Analogue-based design, synthesis and biological evaluation of 3-substituted-(methylenehydrazono)indolin-2-ones as anticancer agents

doi:10.1016/j.ejmech.2014.03.058

European Journal of Medicinal Chemistry

Volume 78, 6 May 2014, Pages 275-280

https://doi.org/10.1016/j.ejmech.2014.03.058 Get rights and content

Highlights

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The title compounds 10a–l were prepared from 3-hydrazonoindolin-2-ones 8a–d.
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Compounds 10a–l showed a significant anticancer activity against MCF-7.
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Compounds 10c, f, i exhibited the highest activity almost the same of doxorubicin.

Abstract

The docking studies on CDK2 and GSK-3β inspired us to synthesis a series of indoline-2,3-dione hydrazones 10a–l. Treatment of indoline-2,3-dione derivatives 7a–d with hydrazine gave 3-hydrazonoindolin-2-ones 8a–d which were reacted with the appropriate aldehydes 9a–c to yield 3-substituted-(methylenehydrazono)indolin-2-ones 10a–l. Compounds 10a–l showed a significant anticancer activity against human breast cell line MCF-7. Compounds 10c, f, i exhibited the highest activity almost the same of doxorubicin (IC₅₀ = 6.10 μM) with IC₅₀ = 7.75, 6.75, 6.25 μM, respectively.

Graphical abstract

Indole-2,3-dione hydrazones 10a–l showed a significant anticancer activity against human breast cell line MCF-7. Compounds 10c, f, i exhibited the highest activity almost the same of doxorubicin (IC₅₀ = 6.10 μM) with IC₅₀ = 7.75, 6.75, 6.25 μM, respectively.

Introduction

Nowadays, cancer is one of the main reasons of death between nations caused by different elements such as presence of mutagenic and cancer causing materials in the environment. On the other hand, 1H-indole-2,3-dione derivatives have aroused great attention due to their wide variety of biological activities, relevant to application in a broad range of drug therapies, including anticancer drugs [1], [2], [3]. A plethora of biologically active C3-substituted indole-2,3-dione has been generated in the literature, these due to the susceptibility of isatin to be attacked by nucleophiles at the C3 position [3]. C3-substituted indole-2,3-dione drugs such as indirubin 1a (X = H, Y = O) and its derivatives 5-bromoindirubin 1b (X = Br, Y = O), indirubin-3′-oxime 1c (X = H, Y = N–OH) and 5-bromoindirubin-3′-oxime 1d (X = Br, Y = N–OH) were found to have potent anticancer activity with excellent inhibitory of tyrosin kinases CDK2, CDK5 and GSK-3β [4], [5], [6], [7]. Moreover, 1H-indole-2,3-dione drugs which contain arylidene branches in position 3 such as SU5416 (semaxanib^®, 2a) [8], SU5402 (2b) [9], SU6668 (2c) [10] and SU14813 (2d) [11] (Fig. 1) showed a significant cytotoxic activity. However, SU11248 (sunitinib, Sutent^®, 2) is an inhibitor of receptor tyrosine kinase (RTK) and it is the standard first-line treatment for the treatment of gastrointestinal stromal cancers and renal cell carcinoma [12] (Fig. 1).

Moreover, hydrazones of 1H-indole-2,3-dione 3 (Fig. 1) have been identified as inhibitors of the protein tyrosine phosphatase Shp2, which plays an important role in cell signaling, cell proliferation, differentiation and migration [13]. In recent years, the cytotoxic activity against Artemia salina of 1H-indole-2,3-dione thiosemicarbazones 4 (a hydrazone derivative containing a sulfur atom) have reported [14], [15] (Fig. 1). Furthermore, thiosemicarbazones 3 have been found to display cytotoxicity against the KB-3-1 cell line (a HeLa derivative) [16], [17].

Recently, we have been reported the synthesis of hydrazino derivative 5 with selective activity against multidrug-resistant cancer cells [18] and in vitro antiproliferative activity of synthesized 2H-chromene-3-carbohydrazides 6 which exhibited good antiproliferative profile against colon HT-29 [19] (Fig. 1).

In the light of the above data and through our docking studies that will be mentioned later, and in a continuation of our interest in the synthesis of hydrazone-based compounds with anticancer activity [18], [19], [20], [21], [22], [23], [24], in this study, we have designed and synthesized certain derivatives of indoline-2,3-dione hydrazones 10a–l (Fig. 1) that have potential utility as anticancer drugs.

Section snippets

Analogue-based design through molecular docking studies

Crystallographic data of CDK2 [4], [5] and GSK-3β [6] in complex with various indirubins has provided valuable information on the active site differences along with specific interactions between those kinases and indirubin analogues [7]. This mode of interaction inspired us to deduce indoline-2,3-dione hydrazone derivatives with an interaction near to indirubin analogues. During the investigation of the interaction between 5-bromoindurubin with human cyclin dependent protein kinase 2 of the

Conclusion

Docking studies were done to predict the possible anticancer activity of a series of 2-oxindolin-3-hydrazones 10a–l. Synthesis and in vitro anticancer activity 10a–l toward MCF-7 cell line were studied to support our hypothesis. From the biological assay results, compounds 10a–l showed a significant activity and we found that 3-(((1H-pyrrol-2-yl)methylene)hydrazono)indolin-2-one (10i) gave the maximum activity with IC₅₀ = 6.25 μM. This result give a new promising venue for further

Molecular docking studies

The molecular modeling studies were carried out using Molecular Operating Environment (MOE 2008.10; Chemical Computing Group, Canada). All the minimizations were performed with MOE until a RMSD gradient of 0.05 kcal mol⁻¹ Å⁻¹ with MMFF94X forcefield and the partial charges were automatically calculated. The X-ray crystallographic structure of GSK-3β and CDK2 complexes with indirubin-3′-oxime (PDB ID: 1Q41 and 2BHE respectively) was obtained from the protein data bank. The interaction mode of

Acknowledgments

This work was supported by the Industrial Biotechnology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), Sadat City University, Egypt. The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group Project no. RGP-VPP-321.

References (28)

P. Pakravan et al.
Pharmacological Reports
(2013)
T.G. Davies et al.
Structure
(2001)
L. Meijer et al.
Chemistry & Biology
(2003)
B. Pandit et al.
Bioorganic & Medicinal Chemistry
(2006)
H.A. Abdel-Aziz et al.
European Journal of Medicinal Chemistry
(2013)
N.A. Hamdy et al.
European Journal of Medicinal Chemistry
(2010)
H.A. Abdel-Aziz et al.
European Journal of Medicinal Chemistry
(2010)
A.M. Alafeefy et al.
Bioorganic & Medicinal Chemistry
(2013)
S. Leclerc et al.
Journal of Biological Chemistry
(2001)
D.K. Chaudhary et al.
Der Pharmacia Lettre
(2013)

K.L. Vine et al.

Advances in Anticancer Agents in Medicinal Chemistry

(2013)

R. Hoessel et al.

Nature Cell Biology

(1999)

P. Polychronopoulos et al.

Journal of Medicinal Chemistry

(2004)

H.-H. Li et al.

Acta Pharmacologica Sinica

(2007)

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Original articleAnalogue-based design, synthesis and biological evaluation of 3-substituted-(methylenehydrazono)indolin-2-ones as anticancer agents

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Analogue-based design through molecular docking studies

Conclusion

Molecular docking studies

Acknowledgments

Pharmacological Reports

Structure

Chemistry & Biology

Bioorganic & Medicinal Chemistry

European Journal of Medicinal Chemistry

European Journal of Medicinal Chemistry

European Journal of Medicinal Chemistry

Bioorganic & Medicinal Chemistry

Journal of Biological Chemistry

Der Pharmacia Lettre

Advances in Anticancer Agents in Medicinal Chemistry

Nature Cell Biology

Journal of Medicinal Chemistry

Acta Pharmacologica Sinica

Original article
Analogue-based design, synthesis and biological evaluation of 3-substituted-(methylenehydrazono)indolin-2-ones as anticancer agents