Electrochemical and peroxidase oxidation study of N'-hydroxyguanidine derivatives as NO donors

The electrochemical properties of a series of N-substituted-N'-hydroxyguanidines were studied. Two oxidation potentials of each compound were obtained by cyclic voltammetry. The E(ox1) values were from 0.51 to 0.62V, while the E(ox2) values were from 1.14 to 1.81V in acetonitrile solution. Next, their enzymatic controlled NO release abilities were evaluated. All N'-hydroxyguanidines exhibited efficient NO release abilities under the oxidation by horseradish peroxidase in the presence of H(2)O(2).     

Synthesis and biological evaluation of stilbene derivatives coupled to NO donors as potential antidiabetic agents

The work is focused on the design of drugs that prevent and treat diabetes and its complications. A novel class of stilbene derivatives were prepared by coupling NO donors of alkyl nitrate and were fully characterised by NMR and other techniques. These compounds were tested in vitro activity, including α-glucosidase inhibitory activity, aldose reductase (AR) inhibitory activity and advanced glycation end products (AGEs) formation inhibitory activity. A class of modified compounds could play a significant effect for treatment of diabetic complications. Target compounds 3e and 7c offered a potential drug design concept for the development of therapeutic or preventive agents for diabetes and its complications.     

Synthesis and promotion angiogenesis effect of chrysin derivatives coupled to NO donors

Two types of new chrysin derivatives were prepared by coupling NO donors of alkyl nitrate and furazan derivatives and were fully characterized by ¹H NMR and other techniques. These compounds were tested in human umbilical vein endothelial cells (HUVECs-12) and all the compounds exhibited cell proliferation. Notable effects of promoting angiogenesis were observed for all the modified compounds using chick chorioallantoic membrane (CAM) assay.     

Pyrrolo-quinoline derivatives as potential antineoplastic drugs

Some novel pyrrolo-quinoline derivatives have been synthesized as potential antineoplastic agents. They contain an angular aromatic tricyclic or tetracyclic system, to which the methanesulfon-anisidide side chain typical of amsacrine as such, or lacking the m-methoxy substituent, is connected. A methyl group can be present at position 7 of the pyrrolo-quinoline ring. The novel compounds exhibit interesting cell growth inhibitory properties when tested against the NCI panel of cell lines, in particular those obtained from solid tumors like CNS-, melanoma- and prostate-derived cells. The mechanism of cytotoxic action does not seem to be related to topoisomerase II poisoning ability. Most active proved to be compound 4a, which lacks both methyl and methoxy substituents, followed by 5a, having the methoxy group only. Biological activity is less pronounced in the tetracyclic family of derivatives 6 and 7.     

Effects of guanidine derivatives on mitochondrial function

Steady-state concentrations of citric acid cycle compounds accumulating during state 3 oxidation of pyruvate by guinea pig heart mitochondria have been measured using isotopic and fluorometric techniques; incubations partially inhibited with several guanidine derivatives and other inhibitors were compared with controls. The changes in levels of intermediates which occurred with guanidine derivatives were quantitatively and qualitatively identical to those with amytal; this pattern of intermediates was therefore not limited to those compounds which possess hypoglycemic propertiesin vitro. With antimycin, rotenone and nigericin the pattern of intermediates was specific for each agent, and differed from that with guanidine derivatives and amytal.Reduced pyridine nucleotides were also estimated at progressively increasing degrees of respiratory inhibition by these same agents. Lower concentrations of phenethylbiguanide and amytal produced identical increases in state 3 level of reduced pyridine nucleotide, while higher phenethylbiguanide concentrations were associated with a phosphatedependent decrease in reduced pyridine nucleotide level in both state 3 and state 4 which was not observed with amytal, and not accompanied by a stimulation of respiratory rate. These changes resemble the metabolic condition termed state 6, and are consistent with a calciumlike activity of guanidine derivatives. Changes in level of reduced pyridine nucleotide were observed which were specific to rotenone and nigericin; these changes, combined with the patterns of citric acid cycle intermediates observed with these inhibitors, are useful in interpreting the effects of these agents on the functional state of intact mitochondria.     

New arylsparteine derivatives as positive inotropic drugs

Positive inotropic agents are fundamental in the treatment of heart failure; however, their arrhythmogenic liability and the increased myocardial oxygen demand strongly limit their therapeutic utility. Pursuing our study on cardiovascular activities of lupin alkaloid derivatives, several 2-(4-substituted-phenyl)-2-dehydrosparteines and 2-(4-substituted-phenyl)sparteines were prepared and tested for inotropic and chronotropic activities on isolated guinea pig atria. Four compounds (6b, 6e, 7b, and 7f) exhibited significant inotropism that, at the higher concentrations, was followed by negative inotropism or toxicity. Compound 7e (2-(4-tolyl)sparteine) exhibited a steep dose-depending inotropic activity up to the highest concentration tested (300?µM) with an E_max of 116.5?±?3.4% of basal force, proving less potent but much more active in comparison to the highest concentrations tested of digoxin and milrinone having E_max of 87.5?±?3.1% and 52.2?±?1.1%, respectively. Finally, docking studies suggested that the relevant sparteine derivatives could target the sigma-1 receptor, whose involvement in cardiac activity is well documented.     

Synthesis, molecular modeling and biological evaluation of guanidine derivatives as novel antitubulin agents

A series of novel chalcone guanidine derivatives (4a–4q) have been designed and synthesized, and their biological activity were also evaluated as potential antiproliferative and antitubulin polymerization inhibitors. Compound 4q showed the most potent biological activity (IC₅₀ = 0.09 ± 0.01 μM for MCF-7 and IC₅₀ = 8.4 ± 0.6 μM for tubulin), which is comparable to the positive controls. Docking simulation was performed to position compound 4q into the colchicine binding site to determine the probable binding model, which suggested probable inhibition mechanism.     

Current-dependent block of endplate channels by guanidine derivatives

Methyl- and ethylguanidine block the endplate current in frog muscle. Both derivatives blocked inward-going endplate currents without affecting outward endplate currents. Repetitive stimulation that evoked several inward endplate currents enhanced the block, which suggests that these agents interact with open endplate channels. The relative conductance vs. potential curve exhibited a transition from a low to a high value near the reversal potential for the endplate current, both in normal and in 50% Na solution. In the latter solution, the reversal potential for endplate current was shifted by a mean value of 16 mV in the direction of hyperpolarization. The results suggest that methyl- and ethylguanidine block open endplate channels in a manner dependent on the direction of current flow rather than on the membrane potential.     

Development of Praziquantel sulphonamide derivatives as antischistosomal drugs

The almost empty armamentarium to treat schistosomiasis, a neglected parasitic disorder caused by trematode flatworms of the genus Schistosoma, except Praziquantel (PZQ), urged to find new alternatives to fight this infection. Carbonic Anhydrase from Schistosoma mansoni (SmCA) is a possible new target against this nematode. Here, we propose new PZQ derivatives bearing a primary sulphonamide group in order to obtain hybrid drugs. All compounds were evaluated for their inhibition profiles on both humans and Schistosoma CAs, X-ray crystal data of SmCA and hCA II in adduct with some inhibitors were obtained allowing the understanding of the main structural factors responsible of activity. The compounds showed in vitro inhibition of immature and adult S. mansoni, but further optimisation is required for improved activity.     

Differential cytostatic effects of NO donors and NO producing cells.

A 3-h exposure to NO donors (spermine-NO, DETA-NO, or SNAP), or to NOS II-expressing cells (activated macrophages or EMT6 cells) reversibly inhibited DNA synthesis in K562 tumor cells. In GSH-depleted K562 cells, cytostasis remained reversible when induced by DETA-NO or NOS II activity, but became irreversible after exposure to spermine-NO or SNAP. Only SNAP and spermine-NO efficiently inhibited GAPDH, an enzyme with a critical thiol, in GSH-depleted cells. Thus, the irreversible cytostasis induced in GSH-depleted cells by spermine-NO or SNAP can be tentatively attributed to S-nitrosating or oxidizing species derived from NO. However, these species did not contribute significantly to the early antiproliferative effects of macrophages. Ribonucleotide reductase, a key enzyme in DNA synthesis. has been shown to be inhibited by NO. Supplementation of the medium with deoxyribonucleosides to bypass RNR inhibition restored DNA synthesis in target cells exposed to DETA-NO and NO-producing cells, but was inefficient for GSH-depleted cells previously submitted to spermine-NO or SNAP. These cells also exhibited a persistent depletion of the dATP pool. In conclusion, GSH depletion reveals striking qualitative differences in the nature of the toxic effectors released by various NO sources, questioning the significance of S-nitrosating or oxidizing nitrogen oxides in NOS II-dependent cytostasis.     

Use of NO donors in biological systems

Owing to the increased interest in the biological roles of nitric oxide (NO) the use of NO donors is a desired method of delivering NO to the tissues of interest. This article gives an overview of the most commonly used classes of NO donors and their biotranstformation to release NO. A major consideration when choosing an NO donor is the preparation and handling of the compounds. A method has been outlined for the preparation of S-nitrosothiols which eliminates the problem of the overall instability of these compounds both as a solid and in solution. The main aim of this article is to outline the methods used in assessing the ability of NO donors to elicit a biological response in vitro in particular relaxation of vascular smooth muscle and inhibition of platelet aggregation. In addition a method is described for assessing the toxicological potential of NO donors in vitro.     

Methotrexate gamma-hydroxamate derivatives as potential dual target antitumor drugs

A series of new aminopteroyl-based hydroxamate derivatives were synthesized and tested in vitro in cell culture models as potential dual target drugs. These compounds were designed to target two families of enzymes, matrix metalloproteinases (MMP) and a folate enzyme, dihydrofolate reductase (DHFR). These enzymes are the components of two unrelated cellular pathways and they are often over-expressed in metastasizing tumors. In addition to the synthesis and full structural characterization of the hybrid molecules, we describe their inhibitory activities against a series of MMPs (MMP-2, MMP-7, MMP-9, MMP-14) and DHFR, as well as their antiproliferative activity in three cancer cell lines. The new hydroxamate derivatives of MTX proved to be effective inhibitors of MMPs and DHFR in the micromolar and nanomolar range, respectively. Furthermore, they showed strong antiproliferative activity against A549 cells (non-small cell lung carcinoma), and PPC-1 and Tsu-Pr1 prostate cancer cell lines. Therefore, based on the present results, these bi-functional drugs may be good candidates to target specific tumors in animal models due to potential combined effects on two pathways crucial for tumor development.     

Current status of artemisinin and its derivatives as antimalarial drugs

Artemisinin is a promising and a potent antimalarial drug, which meets the dual challenge posed by drug-resistant parasites and rapid progression of malarial illness. This review article focuses on the progress achieved during the last years in the production of artemisinin from Artemisia annua. The structure, biosynthesis and analysis of artemisinin and its mode of action are described. The review also focuses on clinical studies, toxicity studies, pharmacokinetics and activity of artemisinin related compounds. The production strategies including organic synthesis, extraction from plants, in vitro cultures and alternative strategies for enhancing the yields are also discussed.     

Heparin-like dextran derivatives as well as glycosaminoglycans inhibit the enzymatic activity of human cathepsin G

6-Phosphofructo-2-kinase catalyzes the synthesis and degradation of fructose 2,6-bisphosphate, activator of phosphofructokinase-1 and inhibitor of fructose 1,6-bisphosphatase. These properties confer to this bifunctional enzyme a key role in the control of glycolysis and gluconeogenesis. Several mammalian isozymes generated by alternative splicing from four genes, designated pfkfb1–4, have been identified. The results presented in this study demonstrate the expression of the pfkfb3 gene in C2C12 cells and its downregulation during myogenic cell differentiation. We also show that the decrease of ubiquitous 6-phosphofructo-2-kinase isozyme levels, product of pfkfb3 gene, is due to its enhanced degradation through the ubiquitin-proteasome proteolytic pathway.