Acetylsalicylic Acid Derivatives Research Articles

In Silico Studies of a Novel Scaffold of Acetylsalicylic Acid Derivatives Against EGFR by Molecular Docking and Molecular Dynamics Simulations

In this study, a molecular docking study was performed to propose the acetylsalicylic acid derivative 2-[(4-Acetylphenyl)carbamoyl]phenyl acetate (AMPBS) as a potential cancer candidate targeting the Epidermal Growth Factor Receptor (EGFR). The native ligand erlotinib was used as a control compound. The calculated docking score of -7.4 kcal/mol compared to the native ligand erlotinib of -7.0 kcal/mol of AMPBS compound revealed a promising anticancer activity. The stability of the complex was interpreted by careful analysis of the root mean square deviation (RMSD), root mean square fluctuations (RMSF) and mean hydrogen bond number (Hb) plots obtained from the MD trajectories. The ADMET properties of AMPBS were evaluated using relevant online tools. Drug-likeness studies showed that AMPBS is suitable for use in living organisms. It was predicted that AMPBS in the active pocket could be a promising inhibitor due to its high binding energy, interaction mechanism and retention in the active pocket.

Physiological healing of chronic gastric ulcer is not impaired by the hydrogen sulphide (H2S)-releasing derivative of acetylsalicylic acid (ATB-340): functional and proteomic approaches.

Gastric ulcers affect approx. 10% of population. Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA) predispose to or impair the physiologically complex healing ofpre-existing ulcers. Since H2S is an endogenous cytoprotective molecule, we hypothesized that new H2S-releasing ASA-derivative (ATB-340) could overcome pathological impact of NSAIDs on GI regeneration.Clinically translational gastric ulcers were induced in Wistar rats using state-of-the-art microsurgical model employing serosal application of acetic acid. This was followed by 9 days long i.g. daily treatment with vehicle, ATB-340 (6-24mg/kg) or equimolar ASA doses (4-14mg/kg). Ulcer area was assessed macro- and microscopically. Prostaglandin (PG)E2 levels,indicating pharmacological activity of NSAIDsand 8-hydroxyguanozine content,reflecting nucleic acids oxidation in serum/gastric mucosa, were determined by ELISA. Qualitative and/or quantitative pathway-specific alterations at the ulcer margin were evaluated using real-time PCR and mass spectrometry-based proteomics.ASA, unlike ATB-340, dose-dependently delayed/impaired gastric tissue recovery, deregulating 310 proteins at the ulcer margin, including Ras signalling, wound healing or apoptosis regulators. ATB-340 maintained NSAIDs-specific cyclooxygenase-inhibiting capacity on systemic and GI level but in time-dependent manner. High dose of ATB-340 (24mg/kg daily), but not ASA, decreased nucleic acids oxidation and upregulated anti-oxidative/anti-inflammatory heme oxygenase-1, 24-dehydrocholesterol reductase or suppressor of cytokine signalling (SOCS3) at the ulcer margin.Thus, ASA impairs the physiological healing of pre-existing gastric ulcers, inducing the extensive molecularly functional and proteomic alterations at the wound margin. H2S-releasing ATB-340 maintains the target activity of NSAIDs with limited impact on gastric PGE2 signalling and physiological GI regeneration, enhancing anti-inflammatory and anti-oxidative response, andproviding the pharmacological advantage.

Anti-Aggregation and Antioxidant Properties of a New Derivative of Acetylsalicylic Acid and Carnosine

Anti-Aggregation and Antioxidant Properties of a New Derivative of Acetylsalicylic Acid and Carnosine

Changes in micro- and central hemodynamic parameters in rats under the action of acetylsalicylic acid and its coordination compounds with metals

Introduction. The cutaneous blood circulation is a representative model both for studying the mechanisms of vascular diseases and for assessing the current state of the central hemodynamics in preclinical researches of various chemical compounds. Aim. The changes in the parameters of cutaneous microcirculation and central hemodynamics (heart rate and blood pressure) were studied in the animals under the action of acetylsalicylic acid and its coordination compounds with cations of cobalt, zinc, nickel and manganese at a dose of 20 mg/kg. Materials and methods. The research was conducted using the laser Doppler flowmetry method on the Lazma-MC device (manufactured by RPE Lazma, Russia) and the NIBP200A system (Biopac Systems, Inc., USA). Results. The study shows that animals develop bradycardia, and microcirculation and central hemodynamics change in two ways after the introduction of acetylsalicylic acid and the tested metal salicylates. These ways are hypotension-related hyperemia (acetylsalicylic acid and cobalt salicylate) and ischemia (zinc, nickel and manganese salicylates) associated with hypertension. Conclusion. The obtained data confirm the cardiotropic activity of new coordination compounds. The data also prove that the generation of the acetylsalicylic acid derivatives allows enhancing it physiological effects, as well as obtaining completely new molecules. The molecules are different from the precursor one and are necessary for the production of effective drugs.

Synthesis and in vitro evaluation of triphenylphosphonium derivatives of acetylsalicylic and salicylic acids: structure-dependent interactions with cancer cells, bacteria, and mitochondria

Salicylic acid (SA) remains one of the most fruitful natural compounds to generate drug molecules with versatile activities. In this study, effective synthesis of SA and acetylsalicylic acid (ASA) derivatives with a carrier triphenylphoshonium (TPP) group was proposed. A series of SA and ASA conjugates linked with the TPP group via alkyl chain linker (C3-C10) was synthesized. The conjugates showed enhanced TPP-mediated cytotoxicity towards MCF-7, Caco-2, PC-3 cells in proportion to the linker length. 7e, 8e (C9), and 7f (C10) were the most active against the cancer cells with IC50 = 0.6–1.9 µM while were less toxic for HSF. Similarly, antibacterial (bactericidal) activity of the compounds against S. aureus increased with the linker elongation. The lowest MIC for SA and ASA derivatives were 4 and 1 µM, respectively. The TPP conjugates induced early linker length-dependent mitochondria depolarization and concurrent superoxide radical production in the cancer cells. The most lipophilic conjugates were found to specifically interact with ROS probe 2′,7′-dichlorofluorescin diacetate, forming mixed aggregates with the probe and inhibiting its fluorescence upon oxidation. These interactions were exploited to probe the compounds inside living cells. The results identify 7e and 7f as promising mitochondria-modulating and anticancer agents with increased cellular availability.

A new derivative of acetylsalicylic acid and carnosine: synthesis, physical and chemical properties, biological activity.

The aim of this study was to create and assess biological activity of a new compound based on carnosine and acetylsalicylic acid (ASA) that will comprise antioxidant effect with antiplatelet activity, while simultaneously preventing side effects on the gastrointestinal tract. Salicyl-carnosine (SC) was synthesized by condensation of ASA and carnosine. Antioxidant activity was determined by spectrophotometric and chemiluminescence methods. Antiplatelet activity was carried out by the light transmission-aggregometry method using the inductor ADP. Chronic gastric ulcer in rats was modeled using glacial acetic acid. Using SOD-like activity, iron-induced chemiluminescence, BaSO4-activated respiratory burst, and evaluation of red blood cell structure stabilization during oxidative damage induced by sodium hypochlorite, it was shown that SC possesses antioxidant activity analogous, or better, than that of carnosine. Antiplatelet activity of SC was evaluated in the blood of healthy individuals, and was also shown to be comparable to, or exceeding that of ASA. Also SC demonstrates high resistance to hydrolysis by tissue and serum carnosinases. Most importantly, it was shown that SC has protected the gastric mucosa against the formation of stomach ulcerative lesions and promoted their epithelization, therefore overcoming the undesirable inherent side effects of ASA. SC preserves pharmacologically significant properties of ASA and carnosine while retaining an anti-ulcer activity and resistance to the carnosinase hydrolysis at the same time. These properties are particularly promising for the potential development of new anti-inflammatory and antithrombotic drugs. Graphical abstract .

Choline Salicylate Analysis: Chemical Stability and Degradation Product Identification.

Choline salicylate (CS) as a derivative of acetylsalicylic acid is commonly used in different drug forms. In medicine, it is applied topically to inflammation of the oral cavity mucosa and in laryngology. However, this substance in the form of an ionic liquid has not been investigated enough. There are no literature studies on stability tests constituting a stage of pre-formulation research. HPLC (Nucleosil C18, 4.6 × 150 mm, 5 μm; methanol-water-acetic acid 60:40:1, 230 nm or 270 nm) and UV (276 nm) methods for the determination of CS in 2% (g/mL) aqueous solutions were developed. Under stress conditions, CS susceptibility to hydrolytic degradation in aqueous medium, hydrochloric acid, sodium hydroxide, and hydrogen peroxide, and the effect of light on the stability of CS solutions were studied with HPLC analysis. The degradation degree of CS and the purity of the solutions were also tested. Choline salicylate has been qualified as practically stable in neutral and acid media, stable in an alkaline medium, very stable in an oxidizing environment, and photolabile in solution. The HPLC-MS/MS method was used to identify 2,3- and 2,5-dihydroxybenzoic acids as degradation products of CS under the tested conditions.

Vasoactive effects of a new nitric oxide donating acetylsalicylic acid derivative

Vasoactive effects of a new nitric oxide donating acetylsalicylic acid derivative

Antioxidant Properties and Electrochemical Behavior of some Acetyl Salicylic Acid Derivatives

Antioxidants are frequently used in several dietary supplements and have been probed for their significant role in the prevention of diseases like cancer or coronary heart disease. Acetyl salicylic acid has grabbed substantial attention due to their ability in impeding oxidative stress. In the present study, nine new salicylic acid derivatives: 5-(2-hydroxyphenyl-5-substituted)-1,3,4-oxadiazole-2(3H)-thiones, N-(2,5-dimethyl-1H-pyrrol-1-yl)-2-hydroxy-5-substituted benzamides, 2-hydroxy-5-substituted-N'-[1-(2-oxo-2substituted-chromen-3-yl)ethylidene] benzohydrazides and Hg (II) complex of N'-[(1Z)-1-(6-bromo-2-oxo-2H-chromen-3-yl) ethylidene]-2-hydroxybenzohydrazide have been synthesized and characterized in the light of advanced spectral techniques. The antioxidant properties of these compounds were investigated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) spectrometric assay and compared with the results of cyclic voltammetry studies. The redox properties shown by the active molecule using cyclic voltammetry correlated well with the biochemical study.

The Pharmacology of Topical Analgesics

Pain management of patients continues to pose challenges to clinicians. Given the multiple dimensions of pain – whether acute or chronic, mild, moderate, or severe, nociceptive or neuropathic – a multimodal approach may be needed. Fortunately, clinicians have an array of nonpharmacologic and pharmacologic treatment choices; however, each modality must be chosen carefully, because some often used oral agents are associated with safety and tolerability issues that restrict their use in certain patients. In particular, orally administered nonsteroidal anti–inflammatory drugs, opioids, antidepressants, and anticonvulsants are known to cause systemic adverse effects in some patients. To address this problem, a number of topical therapies in various therapeutic classes have been developed to reduce systemic exposure and minimize the risks of patients developing adverse events. For example, topical nonsteroidal anti–inflammatory drug formulations produce a site–specific effect (ie, cyclo-oxygenase inhibition) while decreasing the systemic exposure that may lead to undesired effects in patients. Similarly, derivatives of acetylsalicylic acid (ie, salicylates) are used in topical analgesic formulations that do not significantly enter the patient's systemic circulation. Salicylates, along with capsaicin, menthol, and camphor, compose the counterirritant class of topical analgesics, which produce analgesia by activating and then desensitizing epidermal nociceptors. Additionally, patches and creams that contain the local anesthetic lidocaine, alone or co–formulated with other local anesthetics, are also used to manage patients with select acute and chronic pain states. Perhaps the most common topical analgesic modality is the cautious application of cutaneous cold and heat. Such treatments may decrease pain not by reaching the target tissue through systemic distribution, but by acting more directly on the affected tissue. Despite the tolerability benefits associated with avoiding systemic circulation, topically applied analgesics are associated with application–site reactions in patients, such as dryness, erythema, burning, and discoloration. Furthermore, some adverse events that have been observed in patients may be suggestive of some degree of systemic exposure. This article reviews the mechanisms of action, pharmacokinetics, and tolerability of topical treatments for the management of patient pain.

Attenuated effects of Neu2000 on hypoxia-induced synaptic activities in a rat hippocampus

Neu2000 (NEU; 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid), a recently developed derivative of acetylsalicylic acid and sulfasalazine, potently protects against neuronal cell death following ischemic brain injury by antagonizing NMDA receptor-mediated neuronal toxicity and oxidative stress. However, it has yet to be determined whether NEU can attenuate hypoxia-induced impairment of neuronal electrical activity. In this study, we carried out extracellular recordings of hippocampal slices in order to investigate the effects of NEU on the electrical activity of neurons exposed to a hypoxic insult (oxygen and glucose deprivation). NEU prominently suppressed hypoxia-induced impairment of neuronal activity in a concentration-dependent manner. NEU, at a low dose (1μM), competently depressed the hypoxia-induced convulsive activity in a manner similar to trolox. Furthermore, high concentrations of NEU (50μM) markedly abolished all hypoxia-mediated impairment of neuronal activity and accelerated the slow recovery of neuronal activity more efficiently than ifenprodil and APV. These results suggest that NEU attenuates hypoxia-induced impairment of neuronal activity more potently than the antioxidant, trolox, and the NMDA receptor antagonists, ifenprodil and APV. We propose that NEU is a striking pharmacological candidate for neuroprotection against hypoxia because of its defensive action on hypoxia-mediated impairment of electrical neurotransmission as well as its neuroprotective action against neuronal cell death induced by exposure to pathological hypoxic conditions.

Raman Spectroscopy: a Test Novel Technique for Quality Control In the Acetylsalicylic Acid

Raman spectroscopy (RS) is an inelastic scattering technique that is being recently applied in pharmaceutical applications. In this work this technique was applied to analyze the differences in concentrations of a commercial pharmaceutical form of an acetylsalicylic acid derivative present in tablets manufactured by five different laboratories (A, B, C, D and E). Meyer brand acetylsalicylic acid reagent was used to obtain spectral data as active principle. Five samp les of different laboratories were also analyzed. We used a Raman microscopy device Horiba-JY HR800 with an excitation source of 830 n m and 17 mW. Raw data were analyzed by an arith metic difference between the active substance from each different laboratory sample. Principal co mponent analysis (PCA) was also applied to the spectral set to verify the differences in each pharmaceutical form of acetylsalicylic acid. We found a correlation o f 0.7 between laboratory A and the active substance, and 0.98 between all spectra of the same laboratory A, we conclude that this drug was elaborated with better quality control. Results indicate that Raman spectroscopy can be applied in the pharmaceutical industry to determine adulteration or alteration in pharmaceutical formu lations. We have demonstrate that RS together with PCA can be used as a fast and nondestructive method to determine the characteristics of the molecules present in commercially available drugs with very short acquisition times of few seconds.

Aspirin Hybrid Molecules with Improved Antiplatelet Properties Designed As New Drug Candidates to Prevent Atherothrombosis,

Abstract 3364 Introduction.Platelets are involved in atherothrombosis as a consequence of their inappropriate and sustained activation, being thus considered an important target for pharmacological interventions. Aspirin (ASA) is the current drug standard of care of most patients; however the therapy is limited and presents several inconveniences such as lack of effectiveness and bleeding. The use of hybridization strategy allows obtaining compounds with pharmacokinetic and pharmacodynamic properties improved. In this work, we describe new compounds with significant antiplatelet activity induced by ADP. These compounds 2-(2-((4-methyl-1,2,5-oxadiazole-2-oxide)methylene)hydrazinecarbonyl) phenyl acetate (Lapdesf 1) and 2-(2-((4-phenyl-1,2,5-oxadiazole-2-oxide)methylene)hydrazinecarbonyl) phenyl acetate (Lapdesf 2) were structurally planned by modification of acetyl salicylic acid (ASA) based on the use of acylhydrazone subunit, previously reported to contribute to inhibit platelet aggregation. Furthermore, 1,2,5-oxadiazole N-oxide subunit known by its NO-donor properties were included in the hybrid structure in order to contribute for the antiplatelet activity. Methods. 1. Detection of nitrite. A solution of the appropriate compound (20 μL) in DMSO was added to 2 mL of a mixture of 50 mM phosphate buffer (pH 7.4) and methanol (1:1, v:v), containing 5 mM of L-cysteine. The final concentration of the compound was 10–4M. After 1 h at 37 °C, 1 mL of the reaction mixture was treated with 250 μL of Griess reagent. After 10 min at room temperature, the absorbance was measured at 540 nm using a spectrophotometer. Standard sodium nitrite solutions (10–80 nmol/mL) were used to construct the calibration curve. The yields of nitrite are expressed as % NO2– (mol/mol). 2. Antiplatelet activity. Blood was withdrawn from mice central artery and mixed with 3.8% trisodium citrate (9:1 v/v). Platelet-rich plasma (PRP) was prepared by centrifugation at 375 × g for 10 min at room temperature. The platelet-poor plasma (PPP) was prepared by centrifugation of the pellet at 1800 × g for 10 min at room temperature. Platelet aggregation was monitored by the turbidimetric method of Born and Cross using aggregometer. PRP (300 μL) was incubated at 37 °C for 1 min with compounds before addition of the aggregating agent. Platelet aggregation was induced by ADP (10 μM). Compounds and ASA used as control were evaluated at 150 μM. 3. Tail vein bleeding time model. Mice were anesthetized (ketamine 75mg/kg; medetomidine 1 mg/kg IP). A transverse incision is made with a scalpel over a lateral tail vein at a position where the diameter of the tail is 2.25–2.5 mm. The tail was immersed in normal saline (37°C) in a hand-held test tube. This last one is rotated to prevent the shed blood from obscuring the incision site. The time from the incision to the cessation of bleeding is recorded. The results are expressed as mean time + SEM of 6 animals per group. The data were analyzed statistically with Student’s t test at a significance level of P < 0.05. Results. 1. Detection of nitrite: Isosorbide dinitrate used as the control, induced 10.9 + 0.5 % of nitrite (mol/mol) formation while compound Lapdesf 1 and Lapdesf 2 induced 1.3 + 0.1 and 4.7 + 0.2, respectively. 2.Antiplatelet activity. The compounds inhibited platelet aggregation induced by ADP. The aggregation percentage in presence of Lapdesf 1 and Lapdesf 2 were 3.1 + 0,2 and 32 + 0,4 respectively. The aggregation percentage of control (ADP) and ASA were 40.3 + 0,3 and 57.5 + 0,4 respectively. 3. Tail vein bleeding time model. The control used showed an average of 52 + 15 seconds to stop bleeding while ASA demonstrated an average of 73 + 20 seconds. Lapdesf 1 and Lapdesf 2 showed an average of 113 + 25 seconds and 192 + 31 seconds. Conclusions. Results demonstrate that molecular hybridization approach used allows us to obtain new ASA derivatives with property of inhibited platelet aggregation induced by ADP. Lapdesf 1 and 2 demonstrated different NO-donor properties related to methyl and phenyl substitutions. Furthermore, both compounds prolonged tail vein bleeding time using mice model. These compounds could be new drug candidates, alternative to ASA, useful to prevent atherothrombosis events. Disclosures:No relevant conflicts of interest to declare.

Structure, stability, and antiplatelet activity of O-acyl derivatives of salicylic acid and lipophilic esters of acetylsalicylate

The anti-thrombotic activity of acetylsalicylic acid (ASA) has been shown to be due to specific irreversible acetylation of blood platelet cyclooxygenase. The aim of our study was to investigate the associations between the antiplatelet activities of derivatives of both ASA and salicylic acid (SA), as well as the structure, stability, and molecular properties of these compounds. Homologous series of O-acyl derivatives of salicylic acid (propionyl-, butyrylsalicylic acids, PSA, BSA) and lipophilic dodecyl (C12)-, hexadecyl (C16)-, and cholesteryl acetylsalicylates were synthesized and tested for structure-activity relationships. The molecular properties (heat of formation, molecular surface area, dipole moment) of ASA and SA derivatives obtained by theoretical calculations changed with the increasing length of the acyl or alkyl residue. The inhibition of whole blood platelet aggregation and the reduction in thromboxane (TX) generation by O-acyl derivatives were concentration-dependent and decreased along with increasing the length of acyl chain. These effects correlated with the extent of platelet reactivity and P-selectin expression inhibition in collagen-activated platelets. In contrast to ASA and O-acyl derivatives of SA, none of the lipophilic ASA derivatives had a significant inhibitory effect on platelet aggregation.In conclusion, all SA and ASA derivatives studied under in vitro conditions showed much lower antiplatelet activities than ASA itself, despite their higher affinity to plasma proteins or membrane components and their equivalent ability to acetylate protein free amino groups.We suggest the significance of the carboxylic group, dipole moment, geometry, and size of these pharmaceuticals in their ability to bind to the active site of cyclooxygenase and their antiplatelet efficacy.

Comparison of Triple Antiplatelet Therapy Including Triflusal and Conventional Dual Therapy in Patients Who Underwent Drug-Eluting Stent Implantation

Triflusal is a derivative of acetylsalicylic acid but it exhibits different pharmacological and pharmacokinetic properties. The object of this study was to evaluate the efficacy of additional use of triflusal in patients who underwent drug-eluting stent implantation. First, we prospectively tested platelet function with a rapid platelet function analyzer (VerifyNow-Aspirin) in patients with stable angina (male, age, 61.6 +/- 8.3, body weight, 69.3 +/- 11.2 kg) who maintained dual (aspirin 100 mg and clopidogrel 75 mg per day, n = 23) or triple (aspirin 100 mg, clopidogrel 75 mg, and triflusal 300 mg per day, n = 23) therapy for more than one month. They were randomly assigned to a group. The triple group showed superior inhibition of arachidonic acid induced platelet aggregation compared to the dual group (420.2 +/- 47.7 ARU versus 465.0 +/- 71.2 ARU, P = 0.016). Second, we compared composite outcomes (death, myocardial infarction, and nonhemorrhagic stroke) after drug-eluting stent (DES) implantation between the dual (n = 1474) and triple (n = 433) groups in the prospective Seoul National University Hospital drug-eluting stent (SNUH-DES) cohort. The triple group had more current smokers, male patients, and patients with a previous history of revascularization. Also, the triple group underwent more complex interventions such as left main, chronic total occlusion, long lesion, and restenotic lesion than the dual group. In spite of their higher risk profiles, the triple group patients showed comparable composite outcomes (19 cases, 4.4%) to those of the dual group ones (41 cases, 2.8%) (P = 0.12). The triflusal-based triple antiplatelet therapy achieved superior platelet inhibition compared to the dual therapy ex vivo and it could be applied after complex intervention with DES.

The nitric oxide-donating derivative of acetylsalicylic acid, NCX 4016, stimulates glucose transport and glucose transporters translocation in 3T3-L1 adipocytes

NCX 4016 is a nitric oxide (NO)-donating derivative of acetylsalicylic acid. NO and salicylate, in vivo metabolites of NCX 4016, were shown to be potential actors in controlling glucose homeostasis. In this study, we evaluated the action of NCX 4016 on the capacity of 3T3-L1 adipocytes to transport glucose in basal and insulin-stimulated conditions. NCX 4016 induced a twofold increase in glucose uptake in parallel with the translocation of the glucose transporters GLUT1 and GLUT4 to the plasma membrane, leaving unaffected their total expression levels. Importantly, NCX 4016 further increased glucose transport induced by a physiological concentration of insulin. The stimulatory effect of NCX 4016 on glucose uptake appears to be mediated by its NO moiety. Indeed, it is inhibited by a NO scavenger and treatment with acetylsalicylic or salicylic acid had no effect. Although NO is involved in the action of NCX 4016, it did not mainly depend on the soluble cGMP cyclase/protein kinase G pathway. Furthermore, NCX 4016-stimulated glucose transport did not involve the insulin-signaling cascade required to stimulate glucose transport. NCX 4016 induces a small activation of the mitogen-activated protein kinases p38 and c-Jun NH(2)-terminal kinase and no activation of other stress-activated signaling molecules, including extracellular signal-regulated kinase, inhibitory factor kappaB, or AMP-activated kinases. Interestingly, NCX 4016 modified the content of S-nitrosylated proteins in adipocytes. Taken together, our results indicate that NCX 4016 induced glucose transport in adipocytes through a novel mechanism possibly involving S-nitrosylation. NCX 4016 thus possesses interesting characteristics to be considered as a candidate molecule for the treatment of patients suffering from metabolic syndrome and type 2 diabetes.

B11. Efficacy and mechanism of action of NCX 4040, a NO-donating acetyl salicylic acid derivative, as anticancer drug or sensitizing agent of conventional chemotherapeutic agents

B11. Efficacy and mechanism of action of NCX 4040, a NO-donating acetyl salicylic acid derivative, as anticancer drug or sensitizing agent of conventional chemotherapeutic agents

A simple synthesis of functionalized 2-amino-3-cyano-4-chromones by application of the N-hydroxybenzotriazole methodology

A novel and simple method for the synthesis of functionalized 2-amino-3-cyano-4-chromones is reported. The title compounds were isolated after acylation of malononitrile with Nhydroxybenzotriazolyl acetylsalicylates, generated in situ by treating acetylsalicylic acid derivatives with N-hydroxybenzotriazole, followed by cyclization. The described one-pot methodology is characterized by short reaction times, high yields (68 to 77%), no side-products and provides chromones with a variety of substituents on the aromatic ring. The structure of the isolated compounds has been determined by means of H/C NMR and FT-IR Spectroscopy.

Synthesis and transdermal properties of acetylsalicylic acid and selected esters

The primary aim of this study was to determine the transdermal penetration of acetylsalicylic acid and some of its derivatives, to establish a correlation, if any, with selected physicochemical properties and to determine if transdermal application of acetylsalicylic acid and its derivatives will give therapeutic drug concentrations with respect to transdermal flux. Ten derivatives of acetylsalicylic acid were prepared by esterification of acetylsalicyloyl chloride with ten different alcohols. The experimental aqueous solubility, log D and transdermal flux values were determined for acetylsalicylic acid and its derivatives at pH 4.5. In vitro penetration was measured through excised female human abdominal skin in diffusion cells. The experimental aqueous solubility of acetylsalicylic acid (6.56 mg/ml) was higher than that of the synthesised acetylsalicylate derivatives (ranging from 1.76 × 10 −3 to 3.32 mg/ml), and the log D of acetylsalicylic acid (−0.85) was lower than that of its derivatives (ranging from −0.25 to 1.95). There was thus an inverse correlation between the aqueous solubility data and the log D values. The experimental transdermal flux of acetylsalicylic acid (263.83 nmol/cm 2 h) was much higher than that of its derivatives (ranging from 0.12 to 136.02 nmol/cm 2 h).

Protective effect of triflusal and its main metabolite HTB in an in vitro model of anoxia-reoxygenation in rat brain slices: comparison with acetylsalicylic and salicylic acids

Triflusal is a fluorinated derivative of acetylsalicylic acid (ASA) with demonstrated antithrombotic activity. Recently, evidence for a neuroprotective effect has been obtained. The aim of this study was to compare the neuroprotective effects of the main metabolite of triflusal (2-hydroxy-4-trifluoromethylbenzoic acid, HTB) and the ASA metabolite salicylic acid (SA) in an in vitro model of anoxia-reoxygenation in rat brain slices. Rat brain slices (n=10 per group) were subjected to a period of anoxia followed by 180 min reoxygenation. We measured oxidative stress parameters (lipid peroxidation, glutathione system), prostaglandins (PGE(2)), nitric oxide pathway activity (NO) (nitrites+nitrates, constitutive and inducible NO synthase activity) and LDH efflux, a biochemical marker of cell death. Various concentrations (10, 100 and 1,000 microM) of triflusal, HTB, ASA or SA were tested. Triflusal at 10, 100 and 1,000 microM decreased LDH efflux in rat brain slices after anoxia/reoxygenation by 24%, 35% and 49% respectively. This effect was proportionately greater than that of ASA (0%, 13% and 32%). The results with HTB were similar to those with triflusal, whereas SA showed a greater protective effect than ASA (13%, 33% and 35%). The antioxidant effects of HTB and SA on the biochemical mechanisms of cell damage studied here were also greater than the effects of triflusal and ASA, a finding attributable mainly to the decrease in lipid peroxidation and to the ability of HTB to also increase glutathione levels. The triflusal metabolite reduced inducible NO synthase activity by 18%, 21% and 30%, whereas SA inhibited this activity by 9%, 17% and 23%. Triflusal and HTB led to greater increases in NO synthase than ASA or AS. In conclusion, the metabolite HTB plays an important role in the neuroprotective effect of triflusal, at least in the experimental model of anoxia-reoxygenation tested here.