Letters in Drug Design & Discovery - Volume 2, Issue 5, 2005

The synthesis and some pharmacological properties of new symmetrical compounds are described. The cytotoxicity, apoptosis induction and caspase-3 activation of the synthesized compounds have been evaluated against three human cancer cell lines. Compounds that showed cytotoxic activity were tested as proapoptotic and caspase-3 activators. Some of the compounds showed interesting values as apoptosis inducers and caused a notable increase in caspase-3 levels.

The taxane family of compounds has proven to be synthetically challenging targets. Using a novel [2+2] photocycloaddition reaction, several substituted cyclooctatrienes were synthesized and tested for tubulin polymerization activity. Elaboration of this methodology could allow the synthesis of a modified taxoid scaffold thereby permitting the efficient synthesis of paclitaxel analogs.

We identified a non-peptidomimetic HIV protease inhibitor sanguinarine through screening a small compound library with a high-throughput E. coli-based assay. In vitro, sanguinarine inhibits the HIV protease with an IC50 of around 13 μM. Based on docking results, binding modes of sanguinarine to the HIV protease are proposed.

The endogenous cannabinoids (endocannabinoids) are amides, esters and ethers of long chain polyunsaturated fatty acids. These lipids are bioactive signaling molecules that show diverse cellular and physiological effects and play various roles both in the central nervous system and in the periphery. The discovery of N-arachidonoylethanolamine (anandamide, AEA) and of the enzyme that terminates its signaling, i.e. fatty acid amide hydrolase (FAAH), have inspired pharmacological strategies to augment endocannabinoid tone and biological activity through inhibition of FAAH. Here we discuss the role of natural endocannabinoid derivatives, like the hydroxy-anandamides (OH-AEAs) generated from AEA via lipoxygenase activity, as powerful inhibitors of FAAH. We propose that these compounds, by reversibly inhibiting FAAH, may control in vivo the endocannabinoid tone. We discuss also the potential value of OH-AEAs as templates for the development of next-generation therapeutics that act at specific sites of FAAH.

The binding of the indirubin analogue indirubin-3'-aminooxy-acetate (E243) to glycogen phosphorylase (GP) has been studied by kinetic and crystallographic experiments. E243 was shown to be a competitive inhibitor of GPb with respect to both Glc-1-P and AMP (Ki values of 21 ± 7 μM and 16 ± 3 μM, respectively). The crystal structure of the GPb-E243 complex determined at 1.9 Å resolution showed one ligand molecule bound at the inhibitor site, mainly by intercalating between the two aromatic side chains of Phe285 and Tyr613. In addition, two E243 molecules, Mol 1 and Mol 2, were bound at the allosteric activator AMP binding site and a new sub-site in the vicinity of the allosteric site, respectively, with their indole-aminooxyacetate rings inclined approximately 40°. The binding mode of E243 to GPb inhibitor and allosteric site is different from those of flavopiridol, AMP, Glc-6-P, W1807, and a potent phenoxy-phthalate compound, previously described, illustrating how the enzyme can accommodate a number of diverse chemical entities.

Cyclooxygenase and 5-lipoxygenase pathways, which convert arachidonic acid into prostaglandins and leukotrienes, respectively, are the two major pro-inflammatory routes, whereas lipoxins, resolvins and neuroprotectins are potent endogenous anti-inflammatory mediators. Modulation of these pathways is key to control inflammation and to promote its resolution.

Animal models of diseases are essential for drug discovery and development. The availability of a large number of genetically-manipulated mice renders considerable interest in drug discovery by means of experimental models of disease. Ferric chloride-induced thrombosis is one of the most commonly used experimental models of thrombosis in mice. This review provides examples of optimizing this arterial thrombosis model for target validation and drug discovery in mice.

This investigation was planned to assess the therapeutic efficacy of a novel designed nonsteroidal anti-inflammatory drug, M2000 (ß- D- mannuronic acid) in experimental models of rheumatoid arthritis, multiple sclerosis, glomerulonephritis, and nephrotic syndrome. The anti-inflammatory property of M2000 was tested in Adjuvant-induced arthritis (AIA) by intraperitoneal (i.p.) administration of 40 mg/Kg/day M2000 and compared with indomethacin. The immunosuppressive effect of M2000 was evaluated using experimental model of multiple sclerosis, (Experimental autoimmune encephalomyelitis “EAE”). Its therapeutic potency on kidney diseases was studied using experimental models of nephrosis ( Adriamycin-induced nephropathy) and immune complex glomerulonephritis ( bovine serum albumin nephritis) by i.p. injection of M2000( 30mg/Kg/day) and compared with Piroxicam. Biocompatibility and pharmacotoxicology assessment of M2000 was carried out using WEHI-164 cell line, zymography method and determining the serum and urine parameters in healthy controls receiving M2000. Results showed that i.p. administration of M2000 to arthritic rats significantly reduced paw edema, and anti-inflammatory effect of tested drug was equivalent to that observed after treatment by Indomethacin. Immunosuppressive property of M2000 could significantly reduce clinical signs and histological erosions in treated Lewis rats compared with nontreated controls in EAE model, as well as lymph node cells proliferative assay in EAE confirmed immunosuppressive efficacy of tested drug. Our data in experimental model of immune complex glomerulonephritis and experimental nephrosis using Sprague-Dawley rats showed that i.p. administration of M2000 could significantly decrease the urinary protein excretion, blood urea nitrogen (BUN), serum creatinine and plasma concentration of cholesterol, as well as glomerular hypercellularity, PMN infiltration and cast formation in histological assessment of kidney in treated rats by M2000 compared with non-treated animals. Our findings using Fibrosarcoma (WEHI, 164) cell line revealed that tested drug has an inhibitory effect on Matrix Metalloproteinase 2 activity compared to Dexamethasone, Piroxicam and Diclofenac. Pharmacotoxicology study using animal models and in vitro examination showed that M2000 is the safest antiinflammatory and immunosuppressive drug with the greatest tolerability in comparison with Dexamethasone and tested conventional NSAIDs. Additionally, M2000 had no ulcerogenic effect on rat stomach and had no influence on the body temperature of normothermic rats at its anti-inflammatory dose range. Our data indicate that M2000 as a new anti-inflammatory drug with immunosuppressive property and greatest tolerability not only has no gastro-nephrotoxicity, but it is the first novel designed NSAID with lowest molecular weight and therapeutic effects on glomerulonephritis and nephrosis due to which it could be strongly recommended in an extensive scale as a safest drug for decreasing the anti-inflammatory reactions.

A series of aromatic polycationic molecules were synthesised and tested as potential non-classical antiherpes agents. Analogue (4) had a high potency in all four of the HSV cell lines used and is far more potent than ribavirin. The fact that none of the new compounds show any selectivity for HSV-2 over HSV-1 may imply that there is no intervention of a HSV-2 glycoprotein C (gC) dependent pathway.