Original article
Synthesis and tumor inhibitory activity of novel coumarin analogs targeting angiogenesis and apoptosis

https://doi.org/10.1016/j.ejmech.2014.01.050Get rights and content

Highlights

  • Coumarin analogs (5aj) were synthesized starting from hydroxy benzophenones.

  • Compounds (5aj) were screened for angioprevention and tumor inhibition activity.

  • The tumor inhibitory mechanism was due to the antiangiogenesis and apoptosis.

  • Finally compound 5c was identified as potent molecule.

  • Compound 5c could be developed as a potent anticancer drug in the near future.

Abstract

A sequence of coumarin analogs 5aj was obtained by multi step synthesis from hydroxy benzophenones (1aj). The in vitro antiproliferative effect of the title compounds was tested against Ehrlich ascites carcinoma (EAC) and Daltons lymphoma ascites (DLA) cell lines. Among the series, compound 5c with bromo group in the benzophenone moiety was endowed with excellent antiproliferative potency with significant IC50 value. Further, in vivo antitumor effect of compound 5c against murine EAC and solid DL tumor model system was evident by the extended survivality. The tumor inhibitory mechanism of compound 5c was due to the antiangiogenesis and promotion of apoptosis. These results suggest possible applications of compound 5c which could be developed as a potent anticancer drug in the near future.

Introduction

Most, if not all, human cancers share six acquired capabilities that enable malignant growth as proposed by Hanahan and Weinberg. Promotion of angiogenesis and resistant to apoptosis are the two important hallmarks of cancer [1]. Tumor growth and expansion requires an ability not only to proliferate, but also to down-modulate cell death and activate angiogenesis to produce a tumor neovasculature. Thus, the promotion of apoptosis and antiangiogenesis targeting strategies is one of the important focus in current cancer therapy [2]. The development of such novel, effective and less or no toxic compounds with multiple mode of action for targeted cancer therapy has become an innovative approach and efforts have been directed toward discovering such anticancer agents endowed with cytotoxic action [3], [4].

Coumarins are an old class of compounds obtained from both natural products and synthetic methods. The pharmacological and biochemical properties and therapeutic applications of coumarins depend upon the pattern of substitution and have attracted intense interest in recent years because of their diverse pharmacological properties [5]. Among these properties, their cytotoxic effects were the most extensively examined, this reflects in anticancer activity. Studies have revealed the mechanism behind the anticancer effect of coumarin analogs which include antiangiogenesis and induction of apoptosis independently [6], [7], [8], [9], [10], [11], [12]. The current strategies in cancer drug development shifted toward the multiple mechanistic approach and several drugs have been validated and developed. Such validation of structure–system–activity–relationship of coumarins with special respect to angiogenesis and apoptosis leads to cancer-preventing activities should be continued [13]. The vast majority of coumarins, completely innocuous, may be beneficial in a variety of human cancer, in spite of some ongoing controversy [14]. Hence it is very essential to synthesize and develop novel coumarin analogs with multiple targets. In the present study efforts have been made to synthesize novel derivatives of coumarin analogs with antiangiogenic and proapoptotic activity leading to inhibition of tumor growth in mouse model systems.

Section snippets

Chemistry

The synthesis of the title compounds 5aj is as outlined in Scheme 1. A series of N-[2-(2-aroyl-4-methylphenoxy)-acetyl]-hydrazide methanone coumarins 5aj were obtained starting from hydroxyl benzophenones 1aj. Compounds 1aj on reaction with ethyl chloroacetate afford ethyl 2-aroyl-4-methylphenoxy acetates 2aj [19], which on treatment with hydrazine hydrate in the presence of ethanol yields 2-aroyl-4-methylphenoxy acetohydrazides 3aj [22]. Condensation of 3aj with diethyl malonate in the

Conclusion

The complex molecular pathways that govern angiogenesis and apoptosis are two logical targets for pharmacological manipulations given the important role they play in the tumor growth and development of cancers. So targeting the tumor neovasculature and inducing apoptosis is an attractive strategy for effective cancer therapy. As an approach we synthesized a series of coumarin analogs and screened for cytotoxic and antitumor potency against two different cell lines both in vitro and in vivo. The

Experimental section

Chemicals were procured from Sigma Aldrich Chemical Co. TLC was performed on aluminum-backed silica plates and visualized by UV-light. Melting points were determined on a Thomas Hoover capillary melting point apparatus with a digital thermometer. IR spectra were recorded in Nujol on FT-IR Shimadzu 8300 spectrophotometer, 1H NMR spectra were recorded on a Bruker 400 MHz NMR spectrophotometer in CDCl3 and chemical shift were recorded in parts per million down field from tetramethylsilane. Mass

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgment

Shaukath Ara Khanum is grateful to University of Mysore, Mysore, for the grant of MRP [UOM letter No. DV3/389/2005-06]. B. R. Vijay Avin, T. Prabhu, and B.T. Prabhakar gratefully acknowledged for the grant supported by VGST (VGST/P-9/SMYSR/2011-12/1171), SERB-DST (SR/FT/LS-25/2011) and UGC (F.No.41-507/2012 (SR)). V. Lakshmi Ranganatha is thankful for the financial support provided by the DST, New Delhi, under INSPIRE Fellowship scheme [IF110555]. Finally our sincere thanks to National College

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