Effects of saffron and its constituents, crocin-1, crocin-2, and crocetin on α-synuclein fibrils

Journal of Natural Medicines - Saffron, the stigma of Crocus sativus Linné (Iridaceae family), has been known to inhibit aggregation of β-amyloid, a nerve tissue protein. α-Synuclein...     

Antifungal Spectrum,In Vivo Efficacy,and Structure–Activity Relationship of Ilicicolin H

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β-Keto esters from ketones and ethyl chloroformate: a rapid,general, efficient synthesis of pyrazolones and their antimicrobial, <Emphasis Type="Italic">in silico</Emphasis> and <Emphasis Type="Italic">in vitro</Emphasis> cytotoxicity studies

Background

Pyrazolones are traditionally synthesized by the reaction of β-keto esters with hydrazine and its derivatives. There are methods to synthesize β-keto esters from esters and aldehydes, but these methods have main limitation in varying the substituents. Often, there are a number of methods such as acylation of enolates in which a chelating effect has been employed to lock the enolate anion using lithium and magnesium salts; however, these methods suffer from inconsistent yields in the case of aliphatic acylation. There are methods to synthesize β-keto esters from ketones like caboxylation of ketone enolates using carbon dioxide and carbon monoxide sources in the presence of palladium or transition metal catalysts. Currently, the most general and simple method to synthesize β-keto ester is the reaction of dimethyl or ethyl carbonate with ketone in the presence of strong bases which also requires long reaction time, use of excessive amount of reagent and inconsistent yield. These factors lead us to develop a simple method to synthesize β-keto esters by changing the base and reagent.

Results

A series of β-keto esters were synthesized from ketones and ethyl chloroformate in the presence of base which in turn are converted to pyrazolones and then subjected to cytotoxicity studies towards various cancer cell lines and antimicrobial activity studies towards various bacterial and fungal strains.

Conclusion

The β-keto esters from ethyl chloroformate was successfully attempted, and the developed method is simple, fast and applicable to the ketones having the alkyl halogens, protecting groups like Boc and Cbz that were tolerated and proved to be useful in the synthesis of fused bicyclic and tricyclic pyrazolones efficiently using cyclic ketones. Since this method is successful for different ketones, it can be useful for the synthesis of pharmaceutically important pyrazolones also. The synthesized pyrazolones were subjected to antimicrobial, docking and cytotoxicity assay against ACHN (human renal cell carcinoma), Panc-1 (human pancreatic adenocarcinoma) and HCT-116 (human colon cancer) cell line, and lead molecules have been identified. Some of the compounds are found to have promising activity against different bacterial and fungal strains tested.

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Design,Synthesis, and Pharmacological Evaluation of Fluorescent and Biotinylated Antagonists of ρ1 GABAC Receptors

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A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of β-Secretase

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Modulation of tnf-α-induced icam-1 expression,no and h<Subscript>2</Subscript>0<Subscript>2</Subscript> production by alginate,allicin and ascorbic acid in human endothelial cells

Plant nutrients are believed to provide protection against various diseases including inflammation. Since interactions of the cell adhesion molecules are known to play important roles in mediating inflammation, inhibiting adhesion protein upregulation is a possible therapeutic target. In this study, the interacellular adhesion molecule-1 (ICAM-1) was induced in human umbilical endothelial cells (HUVECs) after stimulation with TNF-alpha. In addition, alginate, ascorbic acid and allicin were demonstrated to inhibit the TNF-alpha induced expression of ICAM-1 on the HUVECs in a dose-dependent manner. These compounds also inhibited the production of NO and H2O2 induced by TNF-alpha, which suggests that the inhibition of ICAM-1 expression by the three compounds may be due to the modulated production of the reactive oxygen/nitrogen components. Overall, these results indicate that these dietary components have a therapeutic potential in the treatment of various inflammatory disorders associated with an increase in endothelial leukocyte adhesion molecules.     

Synthesis,structural characterization and biological evaluation of 4′-<Emphasis Type="Italic">C</Emphasis>-methyl- and phenyl-dioxolane pyrimidine and purine nucleosides

Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and biological activity of some 4′-C -methyl- and -phenyl dioxolane-based nucleosides. In particular, α and β anomers of all natural nucleosides were obtained and characterized by NMR, HR-MS and X-ray crystallography. The compounds were tested for antimicrobial activity against some representative human pathogenic fungi, bacteria and viruses. Antitumor activity was evaluated in a large variety of human cancer cell-lines. Although most of the compounds showed non-significant activity, 23α weakly inhibited HIV-1 multiplication. Moreover, 22α and 32α demonstrated a residual antineoplastic activity, interestingly linked to the unnatural α configuration. These results may provide structural insights for the design of active antiviral and antitumor agents.     

PDE inhibitors in psychiatry – future options for dementia,depression and schizophrenia?

Phosphodiesterases are key enzymes in cellular signalling pathways. They degrade cyclic nucleotides and their inhibition via specific inhibitors offers unique 'receptor-independent' opportunities to modify cellular function. An increasing number of in vitro and animal model studies point to innovative treatment options in neurology and psychiatry. This review critiques a selection of recent studies and developments with a focus on dementia/neuroprotection, depression and schizophrenia. Despite increased interest among the clinical neurosciences, there are still no approved PDE inhibitors for clinical use in neurology or psychiatry. Adverse effects are a major impediment for clinical approval. It is therefore necessary to search for more specific inhibitors at the level of different PDE sub-families and isoforms.     

Protolytic constants of nizatidine,ranitidine and N,N′-dimethyl-2-nitro-1,1-ethenediamine; spectrophotometric and theoretical investigation

The prototropic exchange equilibria of two drugs, nizatidine (I) and ranitidine (II), and also of structurally related the N,N′-dimethyl-2-nitro-1,1-ethenediamine molecule (III) were investigated. From the changes in electronic spectra in media of various acidity several protonation constants were determined. For nizatidine pK values were −0.82, 1.95, and 6.67; for ranitidine pK values were 1.95 and 8.13; and for III was 2.60. The hydroxylation equilibrium constant in strongly alkaline media was determined too. Corresponding pK_a values were 13.23 for I, 13.26 for II and 13.76 for III. Molecular orbital calculations of electronic spectra confirmed that pK 1.95 for I and II, and pK 2.60 for III, are associated with C-protonation of nitroethenediamine fragment, while all pK_a values correspond to the addition of HO⁻ anion at the same double bond.     

臭氧消毒水;创伤,急诊;愈合;抗感染

探讨臭氧消毒水对伤口愈合及抗感染的影响方法按臭氧消毒机操作法,制备出≥6mg·L     

Potentiating Metronidazole Scaffold against Resistant Trichomonas: Design,Synthesis, Biology and 3D–QSAR Analysis

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Synthesis,Antiplasmodial Activity,and β-Hematin Inhibition of Hydroxypyridone–Chloroquine Hybrids

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Design,Synthesis, and Pharmacological Evaluation of Fused β-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors

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Low-affinity interactions of BODIPY-FL-GTPγS and BODIPY-FL-GppNHp with G<Subscript>i</Subscript>- and G<Subscript>s</Subscript>-proteins

BODIPY-FL-guanosine 5'-[-thio]triphosphate (B-GTPS) and BODIPY-FL-guanosine 5'-[,-imido]triphosphate (B-GppNHp) induce fluorescence changes upon binding to purified G_s/G_i-proteins and were suggested to serve as probes for monitoring receptor-mediated G-protein activation. However, B-GTPS and B-GppNHp bound to receptor-G_s/G_i fusion proteins expressed in Sf9 cell membranes with 1,100- to 5,600-fold- and 17- to 55-fold lower affinity than GTPS and GppNHp, respectively. The affinity of B-GTPS/B-GppNHp for G_s/G_i-proteins was considerably lower than the affinity of N-methylanthraniloyl (MANT)-substituted GTP analogs for G_s/G_i-proteins. B-GTPS/B-GppNHp were much less potent than GTPS/GppNHp at regulating adenylyl cyclase (AC) via G_s- and G_i-proteins. B-GTPS/B-GppNHp were similarly efficient as GTPS/GppNHp at activating G_i, but less efficient at activating G_s. In contrast to MANT-GTPS/MANT-GppNHp, B-GTPS/B-GppNHp were inefficient at directly inhibiting AC. In conclusion, the bulky BODIPY group strongly reduces the affinity of GTPS/GppNHp for G-proteins, limiting the use of B-GTPS/B-GppNHp as fluorescence probes.Abbreviations AC Adenylyl cyclase - ₂AR ₂-Adrenoceptor - ₂AR-G_olf Fusion protein consisting of the ₂-adrenoceptor and G_olf - ₂AR-G_sL Fusion protein consisting of the ₂-adrenoceptor and the long splice variant of G_s - ₂AR-G_sS Fusion protein consisting of the ₂-adrenoceptor and the short splice variant of G_s - B-GppNHp BODIPY-FL-guanosine 5'-[,-imido]triphosphate - B-GTPS BODIPY-FL-guanosine 5'-[-thio]triphosphate - FPR-G_i1,2,3 Fusion protein consisting of the formyl peptide receptor and G_i1, G_i2 or G_i3 - G Unspecified G-protein -subunit - G_i Inhibitory G-protein of adenylyl cyclase - G_olf Olfactory G-protein that activates adenylyl cyclase - G_s Stimulatory G-protein of adenylyl cyclase - G_sL Long splice variant of the stimulatory G-protein of adenylyl cyclase, G_s - G_sS Short splice variant of the stimulatory G-protein of adenylyl cyclase, G_s - GppNHp Guanosine 5'-[,-imido]triphosphate - GTPS Guanosine 5'-[-thio]triphosphate - M-GppNHp 2'(3')-O-(N-methylanthraniloyl)-guanosine 5'-[,-imido]triphosphate (MANT-GppNHp) - M-GTPS 2'(3')-O-(N-methylanthraniloyl)-guanosine 5'-[-thio]triphosphate (MANT-GTPS)     

Mast cells,peptides and cardioprotection – an unlikely marriage?

1 Mast cells have classically been regarded as the ‘bad guys’ in the setting of acute myocardial ischaemia, where their released contents are believed to contribute both to tissue injury and electrical disturbances resulting from ischaemia. Recent evidence suggests, however, that if mast cell degranulation occurs in advance of ischaemia onset, this may be cardioprotective by virtue of the depletion of mast cell contents that can no longer act as instruments of injury when the tissue becomes ischaemic. 2 Many peptides, such as ET‐1, adrenomedullin, relaxin and atrial natriuretic peptide, have been demonstrated to be cardioprotective when given prior to the onset of myocardial ischaemia, although their physiological functions are varied and the mechanisms of their cardioprotective actions appear to be diverse and often ill defined. However, one common denominator that is emerging is the ability of these peptides to modulate mast cell degranulation, raising the possibility that peptide‐induced mast cell degranulation or stabilization may hold the key to a common mechanism of their cardioprotection. 3 The aim of this review was to consolidate the evidence implying that mast cell degranulation could play both a detrimental and protective role in myocardial ischaemia, depending upon when it occurs, and that this may underlie the cardioprotective effects of a range of diverse peptides that exerts physiological effects within the cardiovascular system.     

The effects of hydrocortisone on rat heart muscarinic and adrenergic α<Subscript>1</Subscript>, β<Subscript>1</Subscript> and β<Subscript>2</Subscript> receptors,propranolol-resistant binding sites and on some subsequent steps in intracellular signalling

Glucocorticoids affect the expression and density of neurotransmitter receptors in many tissues but data concerning the heart are contradictory and incomplete. We injected rats with hydrocortisone for 1–12 days and measured the densities of cardiac muscarinic receptors, ₁-, ₁- and ₂-adrenoceptors and propranolol-resistant binding sites (formerly assumed to be the putative ₄-adrenoceptor). Some aspects of intracellular signalling were also evaluated: we measured adenylyl cyclase activity (basal, isoprenaline- and forskolin-stimulated and carbachol-inhibited), the coupling between muscarinic receptors and G proteins and basal and isoprenaline-stimulated heart rate. The density of cardiac muscarinic receptors increased (in both the atria and the ventricles). The density of ₁-adrenoceptors increased in the atria and was little changed in the ventricles. The density of ₂-adrenoceptors increased in both the atria and the ventricles. The number of ₁-adrenoceptors decreased initially, followed by a transient increase in the atria and did not change in the ventricles. The density of propranolol-resistant binding sites first increased and then diminished in the atria and did not change in the ventricles. Although there were noticeable changes in receptor densities, the stimulatory and inhibitory effects on adenylyl cyclase, basal and isoprenaline-stimulated heart rate and the coupling between muscarinic receptors and G proteins were not significantly altered. This may indicate that changes in receptor densities might be one of the mechanisms maintaining stable functional output. Deceased     

Vitamin D<Subscript>3</Subscript>–Based Conjugates for Topical Treatment of Psoriasis: Synthesis,Antiproliferative Activity,and Cutaneous Penetration Studies

No HeadingPurpose. The goals of the experiments reported in this paper were to explore skin bioavailability and cell growth inhibitory activity of new vitamin D₃–based conjugates studied as a potential drug complex for psoriasis.Methods. Conjugation was made between polyunsaturated fatty acids (PUFAs), such as linolenic acid or -linolenic acid, and calcipotriol—a vitamin D₃ analogue clinically used for topical treatment of psoriasis. These complexes were prepared by coupling the corresponding fatty acid with calcipotriol in the presence of dicyclohexyl-carbodiimide (DCC) and 4-(dimethylamino)-pyridine (DMAP) to obtain an ester bond.Results. The conjugates were capable of enhancing the penetration of the vitamin into the skin as well as inhibiting proliferation of keratinocytes in cultures. The antiproliferative activity even increased after simulating the full hydrolysis of the conjugates. In vitro skin penetration studies revealed that the conjugates penetrated into the skin at higher levels relative to calcipotriol alone. It was also demonstrated that the conjugate containing n-3 fatty acid penetrated into the skin at higher levels as compared to the conjugate containing n-6 PUFA. High-performance liquid chromatography analysis has shown that after penetration, a major portion of calcipotriol-PUFA conjugate was first converted mainly into another isomer form, presumably by transesterification, and only then it was hydrolyzed to form apparently high local concentrations of both calcipotriol and PUFA.Conclusions. The unique biotransformation that occurred after penetration into the skin indicates that these conjugates are mutual prodrugs that are able to be bioprocessed in the skin and fully converted to the parent therapeutic agents.     

5-HT<Subscript>1B</Subscript> receptors, α<Subscript>2A/2C</Subscript>- and,to a lesser extent, α<Subscript>1</Subscript>-adrenoceptors mediate the external carotid vasoconstriction to ergotamine in vagosympathectomised dogs

It has previously been suggested that ergotamine produces external carotid vasoconstriction in vagosympathectomised dogs via 5-HT_1B/1D receptors and ₂-adrenoceptors. The present study has reanalysed this suggestion by using more selective antagonists alone and in combination. Fifty-two anaesthetised dogs were prepared for ultrasonic measurements of external carotid blood flow. The animals were divided into thirteen groups (n=4 each) receiving an i.v. bolus injection of, either physiological saline (0.3 ml/kg; control), or the antagonists SB224289 (300 g/kg; 5-HT_1B), BRL15572 (300 µg/kg; 5-HT_1D), rauwolscine (300 µg/kg; ₂), SB224289 + BRL15572 (300 µg/kg each), SB224289 + rauwolscine (300 µg/kg each), BRL15572 + rauwolscine (300 µg/kg each), rauwolscine (300 µg/kg) + prazosin (100 µg/kg; ₁), SB224289 (300 µg/kg) + prazosin (100 µg/kg), SB224289 (300 µg/kg) + rauwolscine (300 µg/kg) + prazosin (100 µg/kg), SB224289 (300 µg/kg) + prazosin (100 µg/kg) + BRL44408 (1,000 µg/kg; _2A), SB224289 (300 µg/kg) + prazosin (100 µg/kg)+ imiloxan (1,000 µg/kg; _2B), or SB224289 (300 µg/kg) + prazosin (100 µg/kg) + MK912 (300 µg/kg; _2C). Each group received consecutive 1-min intracarotid infusions of ergotamine (0.56, 1, 1.8, 3.1, 5.6, 10 and 18 µg/min), following a cumulative schedule. In saline-pretreated animals, ergotamine induced dose-dependent decreases in external carotid blood flow without affecting arterial blood pressure or heart rate. These control responses were: unaffected by SB224289, BRL15572, rauwolscine or the combinations of SB224289 + BRL15572, BRL15572 + rauwolscine, rauwolscine + prazosin, SB224289 + prazosin, or SB224289 + prazosin + imiloxan; slightly blocked by SB224289 + rauwolscine; and markedly blocked by SB224289 + rauwolscine + prazosin, SB224289 + prazosin + BRL44408 or SB224289 + prazosin + MK912. Thus, the cranio-selective vasoconstriction elicited by ergotamine in dogs is predominantly mediated by 5-HT_1B receptors as well as _2A/2C-adrenoceptor subtypes and, to a lesser extent, by ₁-adrenoceptors.In memoriam: Luis F. Valdivia died on 26 May 2004