Design, synthesis, biological evaluation and molecular docking studies of novel benzofuran–pyrazole derivatives as anticancer agents

doi:10.1016/j.bioorg.2015.08.006

Bioorganic Chemistry

Volume 63, December 2015, Pages 1-12

https://doi.org/10.1016/j.bioorg.2015.08.006 Get rights and content

Highlights

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A new series of benzofuran–pyrazole hybrid compounds were designed and synthesized.
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In vitro anti-cancer evaluation against sixty human tumor cell lines.
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In vitro evaluation of Src kinase inhibition.
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Molecular modelling in the active sites of Src kinase.

Abstract

This study deals with design and synthesis of novel benzofuran–pyrazole hybrids as anticancer agents. Eight compounds were chosen by National Cancer Institute (NCI), USA to evaluate their in vitro antiproliferative activity at 10⁻⁵ M in full NCI 60 cell panel. The preliminary screening of the tested compounds showed promising broad-spectrum anticancer activity. Compound 4c was further assayed for five dose molar ranges in full NCI 60 cell panel and exhibited remarkable growth inhibitory activity pattern against Leukemia CCRF-CEM, MOLT-4, Lung Cancer HOP-92, Colon Cancer HCC-2998, CNS Cancer SNB-75, Melanoma SK-MEL-2, Ovarian Cancer IGROV1, Renal Cancer 786-0, RXF 393, Breast Cancer HS 578T and T-47D (GI₅₀: 1.00–2.71 μM). Moreover, enzyme assays were carried out to investigate the possible antiproliferative mechanism of action of compound 4c. The results revealed that compound 4c has good c-Src inhibitory activity at 10 μM. In addition, molecular docking studies showed that 4c could bind to the ATP Src pocket sites. Fulfilling the Lipinskiís rule of five in addition to its ADME profile and the biological results, all strongly suggest that 4c is a promising Src kinase inhibitor.

Graphical abstract

Introduction

Cancer still remains a potentially life threatening disease and the number of cancer related deaths are increasing alarmingly. Literature clearly indicated that more than 90% of cancer patients die due to chronic tumor metastases. Despite the presence of a large number of anticancer drugs, no currently available agents can eradicate cancer cells without harming normal tissues. Thus, the development of newer chemotherapeutic scaffolds which selectively act on the target without side effects has become a primary objective of medicinal chemists [1], [2].

Literature survey revealed that substituted benzofurans could act as anticancer agents. It has been reported that phenylbenzofuran-2-carboxylic acid ethyl ester derivative (I) showed selective and potent cytotoxicity for human fibroblasts of lung tissues (EC₅₀; 40 ng/mL) [3]. In order to get rid of the biologically unstable ester group the 2-benzoyl-phenylbenzofuran derivative (II) was derived as another lead compound (EC₅₀; 600 ng/mL) [3]. Similarly, it has been reported that the 2-(2,4-dimethoxybenzoyl)-phenylbenzofuran derivative III was exhibiting potent cytotoxic activities against human lung carcinoma cells [4]. Moreover, Ariad Pharmaceuticals disclosed compound IV which carries benzofuran subunit in its structural molecule for the treatment of hyper-resorptive bone disorders through the direct inhibition of the Src protein tyrosine kinase (IC₅₀ = 22 μM) [5].

Further literature survey revealed that various N-substituted pyrazoles have been implemented as antileukemic, antitumor, antiproliferative, anti-angiogenic, DNA interacting, proapoptotic, autophagy and antitubulin agents. In addition, these compounds are capable to exert remarkable anti-cancer effects through inhibition of different types of enzymes, proteins and receptors which play critical roles in cell division [6]. Moreover, the compound V bearing N-phenylpyrazole nucleus was developed by Vertex Pharmaceuticals as an inhibitor of Src kinases and c-Jun N-terminal kinases (JNKs) [5].

The non-receptor tyrosine kinase c-Src belongs to a family of closely related kinases and is widely expressed in all cell types. Over the past century, large amounts of data have been generated supporting the role of c-Src as a key messenger in many important cellular pathways, including those involved in regulating proliferation, differentiation, survival, motility, adhesion, migration, and angiogenesis [7], [8]. Because of its essential role in many intracellular signaling pathways, however, interrupting c-Src signaling may disrupt oncogenic pathways. Research has revealed that c-Src is present in a low concentration inactive form in the normal cells, while increase in its activity can be linked to increased motility/invasiveness of tumor cells and tumor progression [9], [10]. Although c-Src is rarely found as a mutated oncogene in human malignancies, elevated expression and activation of Src family kinases (SFKs) have been implicated in a variety of cancers (including glioblastoma, colon, lung, breast, and prostate cancers), osteoporosis and stroke-induced vascular permeability [11], [12], [13]. Moreover, beneficial effects of c-Src inhibition in several pathological models (cell cycle arrest of tumor cell lines, growth inhibition of Src-transformed fibroblast derived tumors, metastasis inhibition in human tumor models) has been demonstrated [14], [15] (see Fig. 1).

Based on the afore-mentioned findings, and in an attempt to find new potent c-Src inhibitors as anticancer agents; novel hybrid compounds having benzofuran–pyrazole backbone have been designed to evaluate their cytotoxic activity against several tumor cell lines (Fig. 2). This backbone was conjugated with different aromatic or heteroaromatic rings of documented potent antitumor activity such as isoxazole ring [16], [17] or c-Src inhibiting activity such as pyrimidine heterocycle [18], [19] in a trial to generate a new class exhibiting both enzymatic and cellular c-Src inhibition activities for maximal anti-tumor effects (Fig. 2). All the newly synthesized compounds were submitted to the National Cancer Institute (NCI), Bethesda, Maryland, USA, to evaluate their anticancer activity. Only eight compounds were selected by NCI and subjected to in vitro anticancer screening against 60 human cancer cell lines. Furthermore, the inhibitory activity was evaluated against c-Src at Kinexus Corporation. Molecular docking studies were carried out to explain how these compounds could act at the molecular level.

Section snippets

Chemistry

The synthetic pathways adopted for the preparation of the new benzofuran–pyrazole hybrid derivatives in this study is depicted in (Scheme 1). Using Vilsmeier Haach reaction, the key starting material 3-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (1) was prepared according to the reported method [20]. It is documented that chalcones are convenient intermediates for the synthesis of five and six membered-heterocycles [21], [22], [23]. The chalcones 2a–d were obtained in good yields by

Conclusion

In this study, novel benzofuran–pyrazole hybrid derivatives were successfully synthesized and eight of them were selected by NCI, USA to evaluate their in vitro anticancer activities against full 60 human cancer cell lines at a single high dose (10⁻⁵ M) concentration. The hybrids clubbed with 3-furano-N-acetylpyrazoline and 3-furano-isoxazole rings 4d, 5d produced remarkable and broad spectrum anticancer activities. The most potent activity was obtained by the derivative bearing 3-pyrrolo-N

Chemistry

All melting points are uncorrected and were taken in open capillary tubes using Electrothermal apparatus 9100. Elemental microanalyses were carried out at Microanalytical Unit, Central Services Laboratory, National Research Centre, Dokki, Cairo, Egypt, using Vario Elementar and were found within ±0.4% of the theoretical values. Infrared spectra were recorded on FT/IR-4100 Jasco-Japan, Fourier transform, Infrared spectrometer at cm⁻¹ scale using KBr disc technique at Central Services Laboratory,

Acknowledgment

This work was supported financially by National Research Centre fund under project No. P 90202. Also, the authors are thankful to the National Cancer Institute (NCI), Bethesda, Maryland, USA, for performing the anticancer evaluation over the 60-cancer cell line panel.

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Design, synthesis, biological evaluation and molecular docking studies of novel benzofuran–pyrazole derivatives as anticancer agents

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusion

Chemistry

Acknowledgment

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Biochem. Pharmacol.

Biochim. Biophys. Acta

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Blood

Blood

J. Adv. Drug Deliv. Rev.

Expert Opin. Ther. Patents

Front. Chem.

Cancer Metastasis Rev.

Nat. Rev. Cancer

Proc. Natl. Acad. Sci. U.S.A.