Further studies on anti-invasive chemotypes: An excursion from chalcones to curcuminoids Bart I. Roman a,  , Tine De Ryck b , Sigrid Verhasselt a , Marc E. Bracke b , Christian V. Stevens a,⇑ a Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Coupure Links 653, B-9000 Ghent, Belgium b Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium article info Article history: Received 23 December 2014 Revised 13 January 2015 Accepted 15 January 2015 Available online 22 January 2015 Keywords: Invasion Cancer SAR Chalcone Curcuminoids abstract In our ongoing search for new anti-invasive chemotypes, we have made an excursion from previously reported potent 1,3-diarylpropenones (chalcones) to congeners bearing longer linkers between the aromatic moieties. Nine 1,x-diarylalkenones, including curcumin and bisdemethoxycurcumin, were evaluated in the chick heart invasion assay. Unfortunately, these compounds proved less potent and more toxic than earlier evaluated chemotypes. In the 1,3-diarylpenta-2,4-dien-1-one series, fluoro and/or trimethoxy substitution caused an increase in potency. This agrees with observations made earlier for the chalcone class. Ó 2015 Elsevier Ltd. All rights reserved. The hallmark that differentiates malignant neoplasms from benign tumors is the ability of a subpopulation of cells to invade neighboring tissues and cause metastases. 1 These phenomena account for 90% of all cancer deaths and currently present the most significant hurdles in the management of malignant disease. 2,3 Over the last years, our laboratories have been searching for novel chemotypes that can suppress the invasive phenotype of malignant cells (Chart 1). 4 Starting from natural 1,3-diphenyl- prop-2-en-1-ones, 5 the main hits in our Indo-Belgian anti-invasive screening program, 6 we have developed synthetic analogues belonging to the diarylchalcone (1b), 7 stilbene 8 (2,3) and diarylis- oxazole/pyrazole (4,5) classes, 9 and reported on the structure– activity relationship of these compounds. These studies were conducted using the phenotypic chick heart invasion (CHI) assay as an in vitro model of invasion. The most promising molecule identified yet is chalcone 1c, which displays strong anti-invasive efficacy at 0.01 lmolL 1 in the CHI and comparable behavior in the matrigel invasion assay. The present work intends to complement the above SAR studies by evaluating longer unsaturated spacers between the two aromatic moieties. Hence, we have prepared and evaluated an array of 1,x-diarylalkenones 6 (Chart 1). For completeness, also curcumin and bisdemethoxycurcumin (7) were included in this study. With respect to the latter compounds, ambiguous health claims have been put forward in both scientific and alternative literature. http://dx.doi.org/10.1016/j.bmcl.2015.01.027 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +32 9 264 5957; fax: +32 9 264 6221. E-mail addresses: Bart1.Roman@UGent.be (B.I. Roman), Tine.DeRyck@UGent.be (T. De Ryck), Marc1.Bracke@UGent.be (M.E. Bracke), Chris.Stevens@UGent.be (C.V. Stevens). URL: http://www.ugent.be/bw/doct/en (C.V. Stevens).   B.I.R. is a postdoctoral fellow of the Research Foundation—Flanders (FWO— Vlaanderen). OH O 6 7 HO OH OMe MeO i R 1 R 2 R 1 R 2 R 1 R 2 O R 1 R 2 N O R 1 X N R 2 1a 2 3 4 5 present report hit compounds 1,ω-diarylalkenones curcumins stilbenes isoxazoles and pyrazoles chalcones (4 examples) (10 examples) Ar 1 O Ar 2 1b previous SAR work chalcones (70 examples) (2 examples) (7 examples) Ar= substituted phenyl, furyl, indolyl X= O, NH O j i,j= 0, 1, 2 O 1c MeO MeO MeO F active at 0.01 μmol.L -1 Chart 1. Overview of previously and presently investigated chemotypes in search of anti-invasive lead molecules. Bioorganic & Medicinal Chemistry Letters 25 (2015) 1027–1031 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl