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The renin-angiotensin-aldosteron system (RAAS) is a hormonal system that contributes to regulation of blood pressure and volume of extracellular fluids, in both normotensive and hypertensive individuals. Hypertension affects the target organs (kidneys) and leads to a vicious circle that contributes to maintaining a high arterial pressure. Besides the hemodynamic effects of RAAS/Ang II, Ang II has direct impact on structure/function of kidneys, leading to renal injury. Recently, the proinflammatory effect of Ang II has been discovered. Low renal inflammation determined by excessive circulating RAAS, mostly at renal level, promotes and continues the renal disease. This review presents the inflammatory mechanisms initiated by Ang II at renal level, which induce development of renal injury. Identification of such mechanisms might lead to the discovery of new therapeutic approaches for hypertension/ target organs damage. [ABSTRACT FROM AUTHOR]

Alcohol has been considered a risk factor for over a century, but the pathogenesis and natural history of alcohol-related heart disease remains obscure. Numerous researches have demonstrated the beneficial effects of alcohol consumption as long as it is consumed in moderation. Advances have been made in our understanding of the effects of acute and chronic alcohol administration both at hemodynamic and cellular level, and recent studies have indicated that changes in heart dimensions and function are common in alcoholics. Depending on the amount consumed, alcohol increases blood pressure, which increases the risk of hypertension, cardiomyopathy, heart failure, myocardial infarction, arrhythmias etc. In terms of overall mortality, epidemiological investigations have shown that in case of young people, drinking any amount of alcohol increases the overall risk of death, the risk being greater as the amount of alcohol consumed increases. The success of the joint efforts of researchers, clinicians, psychologists and of all those whose activity is related to alcohology lies in the ability to convince the society of the importance of this health issue, and that the dependency syndrome that it creates attracts many biological, psychological, social problems. [ABSTRACT FROM AUTHOR]

The need to treat dyslipidemia in elderly patients in order to reduce coronary risk is the key of primary and secondary prevention. The atherosclerosis process is the same in the elderly as in adults, and the response to the treatment is also the same. In addition, two particularly important elements regarding this segment of the population are emphasized: the biological age becomes more important than the chronological age, and the quality of life remains equally very important. Our study aims to monitor the dyslipidaemic elderly (120 patients) for a period of 6 weeks and also to set the hygienic-dietary treatment (group I) or medication (group II), with the supervision of lipids levels. It was found that the maximum number of dyslipidaemic patients (75%) are aged between 65-80 years old, with a significantly higher percentage of men (72.5%), weighing between 85-100 kg (71.66%). Risk factors taken into account were: smoking present in 33.33%, coffee consumption (43.33%), alcohol (8.33%), but the most important one was physical inactivity (62.5%). In group I, the hygienic-dietary therapy did not change significantly the triglycerides levels in any determination; however the total cholesterol decreased significantly after 3 weeks, but remained constant after 3 weeks. In group II, the drug treatment determined the significant decrease of cholesterol and triglycerides level in both determinations. Therefore, treatment with HMG-CoA reductase inhibitors in combination with cholesterol-lowering diet effectively controls the dyslipidemia of elderly patients. The attempts to correct the lipid profile by diet proved unsuccessful, possibly due to the decrease of patients' compliance as the period of time from the start of the diet increases. [ABSTRACT FROM AUTHOR]

The multifactorial nature of chemotherapy failure incontrollingcancer is often associated with the occurrence of multidrug resistance(MDR), a phenomenon likely related to the increased expression ofmembers of the ATP binding cassette (ABC) transporter superfamily.In this respect, the most extensively characterized MDR transportersinclude ABCB1 (also known as MDR1 or P-glycoprotein) and ABCC1 (alsoknown as MRP1) whose inhibition remains a priority to circumvent drugresistance. Herein, we report how the simple galloyl benzamide scaffoldcan be easily and properly decorated for the preparation of eitherMRP1 or P-gp highly selective inhibitors. In particular, some gallamidesand pyrogallol-1-monomethyl ethers showed remarkable affinityand selectivity toward MRP1. On the otherhand,trimethyl ether galloyl anilides, with few exceptions, exhibited moderateto very high and selective P-gp inhibition. [ABSTRACT FROM AUTHOR]

The design, synthesis, and biological evaluation of a series of new aromatase (AR, CYP19) inhibitors bearing an imidazole ring linked to a 7-substituted coumarin scaffold at position 4 (or 3) are reported. Many compounds exhibited an aromatase inhibitory potency in the nanomolar range along with a high selectivity over 17-α-hydroxylase/C17−20 lyase (CYP17). The most potent AR inhibitor was the 7-(3,4-difluorophenoxy)-4-imidazolylmethyl coumarin 24endowed with an IC50= 47 nM. Docking simulations on a selected number of coumarin derivatives allowed the identification of the most important interactions driving the binding and clearly indicated the allowed and disallowed regions for appropriate structural modifications of coumarins and closely related heterocyclic molecular scaffolds. [ABSTRACT FROM AUTHOR]

Abstract: A number of 1,3-dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines were prepared and evaluated as ligands of recombinant human adenosine receptors (hARs). Several 1,3-dipropyl derivatives endowed with nanomolar binding affinity at hA2B receptors, but poor selectivity over hA2A, hA1 and hA3 AR subtypes were identified. A comparison with the corresponding 7-OH- and 7,9-unsubstituted-deazaxanthines revealed that 9-OH-9-deazaxanthines are more potent hA2B ligands with lower partition coefficients and higher water solubility compared to the other two congeneric classes of deazaxanthines. An optimization of the para-substituent of the 8-phenyl ring of 9-OH-9-deazaxanthines led to the discovery of compound 38, which exhibited outstanding hA2B affinity (Ki=1.0 nM), good selectivity over hA2A, hA1 and hA3 (selectivity indices=100, 79 and 1290, respectively) and excellent antagonist potency in a functional assay on rat A2B (pA2B =9.33). [Copyright &y& Elsevier]

Abstract: A series of N-terminus benzamides of glycine-based symmetric peptides, linked to m-xylylenediamine and 3,4′-oxydianiline spacers, were prepared and tested as inhibitors of β-amyloid peptide Aβ1–40 aggregation in vitro. Compounds with good anti-aggregating activity were detected. Polyphenolic amides showed the highest anti-aggregating activity, with IC50 values in the micromolar range. Structure–activity relationships suggested that π–π stacking and hydrogen-bonding interactions play a key role in the inhibition of Aβ1–40 self-assembly leading to amyloid fibrils. [Copyright &y& Elsevier]

Abstract: A large series of piperazin-, piperidin- and tetrahydroisoquinolinamides of 4-(1,3-dialkyl-9-deazaxanthin-8-yl)phenoxyacetic acid were prepared through conventional or multiple parallel syntheses and evaluated for their binding affinity at the recombinant human adenosine receptors, chiefly at the hA2B and hA2A receptor subtypes. Several ligands endowed with high binding affinity at hA2B receptors, excellent selectivity over hA2A and hA3 and a significant, but lower, selectivity over hA1 were identified. Among them, piperazinamide derivatives 23 and 52, and piperidinamide derivative 69 proved highly potent at hA2B (K i =11, 2 and 5.5nM, respectively) and selective towards hA2A (hA2A/hA2B SI=912, 159 and 630, respectively), hA3 (hA3/hA2B SI=>100, 3090 and >180, respectively) and hA1 (hA1/hA2B SI=>100, 44 and 120, respectively), SI being the selectivity index. A number of selected ligands tested in functional assays in vitro showed very interesting antagonist activities and efficacies at both A2A and A2B receptor subtypes, with pA2 values close to the corresponding pK is. Structure–affinity and structure–selectivity relationships suggested that the binding potency at the hA2B receptor may be increased by lipophilic substituents at the N4-position of piperazinamides and that an ortho-methoxy substituent at the 8-phenyl ring and alkyl groups at N1 larger than the ones at N3, in the 9-deazaxanthine ring, may strongly enhance the hA2A/hA2B SI. [Copyright &y& Elsevier]

Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels–Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side chains and subsequently converted to their hydrochlorides. The structures of the obtained compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was evaluated in human leukemia (K562, MOLT4), cervical cancer (HeLa), and normal endothelial cells (HUVEC). The majority of derivatives exhibited high to moderate cytotoxicity and induced apoptosis in K562 cells. Microarray gene profiling demonstrated upregulation of proapoptotic genes involved in receptor-mediated and mitochondrial cell death pathways as well as antiapoptotic genes involved in NF-kB signaling. Selected dicarboximides activated JNK and p38 kinases in leukemia cells, suggesting that MAPKs may be involved in the regulation of apoptosis. The tested dicarboximides bind to DNA as assessed by a plasmid DNA cleavage protection assay. The selected dicarboximides offer new scaffolds for further development as anticancer drugs. [ABSTRACT FROM AUTHOR]

Polyamidoamine PAMAM dendrimer generation 3 (G3) was modified by attachment of biotin via amide bond and glucoheptoamidated by addition of α-D-glucoheptono-1,4-lacton to obtain a series of conjugates with a variable number of biotin residues. The composition of conjugates was determined by detailed 1-D and 2-D NMR spectroscopy to reveal the number of biotin residues, which were 1, 2, 4, 6, or 8, while the number of glucoheptoamide residues substituted most of the remaining primary amine groups of PAMAM G3. The conjugates were then used as host molecules to encapsulate the 5-aminolevulinic acid. The solubility of 5-aminolevulinic acid increased twice in the presence of the 5-mM guest in water. The interaction between host and guest was accompanied by deprotonation of the carboxylic group of 5-aminolevulinic acid and proton transfer into internal ternary nitrogen atoms of the guest as evidenced by a characteristic chemical shift of resonances in the 1H NMR spectrum of associates. The guest molecules were most likely encapsulated inside inner shell voids of the host. The number of guest molecules depended on the number of biotin residues of the host, which was 15 for non-biotin-containing glucoheptoamidated G3 down to 6 for glucoheptoamidated G3 with 8 biotin residues on the host surface. The encapsulates were not cytotoxic against Caco-2 cells up to 200-µM concentration in the dark. All encapsulates were able to deliver 5-aminolevulinic acid to cells but aqueous encapsulates were more active in this regard. Simultaneously, the reactive oxygen species were detected by staining with H2DCFDA in Caco-2 cells incubated with encapsulates. The amount of PpIX was sufficient for induction of reactive oxygen species upon 30-s illumination with a 655-nm laser beam. [ABSTRACT FROM AUTHOR]

Elastin-like polypeptides (ELPs) undergo a characteristic phase transition in response to ambient temperature. Therefore, it has been be used as a thermosensitive vector for the delivery of chemotherapy agents since it can be used to target hyperthermic tumors. This novel strategy introduces unprecedented options for treating cancer with fewer concerns about side effects. In this study, the ELP system was further modified with an enzyme-cleavable linker in order to release drugs within tumors. This system consists of an ELP, a matrix metalloproteinase (MMP) substrate, a cell-penetrating peptide (CPP), and a 6-maleimidocaproyl amide derivative of doxorubicin (Dox). This strategy shows up to a 4-fold increase in cell penetration and results in more death in breast cancer cells compared to ELP-Dox. Even in doxorubicin-resistant cells (NCI/ADR and MES-SA/Dx5), ELP-released cell-penetrating doxorubicin demonstrated better membrane penetration, leading to at least twice the killing of resistant cells compared to ELP-Dox and free Dox. MMP-digested CPP-Dox showed better membrane penetration and induced more cancer cell death in vitro. This CPP-complexed Dox released from the ELP killed even Dox-resistant cells more efficiently than both free doxorubicin and non-cleaved ELP-CPP-Dox. [ABSTRACT FROM AUTHOR]

• hERG primary anti-target responsible for serious side-effects. • hERG structure–activity relationships, data and models. • hERG channels structure and pathophysiology. • Testing screening methods and CIPA guidelines. • hERG target with a role in cancer. hERG is best known as a primary anti-target, the inhibition of which is responsible for serious side effects. A renewed interest in hERG as a desired target, especially in oncology, was sparked because of its role in cellular proliferation and apoptosis. In this study, we survey the most recent advances regarding hERG by focusing on SAR in the attempt to elucidate, at a molecular level, off-target and on-target actions of potential hERG binders, which are highly promiscuous and largely varying in structure. Understanding the rationale behind hERG interactions and the molecular determinants of hERG activity is a real challenge and comprehension of this is of the utmost importance to prioritize compounds in early stages of drug discovery and to minimize cardiotoxicity attrition in preclinical and clinical studies. We report how the understanding of SAR and the informed use of reliable data and models are pivotal to modulate the interplay with hERG channels. [ABSTRACT FROM AUTHOR]

Cannabinoid type 2 receptor (CB2R) is a G-protein-coupled receptor that, together with Cannabinoid type 1 receptor (CB1R), endogenous cannabinoids and enzymes responsible for their synthesis and degradation, forms the EndoCannabinoid System (ECS). In the last decade, several studies have shown that CB2R is overexpressed in activated central nervous system (CNS) microglia cells, in disorders based on an inflammatory state, such as neurodegenerative diseases, neuropathic pain, and cancer. For this reason, the anti-inflammatory and immune-modulatory potentials of CB2R ligands are emerging as a novel therapeutic approach. The design of selective ligands is however hampered by the high sequence homology of transmembrane domains of CB1R and CB2R. Based on a recent three-arm pharmacophore hypothesis and latest CB2R crystal structures, we designed, synthesized, and evaluated a series of new N -adamantyl-anthranil amide derivatives as CB2R selective ligands. Interestingly, this new class of compounds displayed a high affinity for human CB2R along with an excellent selectivity respect to CB1R. In this respect, compounds exhibiting the best pharmacodynamic profile in terms of CB2R affinity were also evaluated for the functional behavior and molecular docking simulations provided a sound rationale by highlighting the relevance of the arm 1 substitution to prompt CB2R action. Moreover, the modulation of the pro- and anti-inflammatory cytokines production was also investigated to exert the ability of the best compounds to modulate the inflammatory cascade. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: The effects on the inhibition potencies of monoamine oxidase isoforms A (MAO-A) and B (MAO-B) depending upon changes in the physicochemical properties (size, shape, H-bonding, lipophilicity, etc.) of substituents at the C4 position of 2H-chromen-2-one derivatives were extensively investigated, and the results significantly added to our knowledge on this class of MAO inhibitors. All the 67 examined compounds showed high MAO-B selectivity, some of them achieving potency in the low nanomolar range. In particular, the 7-metachlorobenzyloxy-4-oxyacetamido-2H-chromen-2-one (entry 62) showed single digit nanomolar MAO-B potency (IC50 = 3.1 nM) and high selectivity over the MAO-A isoform (selectivity ratio = 7244). The great variety of the investigated substituents at C4 of the 2H-chromen-2-one nucleus, combined with binding models generated from docking studies carried out on selected compounds, allowed us to shed light on the main molecular requirements for potent and selective MAO-B inhibition, highlighting the dominant role of the steric effects. Interestingly, many of the designed substituents could be metabolically related to each other (e.g., CH3/CH2OH/CHO/COOH; NH2/NHCH3, NHAc), and therefore the results obtained may help in predicting the in vivo activity of some putative metabolites of lead MAO-B inhibitors. [Copyright &y& Elsevier]

Abstract: Acetylcholinesterase inhibitors (AChEIs) are currently the drugs of choice, although only symptomatic and palliative, for the treatment of Alzheimer’s disease (AD). Donepezil is one of most used AChEIs in AD therapy, acting as a dual binding site, reversible inhibitor of AChE with high selectivity over butyrylcholinesterase (BChE). Through a combined target- and ligand-based approach, a series of coumarin alkylamines matching the structural determinants of donepezil were designed and prepared. 6,7-Dimethoxycoumarin derivatives carrying a protonatable benzylamino group, linked to position 3 by suitable linkers, exhibited fairly good AChE inhibitory activity and a high selectivity over BChE. The inhibitory potency was strongly influenced by the length and shape of the spacer and by the methoxy substituents on the coumarin scaffold. The inhibition mechanism, assessed for the most active compound 13 (IC50 7.6nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE. [Copyright &y& Elsevier]

Abstract: Matrix metalloproteinases (MMPs) are attractive biological targets that play a key role in many physiopathological processes such as degradation of extracellular matrix proteins, release and cleavage of cell-surface receptors, tumour progression, homeostatic regulation and innate immunity. A series of 5-hydroxy, 5-substituted pyrimidine-2,4,6-triones were rationally designed, prepared and tested as inhibitors of gelatinases MMP-2 and MMP-9 and collagenase MMP-8. On one side, the presence of the 5-hydroxyl group, that represents an typical feature of this class of compounds, ensured an attractive pharmacokinetic profile while on the other suitably substituted biaryl molecular fragments, attached to position 5 through a ketomethylene linker, guaranteed favourable interaction in the deep region of the S1′ enzymatic subsite. This rational design led to the discovery of highly potent MMP inhibitors. In particular, biphenyl derivatives bearing at the para position COCH3 and OCF3 substituents permitted to inhibit gelatinases MMP-2 and MMP-9, with IC50 values as low as 30 nM and 21 nM, respectively, whereas the introduction at the same position of the bulkier SO2CH3 group afforded a potent collagenase MMP-8 inhibitor with an IC50 value equal to 66 nM. Molecular docking simulations allowed us to elucidate key interactions driving the binding of the top active compounds towards their preferred MMP target. [Copyright &y& Elsevier]

Abstract: A number of 1,3-dialkyl-9-deazaxanthines (9-dAXs), bearing a variety of N-substituted benzyloxycarbonylamino substituents at position 8, were prepared and evaluated for their binding affinity to the recombinant human adenosine receptors (hARs), chiefly to the hA2B and hA2A AR subtypes. Several ligands endowed with excellent binding affinity to the hA2B receptors, but low selectivity versus hA2A and hA1 were identified. Among these, 1,3-dimethyl-N-3′-thienyl carbamate 15 resulted as the most potent ligand at hA2B (K i =0.8nM), with a low selectivity versus hA2A (hA2A/hA2B =12.6) and hA1 (hA1/hA2B =12.5) and a higher selectivity versus hA3 (hA3/hA2B =454). When tested in functional assays in vitro, compound 15 exhibited high antagonist activities and efficacies versus both the A2A and A2B receptor subtypes, with pA2 values close to the corresponding pK is. A comparative analysis of structure–affinity and structure–selectivity relationships of the similar analogues 8-N-substituted benzyloxycarbonylamino- and 8-N-substituted phenoxyacetamido-9-dAXs suggested that their binding modes at the hA2B and hA2A ARs may strongly differ. Computational studies help to clarify this striking difference arising from a simple, albeit crucial, structural change, from CH2OCON to OCH2CON, in the para-position of the 8-phenyl ring. [Copyright &y& Elsevier]

Abstract: A number of mono- and bis-quaternary ammonium salts, containing edrophonium-like and coumarin moieties tethered by an appropriate linker, proved to be highly potent and selective dual binding site acetylcholinesterase inhibitors with good selectivity over butyrylcholinesterase. Homobivalent bis-quaternary inhibitors 11 and 12, differing by only one methylene unit in the linker, were the most potent and selective inhibitors exhibiting a sub-nanomolar affinity (IC50 =0.49 and 0.17nM, respectively) and a high butyryl-/acetylcholinesterase affinity ratio (SI=1465 and 4165, respectively). The corresponding hetero-bivalent coumarinic inhibitors 13 and 14 were also endowed with excellent inhibitory potency but a lower AChE selectivity (IC50 =2.1 and 1.0nM, and SI=505 and 708, respectively). Docking simulations enabled clear interpretation of the structure–affinity relationships and detection of key binding interactions at the primary and peripheral AChE binding sites. [Copyright &y& Elsevier]