Current Medicinal Chemistry (v.23, #35)

Meet Our Editorial Board Member by Mariangela Biava (3965-3965).

Regulation of Platelet Function by Acetylation/Deacetylation Mechanisms by Ana Latorre, Antonio Moscardó (3966-3974).
Reversible acetylation of histones is a well-known mechanism of epigenetic regulation of gene expression. More recently, studies have demonstrated that acetylation/deacetylation in several proteins regulate multiple aspects of cellular activity, especially those associated with energetic metabolism. Platelets are key participants in haemostasis and cardiovascular diseases. Although metabolic changes such as diabetes or lipidemia are well recognized risk factors for cardiovascular diseases, there is very little information about the relationship between metabolism and platelet reactivity. Recent studies have reported that different aspects of platelet function such as adhesion, aggregation, or granule release could also be regulated by acetylation of proteins. These cycles of acetylation/deacetylation are regulated by the contrasting action of acetyltransferases and deacetylases, which have been described by the presence of p300 and HDAC6, and sirtuins, respectively, in platelets. Remarkably, deacetylases, especially sirtuins, have been the subjects of intensive pharmaceutical research due to their implication in several physiological and pathological processes in organisms. The discovery of acetylation mechanisms in platelets opens new possibilities for the treatment and prevention of cardiovascular diseases through the regulation of acetylases/deacetylases in platelets. Therefore, the aim of this review is to present some recent reports concerning the role of acetylation of proteins in the control of platelet function, and the new possibilities of regulation of platelet function that this represent.

Myeloperoxidase as a Target for the Treatment of Inflammatory Syndromes: Mechanisms and Structure Activity Relationships of Inhibitors by Jalal Soubhye, Iyas Aldib, Cédric Delporte, Martine Prévost, François Dufrasne, Pierre Van Antwerpen (3975-4008).
Inflammation is an initial response of the body to a harmful stimuli and it is achieved by the increased movement of leukocytes (especially granulocytes) from blood into injured tissues. It is required for healing wounds and infections. Despite their indispensable role in microbial killing, the inflammation reactions may also cause diseases to a host such as hay fever, atherosclerosis, and rheumatoid arthritis. The enzymes and oxidizing species released during the inflammatory process can cause damages to the host tissues which lead to inflammatory syndromes. The role of myeloperoxidase (MPO) in the inflammatory reactions is well documented. It contributes in killing the pathogens but it is also implicated in several inflammatory syndromes such as Parkinson's disease, Alzheimer's disease and atherosclerosis. Thus, this enzyme has attracted more attention of the scientists and it has become a target for drug designing. In the last decade, several reversible and irreversible MPO inhibitors were identified as very high potent inhibitors such as fluoroalkylindole, aromatic hydroxamic acid, thioxanthine and benzoic acid hydrazide derivatives. In this review, we tried to illustrate the MPO inhibitors and highlight their structure activity relationship (SAR). In this paper we also discussed the mechanism of the inhibitory effect of the most potent compounds.

Iron Acquisition Pathways as Targets for Antitubercular Drugs by Fiorella Meneghetti, Stefania Villa, Arianna Gelain, Daniela Barlocco, Laurent Roberto Chiarelli, Maria Rosalia Pasca, Luca Costantino (4009-4026).
Tuberculosis nowadays ranks as the second leading cause of death from an infectious disease worldwide. In the last twenty years, this disease has again started to spread mainly for the appearance of multi-drug resistant forms. Therefore, new targets are needed to address the growing emergence of bacterial resistance and for antitubercular drug development. Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis, because it serves as cofactor in many essential biological processes, including DNA biosynthesis and cellular respiration. Bacteria acquire iron chelating non-heme iron from the host using the siderophore mycobactins and carboxymycobactins and by the uptake of heme iron released by damaged red blood cells, through several acquisition systems. Drug discovery focused its efforts on the inhibition of MbtI and MbtA, which are are two enzymes involved in the mycobactin biosynthetic pathway. In particular, MbtI inhibitors have been studied in vitro, while MbtA inhibitors showed activity also in infected mice. Another class of compounds, MmpL3 inhibitors, showed antitubercular activity in vitro and in vivo, but their mechanism of action seems to be off-target. Some compounds inhibiting 4'-phosphopantetheinyl transferase were discovered but not tested on in vivo assays. The available data reported in this study based on inhibitors and gene deletion studies, suggest that targeting iron acquisition systems could be considered a promising antitubercular strategy. Due to their redundancy, the relative importance of each pathway for Mycobacterium tuberculosis survival has still to be determined. Thus, in vivo studies with new, potent and specific inhibitors are needed to highlight target selection.

Xanthine Oxidoreductase in Drug Metabolism: Beyond a Role as a Detoxifying Enzyme by Maria Giulia Battelli, Letizia Polito, Massimo Bortolotti, Andrea Bolognesi (4027-4036).
The enzyme xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism in the highest uricotelic primates. XOR is an enzyme with dehydrogenase activity that, in mammals, may be converted into oxidase activity under a variety of pathophysiologic conditions. XOR activity is highly regulated at the transcriptional and post-translational levels and may generate reactive oxygen and nitrogen species, which trigger different consequences, ranging from cytotoxicity to inflammation. The low specificity for substrates allows XOR to metabolize a number of endogenous metabolites and a variety of exogenous compounds, including drugs.
The present review focuses on the role of XOR as a drug-metabolizing enzyme, specifically for drugs with anticancer, antimicrobial, antiviral, immunosuppressive or vasodilator activities, as well as drugs acting on metabolism or inducing XOR expression.
XOR has an activating role that is essential to the pharmacological action of quinone drugs, cyadox, antiviral nucleoside analogues, allopurinol, nitrate and nitrite. XOR activity has a degradation function toward thiopurine nucleotides, pyrazinoic acid, methylxanthines and tolbutamide, whose half-life may be prolonged by the use of XOR inhibitors.
In conclusion, to avoid potential drug interaction risks, such as a toxic excess of drug bioavailability or a loss of drug efficacy, caution is suggested in the use of XOR inhibitors, as in the case of hyperuricemic patients affected by gout or tumor lysis syndrome, when it is necessary to simultaneously administer therapeutic substances that are activated or degraded by the drug-metabolizing activity of XOR.

Synthesis and Bioactivity of (R)-Ricinoleic Acid Derivatives: A Review by Sylwia Pabi|, Józef Kula (4037-4056).
(R)-Ricinoleic acid (RA) [(12R,9Z)-hydroxyoctadecenoic acid], the main compound of castor seed oil, because of its unusual structure readily undergoes multi-directional chemical and biochemical transformations to produce derivatives with the retained carbon skeleton or with its degradation. Many of these are of high biological activity, as documented by an in vitro study, and possess therapeutic potential. This review article provides an overview of the recent developments in the area of synthesis of RA based compounds with anticancer and antimicrobial activities. Moreover, the antiinflammatory and analgesic properties of some ricinoleic acid derivatives are also highlighted.

Engineered Zinc Oxide Nanoparticles; Biological Interactions at the Organ Level by Sudhakaran Sruthi, Parayanthala Valappil Mohanan (4057-4068).
Zinc oxide nanoparticles (ZnO NPs) are one of the widely used nanoparticles with spectrum of application, in the areas like daily care products, sensors, antibacterial agents, and biomedical sector. With extensive application the risk of exposure at occupational and consumer level also increases. Huge amount of data are available on the biointeraction of ZnO NPs. Though the toxicity of ZnO NPs is attributed to particle dissolution inside the cellular compartments and their ability to generate the reactive oxygen species, the ambiguity prevails over the exact mechanism of toxicity. The in vivo studies on different animal models and humans suggest different level of toxicity in these organisms. However the synthetic route, physiochemical properties of the nanoparticle, mode of exposure and nature of the test system often influences these studies. Hence the study results vary and sometimes contradict on one another. The current review focuses on the interaction of ZnO NPs with different organ systems. It also points to the factors to be considered while undertaking such studies in order to ensure reliability of the results.