The pleiotropic functions of aspirin: mechanisms of action

Recent studies have suggested that aspirin and aspirin-like compounds have a variety of actions in addition to their well-studied ability to inhibit cyclooxygenases. These actions include inhibition of the uncoupling of oxidative phosphorylation, decreases in adenosine triphosphate stores, increases in extracellular adenosine, downregulation of the expression and activity of inducible nitric oxide synthetase, inhibition and/or stimulation of various mitogen-activated protein kinase activities and inhibition of nuclear factor binding κB site (NF-κB) activation. Moreover, aspirin-like compounds have recently been shown to have previously unappreciated clinical and biological effects, some apparently independent of cyclooxygenase. In this review we discuss the various mechanisms of action of aspirin-like compounds and their relevance to clinical disease and therapy. Received 1 February 1999; received after revision 1 April 1999; accepted 7 May 1999     

Leishmania donovani in hamsters: stimulation of non-specific resistance by some novel glycopeptides and impact on therapeutic efficacy

Several glycopeptides structurally related to muramyl dipeptide (MDP) have been synthesized and evaluated for their ability to stimulate the non-specific resistance of hamsters against L. donovani infection. These compounds have been named CDRI compounds. The synthetic procedure used for compounds 86/448 and 84/212 is described. MDP and its synthetic congeners were administered as immunostimulants at a prophylactic dose of 3 mg/kg at two weeks interval. The challenge infection (1 x 10(7) amastigotes i.c./hamster) was given in between two doses of the compounds. One of the glycopeptides, CDRI comp. 86/448, has been found to be significantly more potent than MDP, effecting 92% inhibition of the challenge dose, whereas MDP produced only 26.5% inhibition. The effect of comp. 86/448 lasted until day 7 of challenge. The efficacy of sodium stibogluconate was appreciably improved in hamsters treated with comp. 86/448.     

Leishmania donovani in hamsters: Stimulation of non-specific resistance by some novel glycopeptides and impact on therapeutic efficacy

Summary Several glycopeptides structurally related to muramyl dipeptide (MDP) have been synthesized and evaluated for their ability to stimulate the non-specific resistance of hamsters againstL. donovani infection. These compounds have been named CDRI compounds. The synthetic procedure used for compounds 86/448 and 84/212 is described.MDP and its synthetic congeners were administered as immunostimulants at a prophylactic dose of 3 mg/kg at two weeks interval. The challenge infection (1×10⁷ amastigotes i.c./hamster) was given in between two doses of the compounds. One of the glycopeptides, CDRI comp. 86/448, has been found to be significantly more potent than MDP, effecting 92% inhibition of the challenge dose, whereas MDP produced only 26.5% inhibition. The effect of comp. 86/448 lasted until day 7 of challenge. The efficacy of sodium stibogluconate was appreciably improved in hamsters treated with comp. 86/448.     

Die Wirkung von Chinonen auf das Hefewachstum

Summary Certain derivatives ofp-benzoquinone and the naphthoquinones cause a strong inhibition of the growth of yeast. The strongest concentrations of some of these compounds even show a fungicidal potency. The authors discuss the possible mode of action of this inhibition.     

Constituents of Egyptian Euphorbiaceae. IX. Irritant and cytotoxic ingenane esters fromEuphorbia paralias L.

Summary The irritant and cytotoxic constituents of the latex ofEuphorbia paralias L. were separated from the hydrocarbon fraction by means of solvent partition. 3 new ingenane esters were identified from the toxic ether fraction. The major compound was 3-angelyl-20-deoxyingenol and the 2 minor compounds were 3-hexanoyl-20-deoxyingenol and 3-angelylingenol. These compounds were of a similar potency to podophyllin in the inhibition of³H-thymidine uptake by TLX/5 mouse lymphoma cells. In addition the compounds produced a persistent erythema of the mouse ear in sub-microgram doses.Acknowledgments. F.J. Evans is grateful to the Royal Society for a travel grant.     

Alpha-hydrazinophloretic acid, competitive inhibitor of fungal tyrosinase]

alpha-Hydrazinophloretic acid, the hydrazino analogue of tyrosine, was shown to behave as a competitive inhibitor of tyrosinase. Some closely related compounds, especially the hydrazino analogue of phenylalanine as well as other hydrazine derivatives, will also inhibit the enzyme, but in these cases, the inhibition observed belonged to the non-competitive type.     

Comparative study, in the Allium test, of the cytotoxicity of tubulosine and of 6 synthetized pseudo-tubulosines]

Comparing cytotoxicity of tubulosine and of six newly synthesized pseudo-tubulosines in the Allium test, we have characterized all the current features of protein inhibition. Nevertheless cytotoxicity of the six pseudotubulosines is much weaker. Furthermore, "floating poles anaphasis", a disturbance characteristic of the action of tubulosine, has been found with a lesser intensity with the other compounds.     

Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 3

Alcohol dehydrogenase 3 (ADH3) has been assigned a role in nitric oxide homeostasis due to its function as an S-nitrosoglutathione reductase. As altered S-nitrosoglutathione levels are often associated with disease, compounds that modulate ADH3 activity might be of therapeutic interest. We performed a virtual screening with molecular dockings of more than 40,000 compounds into the active site of human ADH3. A novel knowledge-based scoring method was used to rank compounds, and several compounds that were not known to interact with ADH3 were tested in vitro. Two of these showed substrate activity (9-decen-1-ol and dodecyltetraglycol), where calculated binding scoring energies correlated well with the logarithm of the k _cat/K _m values for the substrates. Two compounds showed inhibition capacity (deoxycholic acid and doxorubicin), and with these data three different lines for specific inhibitors for ADH3 are suggested: fatty acids, glutathione analogs, and cholic acids.     

Comparison of bicyclic phosphorous esters with bicuculline and picrotoxin as antagonists of presynaptic inhibition in the rat cuneate nucleus

Summary The effects of 2 of a series of bicyclic phosphorous esters, the ethyl (EPTBO) and isopropyl (IPTBO) compounds, were compared with those of the GABA antagonists, picrotoxin and bicuculline, on presynaptic inhibition in the rat cuneate nucleus. Both EPTBO and IPTBO were found to be effective, reversible antagonists of presynaptic inhibition, with IPTBO approximately 10 times more potent than EPTBO and equipotent with bicuculline, EPTBO equipotent with picrotoxin.The authors are grateful to Dr J. F. Collins, Department of Chemistry, Sir John Cass School of Science and Technology, 31 Jewry Street, London, for the gift of bicyclic phosphorous esters.     

Chlorodimeform and its effect on monoamine oxidase activity in the cattle tick, Boophilus microplus.

The action of the acaricide, chlorodimeform and its metabolite. N-desmethylchlorodimeform, on the activity monoamine oxidase (MAO) from the cattle tick, Boophilus microplus, were studied. Both compounds were found to be potent in vitro and in vivo inhibitors of the enzyme. However the inhibition of MAO does not seem to be related to the toxic action of the acaricide.     

Chlorodimeform and its effect on monoamine oxidase activity in the cattle tickBoophilus microplus

Summary The action of the acaricide, chlorodimeform and its metabolite, N-desmethylchlorodimeform, on the activity monoamine oxidase (MAO) from the cattle tick,Boophilus microplus, were studied, Both compounds were found to be potent in vitro and in vivo inhibitors of the enzyme. However the inhibition of MAO does not seem to be related to the toxic action of the acaricide.     

Arylpyridyl-thiosemicarbazones: A new class of anti-juvenile hormones active against Lepidoptera

Summary A new class of anti-juvenile hormone agents is described. Active anti-juvenile hormone compounds were either diazine thiosemicarbazones or aryl substituted pyridyl thiosemicarbazones, synthesized from substituted benzaldehydes. While many analogs in these classes showed feeding and growth inhibition in a variety of insects, a select group caused formation of precocious pupal characteristics inAgrotis ipsilon (black cutworm) andHeliothis virescens (tobacco budworm) and black cuticle and precocious pupae inManduca sexta (tobacco hornworm). They were active only by diet incorporation. The symptoms of precocious development could be reversed by co-administration of a juvenoid. One of the active compounds was shown to inhibit juvenile hormone biosynthesis in vitro by corpora allata of the cockroachDiploptera punctata. However, none of the compounds were active inhibitors of purified chicken liver prenyl transferase.     

Inhibition of glucose transport in human erythrocytes by 2,3-dioxoindole (Isatin)

10 mM isatin (2,3-dioxoindole) inhibited glucose influx into human erythrocytes by over 30%. The inhibition is of the competitive type, where the affinity constant (K_t) was increased from 5.71 (control) to 11.11 mM in the presence of isatin with no change in V_max (130 nmol/min/ml packed cells). The observed inhibition of sugar transport by isatin was not mediated through membrane–SH groups accessible to iodoacetate, iodoacetamide, DTNB, DNP or sodium arsenite. Isatin inhibited sugar transport in the presence of 2 mM harmaline, an alkaloid inhibitor of Na⁺, K⁺–ATP_ase activity. The inhibition was non additive which suggests that these two compounds interact with the same or a similar site on the erythrocyte membrane.     

Vidalols A and B,new anti-inflammatory bromophenols from the Caribbean marine red algaVidalia obtusaloba

Chemical studies of the Caribbean red algaVidalia obtusaloba have resulted in the isolation of two new bromophenolic metabolites, vidalols A and B (1, 2). The new compounds were discovered as part of an organized effort to isolate new naturally-occurring anti-inflammatory agents with a focus upon those which may function through the inhibition of phospholipase A₂.     

Comparative study of the sensitivity of acetylcholinesterases and cholinesterases from animal and bacterial sources to inhibition by serotonin and its derivatives.

Serotonin was found to inhibit human erythrocyte and electric-eel acetylcholinesterase activities. The serotonin amino group, free of negative charges in its vicinity and its hydroxyl group, were important for the inhibition. Serotonin precursors and several related compounds had little or no effect. Human plasma cholinesterase was also inhibited by serotonin and tryptamine. In contrast to these animal enzymes, the cholinesterase of Pseudomonas aeruginosa was refractory to serotonin and its derivatives under the same experimental conditions.     

Comparative study of the sensitivity of acetylcholinesterases and cholinesterases from animal and bacterial sources to inhibition by serotonin and its derivatives

Summary Serotonin was found to inhibit human erythrocyte and electric-eel acetylcholinesterase activities. The serotonin amino group, free of negative charges in its vicinity and its hydroxyl group, were important for the inhibition. Serotonin precursors and several related compounds had little or no effect. Human plasma cholinesterase was also inhibited by serotonin and tryptamine. In contrast to these animal enzymes, the cholinesterase ofPseudomonas aeruginosa was refractory to serotonin and its derivatives under the same experimental conditions.     

Über Pflanzenwachstumsregulatoren

Summary Simazin inhibits the Hill reaction, i.e. the use of light energy for the synthesis of energy-rich compounds. Isolated maize (corn) and spinach chloroplasts are, when analyzed in the Hill reaction, equally sensitive to the inhibitory action of Simazin. Furthermore, it does not influence the activity of catalase, nor does it inhibit respiration.Competitive inhibition of DPN is not seen in the presence of Simazin. On the other hand, this compound appears to interfere directly with the intermediate steps needing chlorophyll.     

Protein arginine deiminase 4: a target for an epigenetic cancer therapy

The recent approvals of anticancer therapeutic agents targeting the histone deacetylases and DNA methyltransferases have highlighted the important role that epigenetics plays in human diseases, and suggested that the factors controlling gene expression are novel drug targets. Protein arginine deiminase 4 (PAD4) is one such target because its effects on gene expression parallel those observed for the histone deacetylases. We demonstrated that F- and Cl-amidine, two potent PAD4 inhibitors, display micromolar cytotoxic effects towards several cancerous cell lines (HL-60, MCF7 and HT-29); no effect was observed in noncancerous lines (NIH 3T3 and HL-60 granulocytes). These compounds also induced the differentiation of HL-60 and HT29 cells. Finally, these compounds synergistically potentiated the cell killing effects of doxorubicin. Taken together, these findings suggest PAD4 inhibition as a novel epigenetic approach for the treatment of cancer, and suggest that F- and Cl-amidine are candidate therapeutic agents for this disease.     

Über einige pharmakologische Untersuchungen synthetischer Alkoxy-tropinderivate

Summary Some pharmacological properties of new synthetic alkoxy-tropine derivatives are reported. The tertiary compounds were relatively potent local anaesthetics with a low anti-cholinergic action. Acetylcholine inhibition, as well as the spasmolytic activityin vivo of the benzilic acid esters were markedly increased by quaternisation while their toxicity decreased. 6-Methoxytropine benzilic acid ester brom-methylate was the most active compound of this series. A pronounced inhibitory activity on neurogenically induced intestinal constriction was found in low doses, whereas larger doses exerted a ganglionic blocking effect.