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A series of novel 1,3,4-oxadiazoles was synthesized and evaluated for their cytotoxic activity in in vitro tumor models. Four of the new compounds (2d, 2j, 2k, and 2n) showed growth inhibition in the XTT dye assay. The most active agent, 2j, showed high potency against human cancer cells with IC50s ranging from 0.05 to 1.7 μM. Preliminary SAR correlations suggested that the nature of chains on the oxadiazole is important for antitumor potency in vitro. Compound 2j determined a G2/M arrest of the cell cycle and also activated a strong apoptotic response. The β-tubulin immunofluorescence analysis indicated that compound 2j effectively inhibited the microtubule organization in all cancer cell lines, causing the formation of abnormal spindle, which did not affect the normal human fibroblast cells NB1, Mrc-5 and IBR3. For all these reasons, compound 2j could be a good candidate in chemopreventive or chemotherapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: In a previous report, we described the in vitro and in vivo antiproliferative and proapoptotic activity of a hydroxylated biphenyl (D6), a structural analogue of curcumin, on malignant melanoma and neuroblastoma tumours. In this paper, we investigated the molecular changes induced by such a compound, underlying cell growth arrest and apoptosis in melanoma cells. Results: To shed light on the mechanisms of action of D6, we firstly demonstrated its quick cellular uptake and subsequent block of cell cycle in G2/M phase transition. A gene expression profile analysis of D6-treated melanoma cells and fibroblasts was then carried out on high density microarrays, to assess gene expression changes induced by this compound. The expression profile study evidenced both an induction of stress response pathways and a modulation of cell growth regulation mechanisms. In particular, our data suggest that the antiproliferative and proapoptotic activities of D6 in melanoma could be partially driven by up-regulation of the p53 signalling pathways as well as by down-regulation of the PI3K/Akt and NF-kB pathways. Modulation of gene expression due to D6 treatment was verified by western blot analysis for single proteins of interest, confirming the results from the gene expression profile analysis. Conclusions: Our findings contribute to the understanding of the mechanisms of action of D6, through a comprehensive description of the molecular changes induced by this compound at the gene expression level, in agreement with the previously reported anti-tumour effects on melanoma cells. [ABSTRACT FROM AUTHOR]

Biomedical applications of molecules that are able to modulate β-adrenergic signaling have become increasingly attractive over the last decade, revealing that β-adrenergic receptors (β-ARs) are key targets for a plethora of therapeutic interventions, including cancer. Despite successes in β-AR drug discovery, identification of β-AR ligands that are useful as selective chemical tools in pharmacological studies of the three β-AR subtypes, or lead compounds for drug development is still a highly challenging task. This is mainly due to the intrinsic plasticity of β-ARs as G protein-coupled receptors in conjunction with the requirement for functional receptor subtype selectivity, tissue specificity and minimal off-target effects. With the aim to provide insight into structure-activity relationships for the three β-AR subtypes, we have synthesized and obtained the pharmacological profile of a series of structurally diverse compounds (named MC) that were designed based on the aryloxy-propanolamine scaffold of SR59230A. Comparative analysis of their predicted binding mode within the active and inactive states of the receptors in combination with their pharmacological profile revealed key structural elements that control their activity as agonists or antagonists, in addition to clues about substituents that mediate selectivity for one receptor subtype over the others. We anticipate that these results will facilitate selective β-AR drug development efforts. [Display omitted] • A series of new β-adrenoreceptor (β-AR) ligands, MC1 - 34 , were synthesized based on the aryloxy propanolamine scaffold. • Their pharmacological profile was evaluated as agonist responses and antagonist affinity for the three β-AR subtypes. • Structure-activity relationships were extracted from docking calculations using the active and inactive states of the β-ARs. • Among the new compounds, MC28 is the most selective β3-AR blocker, and MC30 – 33 are β2-AR selective antagonists. • The known antagonist SR59230A is clearly not a β3-AR selective ligand, while it exhibits β1-/β2-/β3-AR partial agonism. [ABSTRACT FROM AUTHOR]