Original articleSynthesis and tumor inhibitory activity of novel coumarin analogs targeting angiogenesis and apoptosis
Graphical abstract
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 5a–j is as outlined in Scheme 1. A series of N-[2-(2-aroyl-4-methylphenoxy)-acetyl]-hydrazide methanone coumarins 5a–j were obtained starting from hydroxyl benzophenones 1a–j. Compounds 1a–j on reaction with ethyl chloroacetate afford ethyl 2-aroyl-4-methylphenoxy acetates 2a–j [19], which on treatment with hydrazine hydrate in the presence of ethanol yields 2-aroyl-4-methylphenoxy acetohydrazides 3a–j [22]. Condensation of 3a–j 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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Both the authors contributed equally.