Letters in Drug Design & Discovery - Volume 3, Issue 7, 2006

Differential pathophysiological roles of estrogen receptors alpha (ERα) and beta (ERβ) are of particular interest for phytochemical screening. A QSAR incorporating theoretical descriptors was developed in the present study utilizing sequential multiple-output artificial neural networks. Significant steric, constitutional, topological and electronic descriptors were identified enabling ER affinity differentiation.

Malignant gliomas are associated with poor prognoses despite surgical, radiation and chemotherapy interventions. Since notable side-effects are associated with each of the aforementioned therapies, the future design of glioma immunotherapy clinical trials will need to address immune modulation at multiple levels for efficacious results. The review discusses emerging data that provides novel insights into immune modulation and their possible implications for immunotherapeutic approaches. The next generation of immunotherapy is largely focused on improving immune effector targeting and directing the tumor immune microenvironment to work synergistically with systematic immune activation.

Tris-polypyridine ruthenium complexes were synthesized by the reaction methods reported. These compounds were characterized by FAB-mass, Elemental Analysis, 1H/31P NMR, UV-Vis and IR spectroscopies. Absorption and viscometric studies, carried out by the interaction of the complexes [Ru(bipy)2phendiamine] (PF6)2 (1) and [Ru(phen)2Phendione](PF6)2 (2) with calf thymus DNA, suggested that the complex 2 binded by intercalation, whilst the complex 1 did by a nonintercalative way, likely by the groove binding mode. The biological activity of the complexes was tested in vitro on Leishmania (L) mexicana promastigotes. The growth inhibition of 36% and 49% by 1 and 2 respectively, after 48 hours of treatment with 10 μM concentration, was associated with high proportion of parasite fission forms, motility loss and abundant vacuolization. These findings suggest that the leishmanistatic activity could be related to complexes-DNA parasite interactions as possible mechanism of action, constituting new promising chemotherapeutic alternatives in the fight against cutaneous leishmaniasis.

5-Lipoxygenase, which leads to the biosynthesis of proinflammatory lipid mediators, is involved in the pathogenesis of cancer. Experimental studies have demonstrated that 5-lipoxygenase inhibitors have antitumoral properties. Here, we describe the compelling evidence that 5-lipoxygenase inhibition is a rational therapy for certain cancers and for adjuvant approaches to cancer therapy.

Affinity labeling using reactive nucleotide analogues can locate an enzyme's catalytic and/or regulatory nucleotide site and map the amino acid residues accessible from that binding site. This article first summarizes the classes of nucleotide affinity labels available. It then illustrates how such compounds have been used to provide insights into the function and structure of nucleotide-binding enzymes, as exemplified by adenylosuccinate lyase, adenylosuccinate synthetase, glutamate dehydrogenase and cAMP phosphodiesterase.

Free radical damage to endothelial cells is implicated in the pathogenesis of arteriosclerosis. We show that platelet monoamine oxidase (MAO) synthesizes 3,4-dihydroxyphenylglycolaldeyde (DOPEGAL), the free radical generating metabolite of norepinephrine (NE). Platelet synthesis of DOPEGAL could contribute to arteriosclerosis and provide a target for protective therapy to prevent arteriosclerosis in medical conditions with elevated NE levels.

Mycophenolic acid was firstly used in clinical practice during the mid ‘90s in clinical transplantation, documenting its superiority as antiproliferative agent in comparison with azathioprine. Due to its pleiotropic mechanism of action, mycophenolic acid was thought to be effective in both immune and nonimmune diseases involving the kidney. Its efficacy in lupus nephritis is well documented by both single center and multicenter randomized studies. Recent studies documented the efficacy of MMF (morpholinoethyl ester of mycophenolic acid) in some progressive idiopathic glomerulonephritis such as steroid resistant nephritic syndrome, membranous glomerulonephritis and IgA nephritis. MMF efficacy is mostly documented by the reduction of proteinuria and by the stabilization of glomerular filtration rate (GFR).

A hybrid molecule synthesis strategy is employed to develop new molecules with potential antibacterial activity. Three types of coumarin-linked hybrids have been synthesized. The coumarin ring system has been linked to phthalimido, naphthalimido and quinolone moieties at 4-position through piperazino alkane spacers. These compounds have been evaluated for their antibacterial activity. Some of these new hybrids particularly phthalimido and naphthalimido ones have exhibited DNA gyrase inhibition activity.

“Adipopharmacology” connotes the adipotargeting studies aimed at drug discovery. Here we focus on adipopharmacology of nerve growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor and metallothioneins. Because these factors improve glucose, lipid and antioxidant metabolism, we named them metabotrophic factors (metabotrophins).

Sixteen pyrrole containing hydrazones were synthesized from isoniazid (INH) or from 1H-1- pyrrolylcarbohydrazides. Nine products exhibited 92-100% inhibitory activity against Mycobacterium tuberculosis H37Rv at 6.25 μg/mL (Microplate Alamar Blue Assay). Two leads showed MICs 0.78 and >0.1 μg/mL, SIs >12.82 and >100. “Drug likeness” was assessed by “Lipinski rule of five”.