A.). 1H NMR and 13C NMR spectra were recorded on Bruker

Acknowledgments

The work was supported by Program for Innovative Research Team of the Ministry of Education of the People’s Republic of China and Program for Liaoning Innovative Research Team in University.

References (26)

  • L.B. Ye et al.

    Eur. J. Med. Chem.

    (2012)
  • J.G. Christensen et al.

    Cancer Lett.

    (2005)
  • S. Li et al.

    Eur. J. Med. Chem.

    (2013)
  • B.H. Qi et al.

    Bioorg. Med. Chem.

    (2013)
  • S. Li et al.

    Bioorg. Med. Chem.

    (2013)
  • Y.T. Reddy et al.

    Bioorg. Med. Chem. Lett.

    (2010)
  • T. Quang et al.

    Bioorg. Med. Chem.

    (2011)
  • C. Birchmeier et al.

    Nat. Rev. Mol. Cell Biol.

    (2003)
  • E. Gherardi et al.

    Proc. Natl. Acad. Sci. USA

    (2006)
  • P.C. Ma et al.

    Cancer Metastasis Rev.

    (2003)
  • I. Dussault et al.

    Drugs Future

    (2006)
  • F. Yakes et al.

    Mol. Cancer. Ther.

    (2011)
  • M. Norman et al.

    J. Med. Chem.

    (2012)
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