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Introduction: Angiogenesis is the formation of new blood vessels from the pre-existing vasculature and is essential for some physiological processes including wound healing and menstrual cycles. Unregulated angiogenesis can lead to vascular related diseases such as age related macular degeneration, cancer and rheumatoid arthritis. Chalcones (1,3-diphenylpropenones) are naturally occurring phenolic compounds found in a variety of plants and fruits. Their simple molecular structures have demonstrated an array of pharmacological activity including antioxidant and anti-vascular. Due to Chalcones having an easily modifiable scaffold, they are widely used as parent compounds in drug discovery studies. Endothelial cell proliferation and migration are essential for angiogenic growth, so compounds that possess anti-endothelial activity could be developed further as potential inhibitors of angiogenesis. With this in mind, we report the anti-endothelial activity of two novel analogues (AH1 and AH9) derived from the parent compound 2-chloro-2’5’-dihydroxychalcone. Method: Chalcones were synthesised via the Claisen-Schmidt condensation and verified via nuclear magnetic resonance (NMR) and mass spectrometry (MS). Primary Human umbilical vein endothelial cells (HUVECs) were cultured according to manufactures protocol. Cells were seeding into 96-well plates (3500 cells/well) and, 24 hours later, treated either with AH1, AH9 or Sorafenib, a known anti-angiogenic drug for 72hr at a concentration of 10 µM. Effects of the compounds on cell proliferation was assessed by quantifying the colorimetric conversion of 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) to purple formazan product (measured at 560 nm). Data are expressed as mean % inhibition of cell proliferation ± SEM (n=4). Anti-migratory activity was assessed via the wound healing assay and the effects of the compounds at 3 µM on the width of the scratch across an 8 hour period were compared to untreated control. Analysis was performed by one-way ANOVA with Tukey-Kramer’s multiple comparisons test. Data are expressed as mean % of maximum migration ± SEM (n=3). Results: AH1 and AH9 displayed significant anti-proliferative activity with inhibitory values of 94.94 ± 1.64% and 79.62 ± 4.45% compared to Sorafenib, 69.95 ± 4.12%, respectively. Effects on HUVEC migration showed that AH9 limited migration to 16.19 ± 14.44% (P

Many compounds with potential anti-cancer activity fail to reach the latter stages of clinical trials due to adverse effects, often causing cardiac and renal toxicity. Here, we synthesised a group of novel chalcone compounds, thought to have potential anti-cancer activity4 and assessed their effects upon cardiac and renal cell viability. Data revealed that all compounds produced minimal short term toxicity. Further work will be performed to assess the long term effects of these compounds on cell viability, leading to mechanistic studies and structure activity relationship analyses.

Università degli Studi dell'Aquila, Department of Life, Health, and Environmental Sciences Università di Bologna, Department of Pharmacy and Biotechnology It has been widely acknowledged that regular consumption of fresh fruits and vegetables is linked with a relatively low incidence of cancers (e.g. breast, cervix, and colon). Notably, dietary polyphenolic compounds have been proposed to play a role in cancer prevention. However, at present there is no satisfactory explanation for the cancer preventative properties of the group of compounds. Whereas polyphenolic compounds have been shown to inhibit proliferation of tumor cells in vitro, the results of in vivo tests have mostly been disappointing in this respect. It seems that mammalian phase I and phase II detoxification mechanisms make that dietary polyphenols are rapidly and effectively removed from the body, i.e. their concentration in the blood plasma hardly ever reaches levels high enough to have a possible effect on tumor growth. Despite the experimental evidence regarding the antitumor activity of resveratrol, stilbene found in red grapes, the clinical effectiveness of the natural product is limited because of its low bioavailability. Resveratrol, however, has demonstrated antioxidant and antiproliferative activity in in-vitro models and mice. Although resveratrol exhibits significant anticancer activity, its efficacy in-vivo is limited due to its poor pharmacokinetic properties. In order to improve the pharmacokinetic properties of resveratrol and to increase the chemopreventive activity, several methoxylated resveratrol analogues were designed, synthesized and ested in vitro models. These analogues included a synthetic anticancer prodrug based on the structure of the natural product resveratrol namely DMU-212 or trans 3, 4, 4’ 5 -tetramethoxy stilbene. DMU-212 has considerable potency in submicromolar IC50 in cancer cell lines that renders it an important candidate for further studies, as it deviates from the classical acute toxicity of standard chemotherapeutic drugs. These synthesized analogues have been tested for their antitumor activity and in vitro biological assays have been exerted in order to assess the cardiovascular effects of the compounds. In particular, Structure Activity relationships have been studied in relation to their effects towards cardiovascular parameters. The cardiac activity of these compounds, using in vitro biological assays, on guinea-pig left and right atria, as well as their relaxant activity on guinea-pig vascular (aorta) and nonvascular (ileum) smooth muscle has been studied. The chemical modifications of the resveratrol have been made in order to maintain the stilbene scaffold that is crucial for heart selectivity. All the tested compounds exert a cardiovascular pattern activity similar to that of resveratrol. Heart and smooth muscle activity profile is similar for all tested compounds. The same modifications leading to an antitumor activity increase do not affect cardiovascular parameters. Resveratrol is devoid of relaxing effects towards vascular smooth muscle, while it relaxes non vascular smooth muscle with a low potency (EC50 = 24.34 μM (c.l 16.15-29.87)). All the resveratrol analogues have a similar activity pattern, showing selectivity towards non-vascular smooth muscle.