Adriano Guiotto

Angelicins, angular analogs of psoralens: Chemistry, photochemical, photobiological and phototherapeutic properties

Angelicin and some of its derivatives are naturally occuring compounds which show interesting photobiological properties. In this review various aspects of angelicin and its derivatives have been reported. The natural occurrence and the chemical synthesis both of naturally occurring and synthetic angelicins have been reviewed. Photochemical and photophysical properties of angelicins have been considered with particular reference to the capacity to generate active forms of oxygen, photoreactions with nucleic acids, proteins and unsaturated fatty acids. Photobiological effects have been considered: skin phototoxicity, antiproliferative effects, genotoxicity, ability to induce hemolysis in erythrocytes, inactivation of prokaryotic and eukaryotic microorganism and of viruses. The ability of some angelicins to induce photocarcinogenesis has been reviewed as well as in the activity as photochemotherapeutic agents.

Coumarin as attractive casein kinase 2 (CK2) inhibitor scaffold: an integrate approach to elucidate the putative binding motif and explain structure-activity relationships.

Casein kinase 2 (CK2) is an ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Recently, using different virtual screening approaches, we have identified several novel CK2 inhibitors. In particular, we have discovered that coumarin moiety can be considered an attractive CK2 inhibitor scaffold. In the present work, we have synthetized and tested a small library of coumarins (more than 60), rationalizing the observed structure-activity relationship. Moreover, the most promising inhibitor, 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC), has been also crystallized in complex with CK2, and the experimental binding mode has been used to derive a linear interaction energy (LIE) model.

Stearoylethanolamide exerts anorexic effects in mice via down-regulation of liver stearoyl-coenzyme A desaturase-1 mRNA expression

Given the recent demonstration that oleoylethanolamide (OEA), a cannabinoid receptor‐inactive N‐acylethanolamine, decreases food intake by activating the nuclear receptor PPARα (peroxisome proliferator‐activated receptor α) in the periphery, we here evaluated the effects of both saturated and unsaturated C18 N‐acylethanolamides (C18:0; C18:1; C18:2) in mice feeding behavior after overnight starvation. Our results show stearoylethanolamide (SEA, C18:0) exerts, unlike other unsaturated C18 homologs, a marked dose‐dependent anorexic effect evident already at 2 h after its intraperitoneal administration. In addition, oral administration of SEA (25 mg/kg) was also effective in reducing food consumption, an effect ascribed to the molecule itself and not to its catabolites. Moreover, although the anorexic response to oral administered SEA was not associated with changes in the levels of various hematochemical parameters (e.g., glucose, cholesterol, triglycerides, leptin) nor in liver mRNA expression of peroxisome proliferator‐activated receptors (PPARs) including PPARα, the anorexic effect of SEA was interestingly accompanied by a reduction in liver stearoyl‐CoA desaturase‐1 (SCD‐1) mRNA expression. As SCD‐1 has been recently proposed as a molecular target for the treatment of obesity, the novel observation provided here that SEA reduces food intake in mice in a structurally selective manner, in turn, correlated with downregulation of liver SCD‐1 mRNA expression, has the potential of providing new insights on a class of lipid mediators with suitable properties for the pharmacological treatment of over‐eating dysfunctions.

4,5‘‐DIMETHYLANGELICIN: A NEW DNA‐PHOTOBINDING MONOFUNCTIONAL AGENT*

Abstract— 4,5′‐Dimethylangelicin is a new angular furocoumarin showing interesting photochemical and photosensitizing properties. In the dark it forms a complex with native DNA having higher values of the binding parameters than angelicin; by irradiation at 365 nm it is able to photobind with DNA several times faster than angelicin and in about the same degree as psoralen, without forming crosslinkages. It therefore behaves as a pure monofunctional reagent. The same high photobinding capacity with DNA is shown also in vivo in Ehrlich ascites tumor cells and bacterial E. coli cells.

Using the TOPS-MODE approach to fit multi-target QSAR models for tyrosine kinases inhibitors.

Tyrosine kinases constitute an eligible class of target for novel drug discovery. They resulted often overexpressed and/or deregulated in several cancer diseases. Thus, the development of novel tyrosine kinases inhibitors is of value, as well as the finding of novel cheminformatic tools for their design. Among the different ways to rationally design novel compounds, the Quantitative Structure-Activity Relationship (QSAR) plays a key role. The QSAR approach, in fact, allow the prediction of activity against a number of targets (multi-target QSAR), thus leading to models able to predict not only the activity of a compound, but also its selectivity versus a set of targets. Despite it is well known that tyrosine kinase inhibitors have to show multi-kinases inhibitory potency to be useful in anticancer therapy, only few multi-target computational tools have been developed to help medicinal chemists in the design of novel compounds. Herein we present the development of several multi-target classification QSAR (mtc-QSAR) models useful to assess the activity profile of the tyrosine kinases inhibitors.

Exploring Epidermal Growth Factor Receptor (EGFR) Inhibitor Features: The Role of Fused Dioxygenated Rings on the Quinazoline Scaffold

A number of dioxolane, dioxane, and dioxepine quinazoline derivatives have been synthetized and evaluated as EGFR inhibitors. Their cytotoxic activity has been tested against two cell lines overexpressing and not expressing EGFR. Most derivatives were able to counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound PD153035. The size of the fused dioxygenated ring was crucial for the biological activity, the dioxane derivatives being the most promising class of this series.

Quinazoline derivatives as potential anticancer agents: a patent review (2007 - 2010).

Introduction : Due to the increase in knowledge about cancer pathways, there is a growing interest in finding novel potential drugs. Quinazoline is one of the most widespread scaffolds amongst bioactive compounds. A number of patents and papers appear in the literature regarding the discovery and development of novel promising quinazoline compounds for cancer chemotherapy. Although there is a progressive decrease in the number of patents filed, there is an increasing number of biochemical targets for quinazoline compounds. Areas covered : This paper provides a comprehensive review of the quinazolines patented in 2007 – 2010 as potential anticancer agents. Information from articles published in international peer-reviewed journals was also included, to give a more exhaustive overview. Expert opinion : From about 1995 to 2006, the anticancer quinazolines panorama has been dominated by the 4-anilinoquinazolines as tyrosine kinase inhibitors. The extensive researches conducted in this period could have caused the progressive reduction in the ability to file novel patents as shown in the 2007 – 2010 period. However, the growing knowledge of cancer-related pathways has recently highlighted some novel potential targets for therapy, with quinazolines receiving increasing attention. This is well demonstrated by the number of different targets of the patents considered in this review. The structural heterogeneity in the patented compounds makes it difficult to derive general pharmacophores and make comparisons among claimed compounds. On the other hand, the identification of multi-target compounds seems a reliable goal. Thus, it is reasonable that quinazoline compounds will be studied and developed for multi-target therapies.

Cannabidiol, unlike synthetic cannabinoids, triggers activation of RBL‐2H3 mast cells

Cannabidiol (CBD), a prominent psychoinactive component of cannabis with negligible affinity for known cannabinoid receptors, exerts numerous pharmacological actions, including anti‐inflammatory and immunosuppressive effects, the underlying mechanisms of which remain unclear. In the current study, we questioned whether CBD modulates activation of mast cells, key players in inflammation. By using the rat basophilic leukemia mast cell line (RBL‐2H3), we demonstrate that CBD (3–10 μM) augments β‐hexosaminidase release, a marker of cell activation, from antigen‐stimulated and unstimulated cells via a mechanism, which is not mediated by Gi/Go protein‐coupled receptors but rather is associated with a robust rise in intracellular calcium ([Ca2+]i) levels sensitive to clotrimazole and nitrendipine (10–30 μM). This action, although mimicked by Δ9‐tetrahydrocannabinol (THC), is opposite to that inhibitory, exerted by the synthetic cannabinoids WIN 55,212‐2 and CP 55,940. Moreover, the vanilloid capsaicin, a full agonist of transient receptor potential channel VR1, did not affect [Ca2+]ilevels in the RBL‐2H3 cells, thus excluding the involvement of this receptor in the CBD‐mediated effects. Together, these results support existence of yet‐to‐be identified sites of interaction, i.e., receptors and/or ion channels associated with Ca2+ influx of natural cannabinoids such as CBD and THC, the identification of which has the potential to provide for novel strategies and agents of therapeutic interest.

6-Methylangelicins: new monofunctional photochemotherapeutic agents for psoriasis

The monofunctional furocoumarins, the 6‐methylangelicins, were tested for their antiproliferative activity with various animal models and for genotoxicity in micro‐organisms and in mammalian cells. The most active compound was 6,4,4′‐trimethylangelicin, which showed a high antiproliferative effect and reduced genotoxicity in comparison with 8‐methoxypsoralen (8‐MOP). Some of these compounds were also tested clinically by topical application on 17 patients with psoriasis. They appeared to be more active than 8‐MOP in clearing psoriasis without inducing skin phototoxicity. The methylangelicins also caused skin pigmentation.

Microwave-promoted mono-N-alkylation of aromatic amines in water: a new efficient and green method for an old and problematic reaction

A greener improvement to direct mono-N-alkylation of aromatic amines by alkyl halides was achieved using microwave irradiation in water without any catalyst.