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(3,5-Dimethylpyrazol-1-yl)-[4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl]methanone

by
Rania B. Bakr
1,2,* and
Ahmed B. M. Mehany
3
1
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni Suef University, Beni Suef 62514, Egypt
2
Department of Pharmaceutical Chemistry, College of Pharmacy, Al Jouf University, Sakaka, Al Jouf 2014, Saudi Arabia
3
Department of Zoology, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt
*
Author to whom correspondence should be addressed.
Molbank 2016, 2016(4), M915; https://doi.org/10.3390/M915
Submission received: 28 September 2016 / Revised: 29 October 2016 / Accepted: 8 November 2016 / Published: 10 November 2016
(This article belongs to the Section Organic Synthesis and Biosynthesis)
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Abstract

:
In an attempt to enhance cytotoxic activity of pyrazolo[3,4-d]pyrimidine core, we synthesized (3,5-dimethylpyrazol-1-yl)-[4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl]methanone (4) by reacting 4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)benzohydrazide (3) with acetylacetone. Antiproliferative activity of this compound was screened against breast (MCF-7), colon (HCT-116), and liver (HEPG-2) cancer cell lines. The tested compound exhibited cytotoxic activity with IC50 = 5.00–32.52 μM. Moreover, inhibitory activity of this compound was evaluated against the epidermal growth factor receptor (EGFR), the fibroblast growth factor receptor (FGFR), the insulin receptor (IR), and the vascular endothelial growth factor receptor (VEGFR). This target compound showed potent inhibitory activity, especially against FGFR with IC50 = 5.18 μM.

Graphical Abstract

1. Introduction

Protein kinases play an important role in cell proliferation, differentiation, migration, metabolism, and apoptosis [1,2]. Dysregulation of protein kinases occurs in a variety of diseases including cancer [3,4]. Overexpression of protein kinase in tumor cells can be blocked by selective kinase inhibitors, so these inhibitors are considered a promising approach for treatment of cancer [5,6,7,8].
Pyrazolo[3,4-d]pyrimidine derivatives attract great interest because of their diverse biological and pharmacological properties. Among these properties, their anticancer effects have been extensively evaluated [9,10,11,12].
The cytotoxic effect of this class of compounds is attributed to different mechanisms. They have been reported as acting as cyclin dependent kinase (CDK) inhibitors [13,14,15], glycogen synthase kinase (GSK) inhibitors [16,17], epidermal growth factor receptor (EGFR) inhibitors [18], and dual src/Ab1 kinase inhibitors [19].
A new series of 2-(3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)- N-(4-substitutedbenzylidene)acetohydrazides, specifically compound 1 (Figure 1), displayed cytotoxic activity against breast carcinoma (MCF-7), non-small cell lung cancer (A549), and human colorectal adenocarcinoma (HT-29) cell lines, and proved to be inhibitors of EGFR protein kinase [20]. El Hamid et al. synthesized and evaluated a new set of 1-aryl-4-benzylidenehydrazinyl-3-methylsulphanyl-pyrazolo[3,4-d]pyrimidines as anti-breast cancer agents. Compound 2 was the most active compound in this search with an IC50 equal to 7.5 nM [21]. In addition, the literature survey revealed that the pyrazole moiety represents an important pharmacophore in several anticancer active agents [22,23,24,25,26,27,28]. All these facts encouraged us to hybridize the pyrazolo[3,4-d]pyrimidine scaffold with the pyrazole nucleus in a trial to obtain a promising new anticancer active agent.

2. Results and Discussion

2.1. Chemistry

(3,5-Dimethylpyrazol-1-yl)-[4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl]methanone (4) was prepared by refluxing 4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)benzohydrazide (3) [29] with acetylacetone in acetic acid for 10 h, as shown in Scheme 1.
The structure of the target compound 4 was elucidated by IR, 1H-, and 13C-NMR, MS, and elemental analysis. All data are in accordance with the assumed structure. The IR spectrum of this compound revealed the presence of a NH group at 3232 cm−1 and a C=O group at 1697 cm−1.
The 1H-NMR spectrum showed two singlet signals at δ 2.20 and 2.56 ppm corresponding to the two methyl protons in addition to a singlet signal at δ 6.28 ppm, corresponding to the pyrazole H-4proton. Inspection of the 13C-NMR spectrum indicated an appearance of two methyl peaks at δ 13.90 and 14.27 ppm and pyrazole C4 at δ 111.53 ppm. Finally, the mass spectrum of 4 demonstrated a molecular ion peak at m/z 409 (M+.) and a base peak at m/z 314.

2.2. Pharmacological Screening

The newly synthesized compound was screened in vitro for its anticancer activity against three cancer cell lines—breast (MCF-7), liver (HEPG-2), and colon (HCT-116) cancer cell lines. The results were expressed in terms of IC50 values (the concentration that resulted in a 50% inhibition of cell viability) where the well-known anticancer agents doxorubicin was used as a positive control (Table 1).
The tested compound showed a marked antitumor activity against all the tested cell lines with IC50 values of 5.00–32.52 μM. Moreover, this compound was more potent (IC50 = 5.00 μM) than doxorubicin (IC50 = 5.66 μM) against the liver cancer cell line (HEPG-2).
Furthermore, this compound was evaluated against different protein kinases such as the epidermal growth factor receptor (EGFR), the fibroblast growth factor receptor (FGFR), the insulin receptor (IR), and the vascular endothelial growth factor receptor (VEGFR) in an attempt to explore the mechanism of action of this compound. The obtained results demonstrated that this compound exhibited good inhibitory activity against all used protein kinases with IC50 values of 5.18–27.89 μM (Table 2).

3. Materials and Methods

3.1. Chemistry

Melting points was determined on a Thomas–Hoover capillary apparatus and are uncorrected. Infrared (IR) spectrum was recorded as films on NaCl plates using a Nicolet 550 Series II Magna FT-IR spectrometer (Shimadzu, Kyoto, Japan). 1H-NMR and 13C-NMR spectra were measured on a BrukerAvance III 400 MHz for 1H and 100 MHz for 13C (Bruker AG, Fällanden, Switzerland) with a BBFO Smart Probe and a Bruker 400 AEON Nitrogen-Free Magnet, Faculty of Pharmacy, Beni-Suef University, Egypt in DMSO-d6 with TMS as the internal standard, where J (coupling constant) values are estimated in Hertz (Hz), and chemical shifts were recorded in ppm δ scale. Mass spectrum (MS) was recorded on a Hewlett Packard 5988 spectrometer (Hewlett-Packard Co., Palo Alto, CA, USA). Microanalyses for C, H, and N were carried out on a Perkin–Elmer 2400 analyzer (Perkin-Elmer, Norwalk, CT, USA) at the Micro analytical unit of Cairo University, Egypt All other reagents, purchased from the Aldrich Chemical Company (Milwaukee, WI, USA), were used without further purification. 4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)benzohydrazide (3) was prepared according to a literature procedure [29].

(3,5-Dimethylpyrazol-1-yl)-[4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl]methanone) (4)

A mixture of 4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)benzohydrazide (3, 3.59 g, 10 mmol) and acetylacetone (1 g, 10 mmol) in acetic acid (10 mL) was heated under reflux for 10 h. After cooling, the reaction mixture was poured onto ice water. The colorless powder obtained was crystallized from ethanol to yield compound 4. Mp 180–182 °C; yield: 56%; IR (cm−1): 3232 (NH); 3070 (CH aromatic); 2954 (CH aliphatic); 1697 (C=O); 1608 (C=N); 1H-NMR (DMSO-d6) δ ppm: 2.20 (s, 3H, CH3), 2.56 (s, 3H, CH3), 6.28 (s, 1H, pyrazole H-4 7.37–7.41 (m, 1H, phenyl H-4), 7.57–7.61 (m, 2H, phenyl H-3, H-5), 8.01 (d, J = 8.8 Hz, 2H, aminophenyl H-2, H-6), 8.09 (d, J = 8.8 Hz, 2H, aminophenyl H-3, H-5), 8.21 (s, 1H, pyrazole CH), 8.23 (s, 1H, pyrimidine CH), 8.67 (d, J = 12 Hz, 2H, phenyl H-2, H-6), 10.55 (s, 1H, NH, D2O exchangeable); 13C-NMR (DMSO-d6) δ: 13.90, 14.27, 103.35, 111.53, 119.80, 121.45, 127.06, 127.53, 129.70, 132.74, 134.09, 138.95, 143.48, 144.85, 151.92, 153.45, 154.63, 156.34, 167.43; EIMS (m/z) 409 (M+., 28%), 314 (100%). Anal.Calcd for C23H19N7O: C, 67.47; H, 4.68; N, 23.95. Found: C, 67.53; H, 4.42; N, 24.01.

3.2. Pharmacological Studies

3.2.1. Cell Viability Analysis

The mammary gland breast cancer cell line (MCF-7), the human hepatocellular carcinoma cell line (HEPG-2), and the colon carcinoma cell line (HCT-116) were obtained from the American Type Culture Collection (ATCC). Doxorubicin (positive control) and all chemicals used in this study are of high analytical grade and were obtained from either Sigma-Aldrich or Biorad. The different cell lines mentioned above were used to determine the inhibitory effects of the tested compounds on cell growth using the SulphoRhodamine-B (SRB) assay using the method of Skehan et al. [30]. Cells were plated in 96 multi-well plates for 24 h before treatment with the compounds to allow attachment of the cells to the wall of the plate. Different concentrations of the tested compounds (0, 6.25, 12.5, 25, 50, and 100 µg/mL) were added to the cell monolayer. Triplicate wells were prepared for each individual dose. Monolayer cells were incubated with the compounds for 48 h at 37 °C and in an atmosphere of 5% CO2; cells were fixed, washed, and stained with Sulforhodamine B stain. Excess stain was washed with acetic acid and attached stain was recovered with a Tris EDTA buffer. Color intensity was measured in an ELISA reader and the relation between surviving fraction and drug concentration was plotted and IC50 (the concentration required for 50% inhibition of cell viability) was determined for each compound by Sigma plot software (Sigma Plot 11.0 software, Systat Software Inc.; San Jose, California).

3.2.2. Kinases Inhibitory Activity

Kinase activity was determined using Kinase-Glo Plus luminescence kinase assay kit according to the previously reported method [31].

Supplementary Materials

The following are available online at www.mdpi.com/1422-8599/2016/4/M915, Figure S1: spectrum of compound 4, Figure S2: 13C-NMR spectrum of compound 4, Figure S3: IR spectrum of compound 4.
Supplementary File 1Supplementary File 2Supplementary File 3Supplementary File 4

Acknowledgments

Rania B. Bakr is grateful to all members of the Pharmaceutical Organic Chemistry, Faculty of pharmacy, Beni-suef university for all help and supports during progress of research.

Author Contributions

R.B.B. conceived, designed, and performed the experiments, analyzed the data, and wrote the paper. A.B.M. performed the anticancer screening and kinase inhibitory activity.

Conflicts of Interest

The authors declare no conflict of interest.

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Molbank 2016 m915 g001 550
Figure 1. Chemical structures of some reported pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents.
Figure 1. Chemical structures of some reported pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents.
Molbank 2016 m915 g001
Molbank 2016 m915 sch001 550
Scheme 1. Synthetic pathway for target compound 4.
Scheme 1. Synthetic pathway for target compound 4.
Molbank 2016 m915 sch001
Table
Table 1. Cytotoxic activity of compound 4 and doxorubicin on three cancer cell lines—MCF-7, HEPG-2, and HCT-116.
Table 1. Cytotoxic activity of compound 4 and doxorubicin on three cancer cell lines—MCF-7, HEPG-2, and HCT-116.
CompoundIC50 (μM)
MCF-7HEPG-2HCT-116
432.52 ± 0.025.00 ± 0.0214.31 ± 0.05
Doxorubicin2.60 ± 0.025.66 ± 0.128.48 ± 0.32
Table
Table 2. Kinase inhibitory activity of compound 4.
Table 2. Kinase inhibitory activity of compound 4.
IC50 (μM)
EGFRIRVEGFRFGFR
13.4710.2927.895.18

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MDPI and ACS Style

Bakr, R.B.; Mehany, A.B.M. (3,5-Dimethylpyrazol-1-yl)-[4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl]methanone. Molbank 2016, 2016, M915. https://doi.org/10.3390/M915

AMA Style

Bakr RB, Mehany ABM. (3,5-Dimethylpyrazol-1-yl)-[4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl]methanone. Molbank. 2016; 2016(4):M915. https://doi.org/10.3390/M915

Chicago/Turabian Style

Bakr, Rania B., and Ahmed B. M. Mehany. 2016. "(3,5-Dimethylpyrazol-1-yl)-[4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl]methanone" Molbank 2016, no. 4: M915. https://doi.org/10.3390/M915

APA Style

Bakr, R. B., & Mehany, A. B. M. (2016). (3,5-Dimethylpyrazol-1-yl)-[4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl]methanone. Molbank, 2016(4), M915. https://doi.org/10.3390/M915

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