Determination and characterization of organic explosives using porous graphitic carbon and liquid chromatography-atmospheric pressure chemical ionization mass spectrometry.

A new LC-MS method for the determination and characterization of three groups of commonly used organic explosives (nitroaromatic compounds, cyclic nitroamines and nitrate esters) was developed using a porous graphitic carbon (PGC) (Hypercarb) column. Twenty-one different explosive-related compounds--including 2,4,6-trinitrotoluene, its by-products and its degradation products--were chromatographically separated in a single analysis. This efficient separation facilitates the identification of the manufacturer of the explosive using the identified analytes as a fingerprint. A final, conclusive identification of the analytes can be obtained using LC-MS equipped with an atmospheric pressure chemical ionization (APCI) interface. Solvent effects on chromatographic behaviour were investigated, as were the effects of solvent mixtures and mobile phase additives. The number and the relative positions of the nitro groups within analyte molecules influence their order of elution; these effects were investigated. The data thus generated can be interpreted to support a hypothesis concerning the retention mechanism of nitro-containing compounds when using PGC. Limits of detection ranged from 0.5 to 41.2 ng. The new methodology described herein improves the sensitivity and selectivity of explosive detection. The effectiveness of the method is demonstrated by the analysis of soil samples containing explosives residue from test fields in Sweden and Afghanistan.

Nitration of 2-substituted pyrimidine-4,6-diones, structure and reactivity of 5,5-gem-dinitropyrimidine-4,6-diones.

Nitration of some 2-substituted pyrimidine-4,6-diones in sulfuric acid was studied, which afforded previously unknown 5,5-gem-dinitropyrimidine-4,6-diones in high yields. The gem-dinitro products were easily attacked by nucleophiles with concomitant formation of gem-dinitroacetyl derivatives, which in turn could be further hydrolyzed to salts of dinitromethane and triureas.

Structure-based design and synthesis of a thyroid hormone receptor (TR) antagonist.

Antagonists have been developed for several nuclear receptors but not for others, including TRs. TR antagonists may have significant clinical utility for treating hormone excess states and other conditions. A structure derived "extension hypothesis" was applied to synthesize a TR antagonist. The principal design feature was to attach an extension group to a TR agonist whose structure would perturb formation of the TR coactivator-binding surface. The compound, 3,5-dibromo-4-(3',5'-diisopropyl-4'-hydroxyphenoxy)benzoic acid, has no (TRalpha) or very weak partial (TRbeta) TR agonist activity and blocks TR binding of T3, formation of the coactivator-binding surface, and both a positive T3 response on a thyroid hormone response element and a negative T3 response on the TSHbeta promoter in cultured cells. The results suggest that 3,5-dibromo-4-(3',5'-diisopropyl-4'-hydroxyphenoxy)benzoic acid is a TR antagonist for thyroid hormone response element-mediated responses, this approach can be used more generally to generate nuclear receptor antagonists, and this compound or analogues may have medical and research utility.

Design of thyroid hormone receptor antagonists from first principles.

It is desirable to obtain TR antagonists for treatment of hyperthyroidism and other conditions. We have designed TR antagonists from first principles based on TR crystal structures. Since agonist ligands are buried in the fold of the TR ligand binding domain (LBD), we reasoned that ligands that resemble agonists with large extensions should bind the LBD, but would prevent its folding into an active conformation. In particular, we predicted that extensions at the 5' aryl position of ligand should reposition helix (H) 12, which forms part of the co-activator binding surface, and thereby inhibit TR activity. We have found that some synthetic ligands with 5' aryl ring extensions behave as antagonists (DIBRT, NH-3), or partial antagonists (GC-14, NH-4). Moreover, one compound (NH-3) represents the first potent TR antagonist with nanomolar affinity that also inhibits TR action in an animal model. However, the properties of the ligands also reveal unexpected aspects of TR behavior. While nuclear receptor antagonists generally promote binding of co-repressors, NH-3 blocks co-activator binding and also prevents co-repressor binding. More surprisingly, many compounds with extensions behave as full or partial agonists. We present hypotheses to explain both behaviors in terms of dynamic equilibrium of H12 position.