Angiogenesis is a process of development and of growth of new capillary blood vessels from pre-existing vessels. When pathological, it contributes to the development of numerous types of tumors, and the formation of metastases. In order to grow, carcinoma need new blood vessels to form so that they can feed themselves. Therefore, nowadays the concept according to which the development of cancer is angiogenesis dependent is generally recognized. This concept makes the control of tumoral angiogenesis one of the promising therapeutic ways in cancerology. The transition from the latent phase to the invasive and metastatic phase of a cancer is linked to what is called the angiogenic switch. It implies complex cellular and molecular interactions between cancerous cells, endothelial cells and the components of the extra-cellular matrix and namely the existence of specific proteins secreted by the tumoral cells able to stimulate the proliferation of capillary endothelial cells. Among them, VEGF, Vascular Endothelial Growth Factor was found in several types of tumors. It has shown a tumoral angiogenic activity in vitro and in vivo, and thus is a privileged target for the control of angiogenesis in an anti-tumoral goal. The role of VEGF in tumoral angiogenesis has been extensively studied. It has been proved to undergo as well autocrine as paracrine stimulation of tumoral angiogenesis. During the last few years, several members of the VEGF family have been described namely the VEGF-A, B, C, D, E and placenta growth factor (PlGF) among which VEGF-A (121 aminoacids) plays a role of prime importance in angiogenesis. VEGF is a 45 kDA glycoprotein, homodimeric, basic, and able to bind heparin. The three-dimensional structure of VEGF has been recently determined, by X-rays diffraction, and NMR spectroscopy. The different forms of the VEGF bind to receptors that exhibit a tyrosine-kinase activity (RTK). The specific action of the VEGF on the endothelial cells is mainly regulated by two types of RTK of the VEGF family, VEGFR1, or Flt-1, and VEGFR2, or KDR/Flk-1. Mutagenesis studies have shown that only a small number of VEGF residues are important and essential for the binding with RTK. Data described to date from the studies of VEGF/RTK interactions agree to the hypothesis that KDR receptor is the main human receptor responsible for the VEGF activity in both physiological and pathological vascular development, and VEGF-KDR signalling pathway has been validated as a priority target for the development of anti- and pro- angiogenic agents. Therefore angiogenesis mediated by VEGF constitutes a new target for anti-cancer therapy which has explored through different ways of intervention aiming at the blocking of the tumoral angiogenesis. The main ones are: -Struggle against the stroma degradation and invasion by the neo-vessels -Inhibition of activated endothelial cells. -Inhibition of angiogenic factors production and of their receptors. -Inhibition of the VEGF signal pathway, by peptides blocking the bond between VEGF and its recepto...

Blocking angiogenesis is an attractive strategy to inhibit tumor growth, invasion, and metastasis. We describe here the structure and the biological action of a new cyclic peptide derived from vascular endothelial growth factor (VEGF). This 17-amino acid molecule designated cyclopeptidic vascular endothelial growth inhibitor (cyclo-VEGI, CBO-P11) encompasses residues 79 -93 of VEGF which are involved in the interaction with VEGF receptor-2. In aqueous solution, cyclo-VEGI presents a propensity to adopt a helix conformation that was largely unexpected because only ␤-sheet structures or random coil conformations have been observed for macrocyclic peptides. Cyclo-VEGI inhibits binding of iodinated VEGF 165 to endothelial cells, endothelial cells proliferation, migration, and signaling induced by VEGF 165 . This peptide also exhibits anti-angiogenic activity in vivo on the differentiated chicken chorioallantoic membrane. Furthermore, cyclo-VEGI significantly blocks the growth of established intracranial glioma in nude and syngeneic mice and improves survival without side effects. Taken together, these results suggest that cyclo-VEGI is an attractive candidate for the development of novel angiogenesis inhibitor molecules useful for the treatment of cancer and other angiogenesis-related diseases.Angiogenesis takes place during embryonic development and in the adult during wound healing and the female ovulatory cycle. In pathological states, angiogenesis is observed during solid tumor growth and metastasis, diabetic retinopathy, and chronic inflammatory disorders. A number of angiogenic regulators such as vascular endothelial growth factors (VEGFs),

Two coumarin-labelled lysines were conveniently prepared as a fluorescence resonance energy transfer (FRET) pair for peptide cleavage detection. 7-Methoxy and 7-diethylamino coumarin-3-carboxylic acids were synthesized according to a modification of known procedures. Labelling at lysine was achieved in solution via the active N-hydroxysuccinimide ester of the carboxylic acid coumarin derivatives to give the target compounds in good yield. Subsequently, these modified amino acids were used in solid phase peptide synthesis (SPPS), and their potential utility in an extracellular matrix metalloprotease (MMP-1) activity measurement via FRET and/or quenching studies was demonstrated.

The modified cyclo-VEGIs may have a wide range of applications and represent a useful tool to develop delivery/carrier systems for therapeutic targeting or imaging.

Two coumarin-labeled lysines were conveniently prepared as fluorescent probes. 7-Methoxy and 7-diethylamino coumarin-3-carboxylic acids were synthesized according to a modification of known procedures. Labeling at lysine was achieved in solution via the active N-hydroxysuccinimide ester of the carboxylic acid coumarin derivatives to give the target compounds in good yield. Spectroscopic data (UV-vis and fluorescence) were recorded for all compounds.