Blocked dihydropteridines as nitric oxide synthase activators

It has been shown that 6-acetyl-7,7-dimethyl-5,6,7,8-tetrahydropteridin-4(3H)-one can act as a competent cofactor for the production of nitric oxide by neuronal nitric oxide synthase (nNOS). More information was sought on the structural features that could contribute to strong binding within the enzyme whilst maintaining a fast electron transfer rate. This study was concerned with expansion at the C2-position of the pteridine scaffold. The evidence suggests that expansion at the C2-position had a deleterious effect with respect to Km and as a consequence electron transfer rate. Unexpectedly, several lines of evidence suggested that a methyl substituent on nitrogen at C2 reduced the electron density in the pyrimidine and dihydropterin rings

Testing small molecule analogues of acanthocheilonema viteae immunomodulator ES-62 against clinically relevant allergens

ES-62 is a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae that protects against ovalbumin (OVA)-induced airway hyper-responsiveness in mice by virtue of covalently attached anti-inflammatory phosphorylcholine (PC) residues. We have recently generated a library of Small Molecule Analogues (SMAs) of ES-62 based around its active PC moiety as a starting point in novel drug development for asthma, and isolated two compounds - termed 11a and 12b – that mirror ES-62’s protective effects. In the present study we have moved away from OVA, a model allergen, to test the two SMAs against two clinically relevant allergens – house dust mite (HDM) and cockroach allergen (CR) extract. We show that whereas both SMAs offer some protection against development of lung allergic responses to CR, in particular reducing eosinophil infiltration, only SMA 12b is effective in protecting against eosinophil-dependent HDM-induced allergy. These data therefore suggest that helminth molecule-induced protection against model antigens may not necessarily translate to clinically relevant antigens. Nevertheless, in the present study we have managed to demonstrate that it is possible to produce synthetic drug-like molecules based on a parasitic worm product that show therapeutic potential with respect to asthma resulting from known triggers in humans

Minor groove binders 1998-2004

Several classes of compounds, including heterocyclic polyamides, aryl benzimidazoles, pyrrolobenzodiazepines, amidino arylfurans and benzofurans, have been found to bind to the minor groove of DNA with sequence selectivity and potential therapeutic consequences. Many such compounds are synthetic analogues of natural products such as distamycin, netropsin, CC-1065, duocarmycin and anthramycin. Biological activity has been demonstrated in antibacterial, antifungal, antiviral and anticancer applications, and several compounds are in clinical trials. This review covers patents since 1998 and reviews the structures, mechanisms and biological activity of minor groove binders in the context of the current scientific understanding described in the journal literature

Cholest-5-ene-3 beta,4 beta-diyl diacetate

The title steroid, C31 H5004, is shown to pack in a highly anisotropic manner. Only a-face-to-/~-face contacts are found in the stacks formed along the b direction, there are only head-to-tail contacts in the c direction and the acetate groups lie in layers normal to c

3-Acetoxycyclohex-4-ene-1,2-di-carboxylic anhydride

The title compound, C10H10O5, was found to exist as the endo-cis isomer with a pair of enantiomers in the asymmetric unit. The cyclo­hexene ring is folded about the methyl­ene-to-CH(acetoxy) vector to give a boat conformation

Syntheses of highly functionalised 6-substituted pteridines

Methods for the synthesis of polyfunctional 6-substituted pteridines from the corresponding 6-aldehydes are described. Alkene, ester, ketone, amide, cyano, oxime, bromo, methoxy and dihydroxy functional groups have all been introduced principally through improved methodologies for Wittig reactions using 2-thioalkyl-6-formylpteridines as substrates. Further modification of the alkenes derived from the Wittig reactions was difficult but selective conversion to the vic-diol was possible using ligand assisted catalysis with osmium tetraoxide. These methods are a component of an extensive methodology for the preparation of compounds that might serve as modulators of tetrahydrobiopterin activity or as inhibitors of dihydroneopterin aldolase

Pteridine derivatives as nitric oxide synthase activators

The present invention relates to the use of pteridine derivatives as nitric oxide synthase activators. In particular, the derivatives find use in the treatment of diseases associated with endothelial dysfunction such as cardiovascular diseases

A divergent synthesis of minor groove binders with tail group variation

A new synthesis of polyamide minor groove binders in which diversity is introduced by the nucleophilic substitution of a 2-sulfido-1,3,2-diazaphospholidinyloxy substituent by volatile secondary amine nucleophiles is described. Such a method has potential value for economically investigating structure-activity relationships in this important class of compounds through library synthesis. As an example using this method are prepared two new minor groove binders with pyrrolidinyl or piperidinyl tail groups that are close relatives of highly active antibacterial minor groove binders with morpholinyl tail groups. The antibacterial activity found against Staphylococcus aureus and Mycobacterium spp. indicates that the pKa of this set of compounds is not the dominant factor in determining the antibacterial activit