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Di Marzo V.,CNR Institute of Biomolecular Chemistry | De Petrocellis L.,Institute of Cybernetics
Current Medicinal Chemistry | Year: 2010

In the late 1990's, a series of experiments carried out independently in two laboratories led to establish an important connection between the function of the endocannabinoids, which, as exemplified in this special issue, is per se very complex and ubiquitous in animals, and that of the transient receptor potential (TRP) channels, a large family of plasma membrane cation channels involved in several mammalian and non-mammalian physiological and pathological conditions, overlapping only in part with those in which the cannabinoid receptors participate. These experiments were initially based on the observation that the endocannabinoid anandamide and the xenobiotic ligand of TRP channels of V1 type (TRPV1), capsaicin, are somehow chemically similar, both compounds being fatty acid amides, as are also synthetic activators of these channels and inhibitors of anandamide cellular re-uptake. As discussed in this article, the same type of "chemical thoughts" led to the discovery of N-arachidonoyl-dopamine, an endogenous ligand of TRPV1 channels that behaves also an endocannabinoid. The overlap between the ligand recognition properties of some TRP channels and proteins of the endocannabinoid system, namely the cannabinoid receptors and the proteins and enzymes catalyzing anandamide cellular re-uptake and hydrolysis, is being actively explored through the rational design and synthesis of new endocan-nabinoid-based drugs with multiple mechanisms of action. These aspects are discussed in this review article, together with the possible functional and pharmacological consequences of endocannabinoid-TRP channel interactions. © 2010 Bentham Science Publishers Ltd.


Gladiali S.,University of Sassari | Alberico E.,CNR Institute of Biomolecular Chemistry | Junge K.,Leibniz Institute for Catalysis at the University of Rostock | Beller M.,Leibniz Institute for Catalysis at the University of Rostock
Chemical Society Reviews | Year: 2011

The atropisomeric structure of 4,5-dihydro-3H-dinaphtho[2,1-c;1′, 2′-e]phosphepine is the common axially chiral scaffold of a library of monophosphine ligands nicknamed BINEPINES that have shown a quite remarkable stereoselection efficiency in a broad variety of enantioselective reactions involving the formation of new C-H or C-C or C-X bonds. In this critical review the properties and scope of this type of chiral ligands are illustrated (70 references). © 2011 The Royal Society of Chemistry.


Di Marzo V.,CNR Institute of Biomolecular Chemistry | De Petrocellis L.,Olivetti
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2012

The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, Δ9-tetrahydrocannabinol, and includes two G-proteincoupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2-arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG have also been suggested to act as endocannabinoids. Thus, unlike most other GPCRs, cannabinoid receptors appear to have more than one endogenous agonist, and it has been often wondered what could be the physiological meaning of this peculiarity. In 1999, it was proposed that anandamide might also activate other targets, and in particular the transient receptor potential of vanilloid type-1 (TRPV1) channels. Over the last decade, this interaction has been shown to occur both in peripheral tissues and brain, during both physiological and pathological conditions. TRPV1 channels can be activated also by another less abundant endocannabinoid, N-arachidonoyldopamine, but not by 2-AG, and have been proposed by some authors to act as ionotropic endocannabinoid receptors. This article will discuss the latest discoveries on this subject, and discuss, among others, how anandamide and 2-AG differential actions at TRPV1 and cannabinoid receptors contribute to making this signalling system a versatile tool available to organisms to fine-tune homeostasis. © 2012 The Royal Society.


Maione S.,The Second University of Naples | Costa B.,University of Milan Bicocca | Di Marzo V.,CNR Institute of Biomolecular Chemistry
Pain | Year: 2013

After 4 millennia of more or less documented history of cannabis use, the identification of cannabinoids, and of Δ9-tetrahydrocannabinol in particular, occurred only during the early 1960s, and the cloning of cannabinoid CB1 and CB2 receptors, as well as the discovery of endocannabinoids and their metabolic enzymes, in the 1990s. Despite this initial relatively slow progress of cannabinoid research, the turn of the century marked an incredible acceleration in discoveries on the "endocannabinoid signaling system," its role in physiological and pathological conditions, and pain in particular, its pharmacological targeting with selective agonists, antagonists, and inhibitors of metabolism, and its previously unsuspected complexity. The way researchers look at this system has thus rapidly evolved towards the idea of the "endocannabinoidome," that is, a complex system including also several endocannabinoid-like mediators and their often redundant metabolic enzymes and "promiscuous" molecular targets. These peculiar complications of endocannabinoid signaling have not discouraged efforts aiming at its pharmacological manipulation, which, nevertheless, now seems to require the development of multitarget drugs, or the re-visitation of naturally occurring compounds with more than one mechanism of action. In fact, these molecules, as compared to "magic bullets," seem to offer the advantage of modulating the "endocannabinoidome" in a safer and more therapeutically efficacious way. This approach has provided so far promising preclinical results potentially useful for the future efficacious and safe treatment of chronic pain and inflammation. © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


Casiraghi G.,University of Parma | Battistini L.,University of Parma | Curti C.,University of Parma | Rassu G.,CNR Institute of Biomolecular Chemistry | Zanardi F.,University of Parma
Chemical Reviews | Year: 2011

Methodology-oriented and target-oriented researches focused on the various aspects of the vinylogous aldol addition reaction and studies devoted to the related Mannich (VMnR) and Michael (VMcR) processes are summarized. Gademann et al. constructed stereoisomeric seven carbon long galantinic acid substructures during a biomimetic total synthesis of anachelin H, an iron chelator isolated from the cyanobacterium Anabaena cylindrica. Suenaga and co-workers have investigated the stereostructure of Palau'amide by total synthesis, utilizing a VMAR addition as the key step of the entire construction. Kobayashi and co-workers introduced a series of acyclic vinyl ketene silyl N,O-acetals as chiral d4 donor substrates in VMAR processes. Boeckman Jr. et al employed Corey chiral oxazaborolidine to fuel the asymmetric VMAR between silyloxy furan and chiral nonracemic aldehyde.


Trincone A.,CNR Institute of Biomolecular Chemistry
Journal of Molecular Catalysis B: Enzymatic | Year: 2010

This review is intended to give an account of the knowledge about known enzymes of marine origin described in literature thus stimulating future applications in biocatalysis that these biocatalysts can offer to a large spectra of end-users. The uniqueness of marine biocatalysts is not only based on habitat-related properties such as salt tolerance, hyperthermostability, barophilicity, cold adaptivity, etc. A marine enzyme in fact may carry more, e.g. novel chemical and stereochemical properties. This "chemical biodiversity" increases interest in this field; substrate specificity and affinity are evolved properties linked to the metabolic functions of the enzymes and to ecological asset related to the natural source and this is an important aspect in the bioprospecting for new biocatalysts. The importance of all examples reported should be sufficient to trigger the attention of the biocatalytically oriented scientific community towards marine environment as source of biocatalysts, and this could in turn enhance both new discovery and improvement of marine enzymes. © 2010 Elsevier B.V. All rights reserved.


Patti A.,CNR Institute of Biomolecular Chemistry | Pedotti S.,CNR Institute of Biomolecular Chemistry
European Journal of Organic Chemistry | Year: 2014

Ferrocenyl substituents were employed as lipophilic moieties and introduced into a prolinamide scaffold to afford new catalysts that were suitable for use in "on water" conditions. Five proline amides that contain a ferrocene unit were synthesized from easily accessible ferrocenylamines and evaluated as catalysts in the asymmetric direct aldol condensation of cyclohexanone with aldehydes in an aqueous medium. Optimal substrate conversion and stereoselectivity were achieved in brine and in the presence of benzoic acid as an additive. All the examined catalysts displayed good activity with a catalyst loading of 5 mol-%, and the best results in terms of enantioselectivity were obtained by using a ferrocenyl-prolineamide with an additional (S) chiral center. In the presence of this catalyst, a variety of aromatic aldehydes underwent a reaction in a reasonable amount time with just 2 equiv. of the cyclic ketone to give the expected aldol products in high yields (65-98 %) and with high stereoselectivities (up to 94 % ee, dr up to 93:7). Hydrophobic proline amides that have a ferrocene fragment incorporated into the molecule proved to be efficient catalysts for asymmetric aldol reactions of aromatic aldehydes and cyclic ketones. These reactions were carried out in brine and in the presence of benzoic acid as an additive. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Foti M.C.,CNR Institute of Biomolecular Chemistry
Journal of Agricultural and Food Chemistry | Year: 2015

The 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical is approaching 100 years from its discovery in 1922 by Goldschmidt and Renn. This radical is colored and remarkably stable, two properties that have made it one of the most popular radicals in a wide range of studies. First, there is the evaluation of the antioxidant abilities of phenols and other natural compounds (A-H) through a "test" that-at a closer look-is utterly inappropriate. In fact, the test-derived EC50, that is, the concentration of A-H able to scavenge 50% of the initial DPPH•, is not a kinetic parameter and hence its purported correlation with the antioxidant properties of chemicals is not justified. Kinetic measurements, such as the second-order rate constants for H-atom abstraction from A-H by DPPH•, in apolar media, are the only useful parameters to predict the antioxidant ability of A-H. Other applications of DPPH• include kinetic and mechanistic studies, kinetic solvent effects, EPR spectroscopy, polymer chemistry, and many more. In this review these applications are evaluated in detail by showing the usefulness of some and the uselessness of others. The chemistry of DPPH• is also briefly reviewed. © 2015 American Chemical Society.


Silvestri C.,CNR Institute of Biomolecular Chemistry | Di Marzo V.,CNR Institute of Biomolecular Chemistry
Expert Opinion on Investigational Drugs | Year: 2012

Introduction: Excessive abdominal obesity along with other risk factors results in the metabolic syndrome, which can lead to heart disease, Type-2 diabetes, and death. The endocannabinoid system (ECS) is composed of neutral lipids which signal through the G-protein coupled cannabinoid receptors CB1 and CB2. In abdominal obesity, the ECS is generally up-regulated in central and peripheral tissues and its blockade results in positive metabolic changes. Rimonabant (SR141716) was the first selective CB1 inverse agonist/antagonist marketed for the treatment of obesity; however, psychiatric side effects, which may result from its actions in the brain or its inverse agonism, resulted in its removal from the market. Recently, key metabolic-modulatory roles for the ECS within peripheral tissues have come to light. Thus there has been significant effort put forth by several laboratories to develop either neutral or peripherally restricted CB1 antagonists. Areas covered: In this review we shall provide an overview of the roles the ECS plays outside the brain in regulating metabolism, and highlight the latest advances in the development of neutral and/or peripherally restricted CB1 antagonists, and other state of the art strategies that minimize endocannabinoid overactivity. Expert opinion: The CB1 receptor is potentially a clinically relevant target for the design of therapies against metabolic syndrome, deserving the development and clinical testing of CB1-neutral antagonists which can pass the blood brain barrier or of peripherally restricted inverse agonists/neutral antagonists. Furthermore, reducing endocannabinoid biosynthesis could represent an alternative strategy to counteract peripheral endocannabinoid overactivity through dietary n-3 polyunsaturated fatty acids or the development of diacylglycerol lipase inhibitors. © 2012 Informa UK, Ltd.


Renzi P.,CNR Institute of Biomolecular Chemistry | Bella M.,CNR Institute of Biomolecular Chemistry
Chemical Communications | Year: 2012

Asymmetric organocatalysis is now an established methodology for the preparation of chiral compounds. However, these are not the only valuable molecules which can be conveniently obtained. Organocatalytic reactions affording achiral compounds are gaining momentum, opening unexplored pathways in the synthesis of densely functionalized aromatic moieties, olefins and useful molecules such as natural substances. © 2012 The Royal Society of Chemistry.

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