Development of 1,2,3-Triazole-Based Sphingosine Kinase Inhibitors and Their Evaluation as Antiproliferative Agents

Two series of N-(aryl)-1-(hydroxyalkyl)pyrrolidine-2-carboxamides (2a-2g and 3a-3g) and 1,4-disubstituted 1,2,3-triazoles (5a-5h and 8a-8h) were synthesized. All the compounds, containing a lipophilic tail and a polar headgroup, were evaluated as sphingosine kinase (SphK) inhibitors by assessing their ability to interfere with the acetylcholine (Ach) induced relaxation of aortic rings pre-contracted with phenylephrine. Moreover, their antiproliferative activity was tested on several cell lines expressing both SphK1 and SphK2. Compounds 5h and 8f, identified as the most efficient antiproliferative agents, showed a different selectivity profile, with 8f being selective for SphK1

sintesi di nuovi modulatori della via del segnale mediata dalla sfingosina 1-fosfato

La sfingosina 1-fosfato (S1P) è un mediatore lipidico pleiotropico coinvolto in maniera critica in importanti eventi fisiopatologici come lo sviluppo vascolare, la circolazione delle cellule del sistema immunitario, l'angiogenesi, l'infiammazione ed il cancro. La sintesi di composti in grado di modulare il signaling S1P, o attraverso l'inibizione degli enzimi preposti alla sua produzione (SphKs) o attraverso l'antagonismo sui suoi recettori(S1PRs), può risultare utile nel trattamento di molteplici processi patologici

Improved synthesis on solid phase of dithiocarbamic cRGD-derivative and 99m Tc-radiolabelling

In the field of angiogenesis, small cyclic pentapeptides containing the RGD motif are playing a relevant role for their high affinity and specificity for integrin receptors and for the possibility to act at both therapeutic and diagnostic level by inhibiting pathological angiogenesis and by serving as shuttles to deliver imaging-probe including SPECT/PET radionuclides to specific tissues. In the last decade, several new protocols were reported in literature for the direct synthesis of cyclic RDG either in solution or by SPPS. Here, we have elaborated and tested some alternative approaches using different resins and different protective groups. The introduction of the dithiocarbamate function, useful to complex radio-metals suitable for nuclear medicine applications, has also been considered and achieved

Targeting VEGF receptors with non-neutralizing cyclopeptides for imaging applications

Pharmacological strategies aimed at preventing cancer growth are in most cases paralleled by diagnostic investigations for monitoring and prognosticating therapeutic efficacy. A relevant approach in cancer is the suppression of pathological angiogenesis, which is principally driven by vascular endothelial growth factor (VEGF) or closely related factors and by activation of specific receptors, prevailingly VEGFR1 and VEGFR2, set on the surface of endothelial cells. Monitoring the presence of these receptors in vivo is henceforth a way to predict therapy outcome. We have designed small peptides able to bind and possibly antagonize VEGF ligands by targeting VEGF receptors. Peptide systems have been designed to be small, cyclic and to host triplets of residues known to be essential for VEGF receptors recognition and we named them 'mini-factors'. They have been structurally characterized by CD, NMR and molecular dynamics (MD) simulations. Mini-factors do bind with different specificity and affinity VEGF receptors but none blocks receptor activity. Following derivatization with suitable tracers they have been employed as molecular probes for sensing receptors on cell surface without affecting their activity as is usually observed with other binders having neutralizing activity

New Potent 5-HT2A Receptor Ligands Containing a N'-Cyanopicolinamidine Nucleus: Synthesis and In Vitro Pharmacological Evaluation

N’-Cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors were evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to be critical for affinity to 5-HT1A receptors and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed affinity in nanomolar and subnanomolar range at 5-HT2A and moderate to no affinity for other relevant receptors (5-HT1A, 5-HT2C, D1, D2, 1 and 2). N'-Cyano-N-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)-picolinamidine (4l) with Ki = 0.000185 nM, was the most active and selective derivative for the 5-HT2A receptor compared to other serotoninergic, dopaminergic and adrenergic receptors

Synthesis of benzamide derivatives and their evaluation as antiprion agents

A new set of 5-(2-(pyrrolidin-1-yl)acetamido)-N-butyl-2-(substituted)benzamide and 5-(2-(piperidin-1-yl)acetamido)-N-butyl-2-(substituted) benzamide derivatives were synthesized in which as structural features the 2-(1-pyrrolidinyl)- or 2-(1-piperidyl)acetylamino group or a diphenylether moiety are associated to a benzamide scaffold. Their binding affinity for human PrPC and inhibition of its conversion into PrPSc were determined in vitro; moreover, the antiprion activity was assayed by inhibition of PrPSc accumulation in scrapie-infected mouse neuroblastoma cells (ScN2a) and scrapie mouse brain (SMB) cells. The results clearly indicate the benzamide derivatives as attractive lead compounds for the development of potential therapeutic agents against prion disease