No abstract

A series of ethacrynic acid analogues, lacking the α,β-unsaturated carbonyl unit, was synthesized and subsequently evaluated for their ability to inhibit the migration of human breast cancer cells, Hs578Ts(i)8 as well as of human prostate cancer cells, C4-2B. These cell lines provide a good model system to study migration and invasion, since they represent metastatic cancer. Our studies show that ethacrynic acid analogues with methyl substituents at the aromatic ring demonstrate no inhibitory effect on the migration of both cancer cell lines, whereas a precursor in the synthesis of these ethacrynic acid analogues (II-1, a paraacylated m-cresol) is an excellent inhibitor of the migration of both cancer cell lines.Ethacrynic acid (EA) (Fig. 1) is a loop diuretic and is used to treat high blood pressure and the swelling caused by diseases like liver, kidney, and congestive heart failure. 1,2 EA possesses an α,β-unsaturated carbonyl unit (a Michael acceptor) and can be attacked by nucleophiles (e.g. sulfur-atoms) at the β-carbon. This α,β-unsaturated carbonyl moiety is often employed in the design of SH-enzyme inhibitors (e.g. cysteine proteases). 3-6 EA inhibits the enzyme by binding to the cysteinyl residue in the active site by means of a Michael-like addition and is therefore a good glutathione S-transferase P1-1 (GST P1-1) inhibitor. 7 Several research groups have synthesized EA analogues in order to increase the inhibitory effect on GST P1-1. GST P1-1 is also of importance in controlling multidrug resistance (MDR), proliferation and apoptosis processes and hence can be considered a target for cancer treatment. Along this line, it has been demonstrated that EA exerts antiproliferative effects against tumor cells, but only at higher concentrations (60-100 μM). 2,[8][9][10] Additionally, it has also been shown that EA is cytotoxic towards primary chronic lymphocytic leukemia (CLL) cells. 11 However, the relative lack of potency and the diuretic properties do not support the use of EA as a chemotherapeutic agent. 12 Recently, we Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Our previous studies show that the most potent candidates to inhibit the migration of human breast cancer cells, MCF-7/AZ, are EA analogues with one or two methoxy-groups attached to the aromatic system but lacking the α,β-unsaturated carbonyl unit. We hypothesized that the increase in electron density of the aromatic system, caused by electron donating groups like the methoxy group, is responsible for the anti-migratory properties of the corresponding compounds. 13 To further investigate this hypothes...