A versatile synthesis of dihydropyrimidinone C-nucleosides

A versatile synthesis of N-substituted dihydropyrimidinone C-nucleosides (20-29) is described. Glycosyl amino esters (3-9), obtained by reductive alkylation of glycosyl amino esters 1 and 2, on condensation with different isocyanates afforded respective ureido derivatives (10-19) in good to quantitative yields. The latter on cyclative amidation with a combination of DBU/TBAB (tetrabutylammonium bromide)/4A molecular sieve gave the corresponding nucleosides (20-29) in good yields.     

Synthesis of galactopyranosyl amino alcohols as a new class of antitubercular and antifungal agents

The galactopyranosyl amino alcohols (3-16) were synthesised by regioselective oxirane ring opening of compound 2 with variety of amines and screened for antitubercular and antifungal activities. One of the compounds (16) showed potent activity against Mycobacterium tuberculosis H37 Rv in vitro and also displayed activity in MDR TB. The compound (16) was found to be superior to ethambutol clinically used anti TB drug in in vitro screen.     

Leishmanicidal activity of phenylene bridged C2 symmetric glycosyl ureides

A number of phenylene bridged C2 symmetric glycosyl uerides with ester (3a-f), alcohol (4a-c) and acid (5a-d) functionalities were prepared by addition of glycosyl amino esters with phenyl diisocyanates and their further reaction with LiAlH(4) or hydrolysis with LiOH. All the compounds were screened for their in vitro and in vivo antileishmanial activity. Most of the compounds exhibited good activity while two of the compounds 3e and 3f reduced the clinical dose of standard drug SSG.     

GABA receptors and nitric oxide ameliorate constrictive collagen remodeling in hyperhomocysteinemia

Elevated plasma levels of homocysteine (Hcy) are associated with vascular dementias and Alzheimer's disease. The role of Hcy in brain microvascular endothelial cell (MVEC) remodeling is unclear. Hcy competes with muscimol, an gamma-amino butyric acid (GABA)-A receptor agonist. GABA is the primary inhibitory neurotransmitter in the brain. Our hypothesis is that Hcy induces constrictive microvascular remodeling by altering GABA-A/B receptors. MVEC from wild type, matrix metalloproteinase-9 (MMP-9) knockout (-/-), heterozygote cystathionine beta synthase (CBS-/+), and endothelial nitric oxide synthase knockout (eNOS-/-) mouse brains were isolated. The MVEC were incorporated into collagen (3.2 mg/ml) gels and the decrease in collagen gel diameter at 24 h was used as an index of constrictive MVEC remodeling. Gels in the absence or presence of Hcy were incubated with muscimol or baclofen, a GABA-B receptor agonist. The results suggested that Hcy-mediated MVEC collagen gel constriction was ameliorated by muscimol, baclofen, MMP-9, and eNOS gene ablations. There was no effect of anti-alpha 3 integrin. However, Hcy-mediated brain MVEC collagen constriction was abrogated with anti-beta-1 integrin. The co-incubation of Hcy with L-arginine ameliorated the Hcy-mediated collagen gel constriction. The results of this study indicated amelioration of Hcy-induced MVEC collagen gel constriction by induction of nitric oxide through GABA-A and -B receptors.     

PPAR gamma agonist normalizes glomerular filtration rate, tissue levels of homocysteine, and attenuates endothelial-myocyte uncoupling in alloxan induced diabetic mice

Background: Homocysteine (Hcy) is an independent cardiovascular risk factor; however, in diabetes, the role of tissue Hcy leading to cardiac dysfunction is unclear.Aims: To determine whether tissue Hcy caused endothelial-myocyte uncoupling and ventricular dysfunction in diabetes.Methods: Diabetes was created in C57BL/6J male mice by injecting 65 mg/kg alloxan. To reverse diabetic complications, ciglitazone (CZ) was administered in the drinking water. Plasma glucose, Hcy, left ventricular (LV) tissue levels of Hcy and nitric oxide (NO) were measured. Glomerular filtration rate (GFR) was measured by inulin-FITC. Endothelial-myocyte coupling was measured in cardiac rings. In vivo diastolic relaxation and LV diameters were measured by a Millar catheter in LV and by M-mode echocardiography, respectively.Results: Plasma glucose, GFR and LV tissue Hcy were increased in diabetic mice and were normalized after CZ treatment; whereas, elevated plasma Hcy level remained unchanged with or without CZ treatment. NO levels in the LV were found inversely related to tissue Hcy levels. Attenuated endothelial-myocyte function in diabetic mice was ameliorated by CZ treatment. Cardiac relaxation, the ratio of LV wall thickness to LV diameter was decreased in diabetes, and normalized after CZ treatment.Conclusion: CZ normalized LV tissue levels of Hcy and ameliorated endothelial-myocyte coupling; therefore, specifically suggest the association of LV tissue Hcy levels with impair endothelial-myocyte function in diabetes.     

Genome Sequence of the ethene- and vinyl chloride-oxidizing actinomycete Nocardioides sp. strain JS614

Nocardioides sp. strain JS614 grows on ethene and vinyl chloride (VC) as sole carbon and energy sources and is of interest for bioremediation and biocatalysis. Sequencing of the complete genome of JS614 provides insight into the genetic basis of alkene oxidation, supports ongoing research into the physiology and biochemistry of growth on ethene and VC, and provides biomarkers to facilitate detection of VC/ethene oxidizers in the environment. This is the first genome sequence from the genus Nocardioides and the first genome of a VC/ethene-oxidizing bacterium.     

Aminopyridinecarboxamide-based inhaled IKK-2 inhibitors for asthma and COPD: Structure-activity relationship

Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK-2 inhaled program. This paper reports our efforts to identify a novel series of aminopyridinecarboxamide-based IKK-2 inhibitors, which display low nanomolar potency against IKK-2 with long duration of action (DOA), and metabolically labile to phase I and/or phase II metabolizing enzymes with potential capability for multiple routes of clearance. Several compounds have demonstrated their potential usefulness in the treatment of asthma and chronic obstructive pulmonary disease (COPD).