Aspirin Derivatives Research Articles

Design and synthesis of resveratrol–salicylate hybrid derivatives as CYP1A1 inhibitors

Resveratrol and aspirin are known to exert potential chemopreventive effects through modulation of numerous targets. Considering that the CYP450 system is responsible for the activation of environmental procarcinogens, the aim of this study was to design a new class of hybrid resveratrol–aspirin derivatives possessing the stilbene and the salicylate scaffolds. Using HepG2 cells, we evaluated (a) the inhibition of TCDD-mediated induction of CYP1A1 exerted by resveratrol–aspirin derivatives using the EROD assay, and (b) CYP1A1 mRNA in vitro. We observed significant inhibition (84%) of CYP1A1 activity and a substantial decrease in CYP1A1 mRNA with compound 3, compared to control. Resveratrol did not exert inhibition under the same experimental conditions. This inhibitory profile was supported by docking studies using the crystal structure of human CYP1A1. The potential effect exerted by compound 3 (the most active), provide preliminary evidence supporting the design of hybrid molecules combining the chemical features of resveratrol and aspirin.

Phospho-aspirin-2 (MDC-22) inhibits estrogen receptor positive breast cancer growth both in vitro and in vivo by a redox-dependent effect.

Phospho-aspirin (PA-2) is a novel aspirin derivative that exhibits promising anticancer properties and is considerably safer than conventional aspirin. In this study, we investigated the chemotherapeutic efficacy of PA-2 in preclinical models of estrogen receptor positive (ER+) breast cancer and elucidated its mechanism of action. PA-2 inhibited the growth of ER+ cells more potently than aspirin in vitro, and exerted a triple cytokinetic effect that includes induction of apoptosis and cell cycle arrest as well as the inhibition of cell proliferation. PA-2 is highly efficacious in vivo, as treatment of established MCF7 xenografts with PA-2 induced tumor stasis (98.2% inhibition, p<0.01). PA-2 triggered the activation of p53-dependent apoptosis via two distinct mechanisms: 1) acetylation of p53 (at K373), which disrupts its interaction with its transcription repressor MDM2, and 2) translocation of p53 to the mitochondria leading to the dissipation of mitochondrial transmembrane potential (ΔΨm). Consistent with these observations, both the RNAi-mediated knockdown of p53 and forced deactylation via HDAC1 over-expression attenuated the anticancer effect of PA-2 in MCF7 cells. An upstream mediator of the signaling effects of PA-2 is RONS. PA-2 induced oxidative stress in vitro and in mice bearing MCF7 xenografts; its induction effect appears to be tumor-specific. Crucially, administration of N-acetylcysteine, a ROS scavenger, abrogated the effect of PA-2 on p53 acetylation and mitochondria translocation, thus identifying RONS as proximal molecules mediating the anticancer effect of PA-2. In summary, our findings demonstrate that PA-2 is a promising antineoplastic compound against ER+ breast cancer, warranting further evaluation as an anticancer agent.

Hydrogen Sulfide Inhibits Human Platelet Aggregation In Vitro in Part by Interfering Gap Junction Channels: Effects of ACS14, a Hydrogen Sulfide-releasing Aspirin

Hydrogen sulfide (H2S), as a newly identified gaseous mediator, has been widely investigated in various systems. However, the effect of H2S on cardiovascular system haemostasis, including platelet aggregation and the precise mechanisms remain unclear. Therefore, the present study was aimed to examine the inhibitory effect of H2S on human platelet aggregation in vitro and its relevance to gap junction channels. The antiaggregatory property of H2S-releasing aspirin derivative (ACS14) was compared with its mother compound, aspirin. In comparison to an equimolar dose of aspirin, ACS14 not only exerted a more potent inhibitory effect on platelet aggregation induced by ADP or thrombin, but also significantly inhibited αIIbβ3 integrin activation and P-selectin expression. Similarly, NaHS (100μM), a conventional H2S donor significantly inhibited platelet aggregation as well as αIIbβ3 integrin activation and P-selectin expression induced by ADP or thrombin. Furthermore, pretreatment with rotigaptide, a gap junction modifier abolished the inhibitory properties of ACS14 or NaHS on platelet aggregation, suggesting that suppression of platelet aggregation by H2S is, at least in part, gap junction channel-dependent. H2S may inhibit human platelet aggregation at least in part by depressing gap junction intercellular communication and H2S released from ACS14 may contribute to its additional anti-platelet effect in vitro in comparison to aspirin.

Preparation and characterization of a novel aspirin derivative with anti-thrombotic and gastric mucosal protection properties.

The use of acetylsalicylic acid (ASP) is limited by its adverse effects, especially the effect on the gastric mucosa. To address this problem, we synthesized a derivative form of ASP, prepared by modification of ASP with nano-hydroxyapatite (a kind of inorganic particle containing Ca2+). The derivative was named Ca-ASP. Structural study showed that Ca-ASP was a kind of carboxylate containing intramolecular hydrogen bonds. Rats given a high dose of Ca-ASP (5 mmol per kg body weight) showed similar anti-thrombotic activity as those given the same dose of ASP, but had much lower gastric mucosal damage than ASP (UI: 2 versus UI: 12.5). These rats also showed reduced expression of COX-2, but their COX-1 expression was similar to that of control rats, but significantly higher than that of ASP-administered rats. Furthermore, the level of prostaglandin E2 (PGE2) was up-regulated in Ca-ASP-administered rats compared to ASP-administered rats. Taken together, the results showed that Ca-ASP possessed similar antithrombotic activity as ASP but without the side effect associated with ASP, and the underlying mechanism may center on inhibiting COX-2 without inhibiting COX-1, and thus favouring the production of PGE2, the prostaglandin that plays a vital role in the suppression of platelet aggregation and thrombosis, as well as in the repair of gastric damage.

Molecular targets of aspirin and cancer prevention.

Salicylates from plant sources have been used for centuries by different cultures to treat a variety of ailments such as inflammation, fever and pain. A chemical derivative of salicylic acid, aspirin, was synthesised and mass produced by the end of the 19th century and is one of the most widely used drugs in the world. Its cardioprotective properties are well established; however, recent evidence shows that it can also act as a chemopreventive agent. Its antithrombotic and anti-inflammatory actions occur through the inhibition of cyclooxygenases. The precise mechanisms leading to its anticancer effects are not clearly established, although multiple mechanisms affecting enzyme activity, transcription factors, cellular signalling and mitochondrial functions have been proposed. This review presents a brief account of the major COX-dependent and independent pathways described in connection with aspirin's anticancer effects. Aspirin's unique ability to acetylate biomolecules besides COX has not been thoroughly investigated nor have all the targets of its primary metabolite, salicylic acid been identified. Recent reports on the ability of aspirin to acetylate multiple cellular proteins warrant a comprehensive study to investigate the role of this posttranslational modification in its anticancer effects. In this review, we also raise the intriguing possibility that aspirin may interact and acetylate cellular molecules such as RNA, and metabolites such as CoA, leading to a change in their function. Research in this area will provide a greater understanding of the mechanisms of action of this drug.

Phospho-aspirin (MDC-22) inhibits breast cancer in preclinical animal models: an effect mediated by EGFR inhibition, p53 acetylation and oxidative stress

BackgroundThe anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we synthesized phospho-aspirin (PA-2; MDC-22), a novel derivative of aspirin, and evaluated its chemotherapeutic and chemopreventive efficacy in preclinical models of triple negative breast cancer (TNBC).MethodsEfficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous TNBC xenografts in nude mice. Mechanistic studies were also carried out to elucidate the mechanism of action of PA-2.ResultsPA-2 inhibited the growth of TNBC cells in vitro more potently than aspirin. Treatment of established subcutaneous TNBC xenografts (MDA-MB-231 and BT-20) with PA-2 induced a strong growth inhibitory effect, resulting in tumor stasis (79% and 90% inhibition, respectively). PA-2, but not aspirin, significantly prevented the development of orthotopic MDA-MB-231 xenografts (62% inhibition). Mechanistically, PA-2: 1) inhibited the activation of epidermal growth factor receptor (EGFR) and suppressed its downstream signaling cascades, including PI3K/AKT/mTOR and STAT3; 2) induced acetylation of p53 at multiple lysine residues and enhanced its DNA binding activity, leading to cell cycle arrest; and 3) induced oxidative stress by suppressing the thioredoxin system, consequently inhibiting the activation of the redox sensitive transcription factor NF-κB. These molecular alterations were observed in vitro and in vivo, demonstrating their relevance to the anticancer effect of PA-2.ConclusionsOur findings demonstrate that PA-2 possesses potent chemotherapeutic efficacy against TNBC, and is also effective in its chemoprevention, warranting further evaluation as an anticancer agent.

Green Synthesis of Novel Phthalimide Derivatives of Aspirin and P-aminosalicylic Acid as Potential Analgesic- antipyretic and Anti-tuberculosis Agents

Green synthesis of novel compounds 4-(2-carboxybenzamido)-2-hydroxybenzoic acids 3a-3e, 4-(1, 3- dioxoisoindolin-2-yl)-2-hydroxybenzoic acids 4a-4e, 2-acetoxy-4-(2-carboxybenzoylamino)benzoic acids 6a-6e and 2- acetoxy-4-(1, 3-dioxo-1, 3-dihydroisoindol-2-yl)-benzoic acids 8a-8e has been developed which were analogs of aspirin (used as analgesic, anti-pyretic and cardiovascular drug) and para-aminosalicylic acid ( used as anti-tuberculosis agent).

Synthesis and Antifungal Activity of Aspirin Derivatives

Synthesis and Antifungal Activity of Aspirin Derivatives

Synthesis and In Vitro Anticancer Activity of Novel 2-((3-thioureido)carbonyl) phenyl Acetate Derivatives

Novel simplified Aspirin derivatives were developed, characterized by using IR, 1H NMR, 13C NMR and elemental analysis techniques and evaluated for anticancer activity in human cell lines. The results revealed that most of the compounds exhibited inhibitory effects of growth of cancer cell lines in vitro against T-acute lymphoblastic leukemia cell lines Molt-4, chronic myclogenous leukemia cell lines K-562, acute myelocytic leukemia cells lines HL-60, human breast cancer cell lines MCF-7, human hepatic carcinoma cell lines HepG-2 and human lung cancer cell lines A-549. It was observed that some of these compounds exhibited significant anticancer activity particularly 5i which had stronger antileukemia activity with IC50 values ranging from 11.12 to 19.25 µmol·L-1 against 3 leukemia cells than control fluorouracil, so some of the compounds may constitute a novel class of anticancer medicines, which deserves further study.

Synthesis and Chemical and Biological Comparison of Nitroxyl- and Nitric Oxide-Releasing Diazeniumdiolate-Based Aspirin Derivatives

Structural modifications of nonsteroidal anti-inflammatory drugs (NSAIDs) have successfully reduced the side effect of gastrointestinal ulceration without affecting anti-inflammatory activity, but they may increase the risk of myocardial infarction with chronic use. The fact that nitroxyl (HNO) reduces platelet aggregation, preconditions against myocardial infarction, and enhances contractility led us to synthesize a diazeniumdiolate-based HNO-releasing aspirin and to compare it to an NO-releasing analogue. Here, the decomposition mechanisms are described for these compounds. In addition to protection against stomach ulceration, these prodrugs exhibited significantly enhanced cytotoxcity compared to either aspirin or the parent diazeniumdiolate toward nonsmall cell lung carcinoma cells (A549), but they were not appreciably toxic toward endothelial cells (HUVECs). The HNO-NSAID prodrug inhibited cylcooxgenase-2 and glyceraldehyde 3-phosphate dehydrogenase activity and triggered significant sarcomere shortening on murine ventricular myocytes compared to control. Together, these anti-inflammatory, antineoplasic, and contractile properties suggest the potential of HNO-NSAIDs in the treatment of inflammation, cancer, or heart failure.

EP03 Therapeutic outlook for hydrogen sulfide donors

Considerable evidence has accumulated in recent years suggesting that H 2 S, synthesised from l -cysteine via cystathionine γ lyase (CSE) or cystathionine β synthase (CBS) or from 3-mercaptopyruvate via 3-mercaptopyruvate transferase (3-MST), plays a significant part in a range of physiological and/or pathophysiological processes. The possibility that either manipulating endogenous H 2 S biosynthesis or using H 2 S donor drugs may lead to new therapeutic entities was raised several years ago (e.g. [1] ). Increasingly, H 2 S is being thought of as a cytoprotective agent which restores physiological function in diseased cells or organ systems and hence interest has centred on identifying novel H 2 S donors. To date, a number of H 2 S donors have been characterized. These include thiones such as 5-( p -hydroxyphenyl)-1,2-dithione-3-thione (ADT-OH), cysteine derivatives such as S-allylcysteine (SAC) and S-propargyl-cysteine (S-SPRC), GYY4137 (morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate), H 2 S-releasing derivatives of non-steroidal anti-inflammatory drugs (NSAID) such as S-diclofenac and, recently, a nitric oxide (NO) and H 2 S-releasing derivative of aspirin. In addition, sulfide salts such as sodium hydrosulfide (NaHS) also release H 2 S. Other H 2 S-releasing drugs are no doubt in the pipeline. Potential applications of some or all of these compounds include such diverse conditions as hypertension, cardiac failure, ischemic reperfusion injury, acute and chronic inflammation, cancer and even to promote healthy aging. For example, GYY4137 reduces knee joint swelling in mice injected with Freund’s adjuvant [2] and is anti-tumor in the mouse [3] . Thus, H 2 S donors have shown early promise in a range of therapeutic areas. The further development of H 2 S donors presents a number of difficulties. For example, equating plasma concentration of released H 2 S from such donors with biological activity in an animal model (or in man) is problematic since, not only is H 2 S rapidly metabolized to an array of products, but current techniques to measure the concentration of this endogenous gas are likely insufficiently sensitive or selective. In addition, efficacy would be better correlated with H 2 S concentration at the site where the gas produces its biological effect (not plasma) which may be extracellular or even intracellular perhaps close to or in mitochondria. Further work is also needed to assess the cell permeability of H 2 S donors in order to determine whether they ‘carry’ H 2 S into cells thereby ‘loading’ the cell with the gas. This presentation will provide an overview of the potential for H 2 S donors in the clinic.

“In-Silico Seeding”: Isostructurality and Pseudoisostructurality in a Family of Aspirin Derivatives

Novel crystal packings of the aspirin molecule and 17 molecules that are related to aspirin by substitution are studied using a computational approach. The packings are created by taking a crystal structure for which the crystal packing and molecular geometry have been determined experimentally and replacing the native molecule with a different one. The resulting crystal structures are optimized using molecular mechanics, followed by a quantum mechanical method based on density functional theory and including a correction for dispersive interactions. There are 21 known, experimental, crystal structures for the molecules considered, some of which are polymorphic. For any given molecule, the lowest, calculated lattice energy is always found to be that of a crystal structure which corresponds to experiment. For the three polymorphic molecules, the second lowest lattice energy is also found to correspond to an experimental structure. The agreement between the observation of a particular packing and its low rank in the list of possible packings is evidence of the accuracy of the method for calculating the lattice energy. Further analysis of the results shows patterns reflecting the underlying supramolecular constructs that are common to the different packings of these molecules. This leads to some speculation as to the possibilities of finding new polymorphs for some of these molecules.

The safety and efficacy of aspirin intake in photoselective vaporization laser treatment of benign prostate hyperplasia

Endoscopic surgical treatment has become an option to treat benign prostate hyperplasia. We evaluated the safety and effectiveness of photoselective vaporization of the prostate (PVP) in patients. We evaluated preoperative and perioperative parameters, functional outcomes, and adverse events up to 12 months postoperatively of patients on oral anticoagulation therapy undergoing PVP, and compared the results with patients who did not take anticoagulation therapy. A total of 89 patients who received photoselective vaporization laser for benign prostate hyperplasia from May 2006 to February 2011 in our hospital were enrolled in our study. The patients were divided into two groups based on whether or not they were taking oral aspirin; 23 (25.8%) patients were taking aspirin derivatives (aspirin group), and 66 (74.2%) were not taking aspirin derivatives (control group). The mean prostate volume (58.8 mL vs 51 mL; P = 0.16) and mean energy consumption (235,268 J vs 289,793 J; P = 0.097) were comparable between the aspirin group and control group. The average postoperative results of hemoglobin were 13.4 mg/ dL for the aspirin group versus 13.9 mg/dL for the control group (P = 0.327). A significantly higher maximum flow rates and 80% improved post-void residual urine were noted during the followup. Postoperatively all variable showed significant improvement starting at month 1 of followup and remained improved for the 12 month followup. Postoperative complications were low and comparable between groups. PVP was characterized by excellent hemostatic properties and a very low intraoperative complication rate, even in the patients who were taking aspirin. On the basis of our perioperative results, we recommend PVP as a safe and effective procedure for patients with symptomatic benign prostate hyperplasia when taking an aspirin derivative.

Molecular Docking Study of Aspirin and Aspirin Derivatives

Molecular Docking Study of Aspirin and Aspirin Derivatives

The hexacarbonyldicobalt derivative of aspirin acts as a CO-releasing NSAID on malignant mesothelioma cells

The antiproliferative activity of the aspirin derivative [2-acetoxy-(2-propynyl)benzoate]hexacarbonyldicobalt (Co-ASS) and its analogue hexacarbonyl[μ-(2-ethylphenyl)methanol]dicobalt (Co-EPM) was investigated on malignant pleural mesothelioma (MPM) cell lines, having an epithelioid or a sarcomatoid phenotype. In sarcomatoid cell lines Co-ASS was more potent than Co-EPM and the prototypal metallo-drug cisplatin, and induced cell death through the intrinsic apoptotic pathway, associated with a strong NF-κB inhibition. In contrast, both Co-ASS and Co-EPM showed only a modest cytostatic activity against epithelioid MPM cells. Co-EPM induced an increase of senescent cells, while Co-ASS did not; the different outcomes were traced back to the organic (aspirin-like) portion of the molecule. Both Co-EPM and Co-ASS significantly reduced reactive oxygen/nitrogen species (ROS/RNS), and in turn nitrites, suggesting that the hexacarbonyldicobalt moiety may deliver CO within the cell, acting as a CO-releasing molecule (CO-RM). In perspective, Co-ASS would be better considered as a CO-NSAID agent (a CO-releasing molecule retaining the NSAID properties similar to NO- and H2S-NSAIDs) than as an antitumor drug candidate.

Antifungal Activity of Aspirin Derivatives against Sclerotinia sclerotiorum

Antifungal Activity of Aspirin Derivatives against Sclerotinia sclerotiorum

Synthesis and Evaluation of Diorganotin(IV) and Triorganotin(IV) Derivatives of Aspirin, Paracetamol and Metronidazole as Antimicrobial Agents

Synthesis and Evaluation of Diorganotin(IV) and Triorganotin(IV) Derivatives of Aspirin, Paracetamol and Metronidazole as Antimicrobial Agents

Evaluation of the In Vivo Anti‐Inflammatory and Analgesic Activity of a Highly Water‐Soluble Aspirin Conjugate

Glucose-aspirin (GA) was synthesized by conjugating aspirin (ASA) to the 3-carbon of glucose to produce a stable water-soluble aspirin derivative. The in vivo activities were compared with those of aspirin. The mouse tail flick assay showed that at 120 min., both aspirin and GA showed the maximum possible effect, and the higher dose (200 mg/kg) generally had less of an effect than the lower dose (100 mg/kg). Per cent inhibition of paw oedema was 63% and 69% for ASA and GA at 100 mg/kg, respectively. In the tail immersion test, the increase in reaction time was significantly greater with GA as compared to aspirin (100 mg/kg) at 60 min. In conclusion, there was significant anti-inflammatory and analgesic activity for GA at the doses studied under the experimental conditions.

H(2)S-Releasing Aspirin Protects against Aspirin-Induced Gastric Injury via Reducing Oxidative Stress

The aim of this study was to examine the effect of ACS14, a hydrogen sulfide (H2S)-releasing derivative of aspirin (Asp), on Asp-induced gastric injury. Gastric hemorrhagic lesions were induced by intragastric administration of Asp (200 mg/kg, suspended in 0.5% carboxymethyl cellulose solutions) in a volume of 1 ml/100 g body weight. ACS14 (1, 5 or 10 mg/kg) was given 30 min before the Asp administration. The total area of gastric erosions, H2S concentration and oxidative stress in gastric tissues were measured three hours after administration of Asp. Treatment with Asp (200 mg/kg), but not ACS14 (430 mg/kg, at equimolar doses to 200 mg/kg Asp), for 3 h significantly increased gastric mucosal injury. The damage caused by Asp was reversed by ACS14 at 1–10 mg/kg in a concentration-dependent manner. ACS14 abrogated Asp-induced upregulation of COX-2 expression, but had no effect on the reduced PGE2 level. ACS14 reversed the decreased H2S concentrations and blood flow in the gastric tissue in Asp-treated rats. Moreover, ACS14 attenuated Asp-suppressed superoxide dismutase-1 (SOD-1) expression and GSH activity, suggesting that ACS14 may stimulate antioxidants in the gastric tissue. ACS14 also obviously inhibited Asp-induced upregulation of protein expression of oxidases including XOD, p47phox and p67phox. In conclusion, ACS14 protects Asp induced gastric mucosal injury by inhibiting oxidative stress in the gastric tissue.

Hydrogen Sulfide–Releasing Aspirin Derivative ACS14 Exerts Strong Antithrombotic Effects In Vitro and In Vivo

Hydrogen sulfide (H(2)S)-releasing NSAIDs exert potent anti-inflammatory effects beyond classical cyclooxygenase inhibition. Here, we compared the platelet inhibitory effects of the H(2)S-releasing aspirin derivative ACS14 with its mother compound aspirin to analyze additional effects on platelets. In platelets of mice fed with ACS14 for 6 days (50 mg/kg per day), not only arachidonic acid-induced platelet aggregation but also ADP-dependent aggregation was decreased, an effect that was not observed with an equimolar dose of aspirin (23 mg/kg per day). ACS14 led to a significantly longer arterial occlusion time after light-dye-induced endothelial injury as well as decreased thrombus formation after ferric chloride-induced injury in the carotid artery. Bleeding time was not prolonged compared with animals treated with equimolar doses of aspirin. In vitro, in human whole blood, ACS14 (25-500 µmol/L) inhibited arachidonic acid-induced platelet aggregation, but compared with aspirin additionally reduced thrombin receptor-activating peptide-, ADP-, and collagen-dependent aggregation. In washed human platelets, ACS14 (500 µmol/L) attenuated αIIbβ3 integrin activation and fibrinogen binding and increased intracellular cAMP levels and cAMP-dependent vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The H(2)S-releasing aspirin derivative ACS14 exerts strong antiaggregatory effects by impairing the activation of the fibrinogen receptor by mechanisms involving increased intracellular cyclic nucleotides. These additional antithrombotic properties result in a more efficient inhibition of thrombus formation in vivo as achieved with aspirin alone.