Various chromone derivatives have been used in asthma therapy, and their biological activity is apparently related to certain chemical features which include conformation and acidity. In the present study, substituent effects on conformation and acidity have been explored in chromone systems with potential biological activity. A range of variously substituted symmetrical chromone-2-carboxamides (including a series of N,N-dimethylchromone-2-carboxamides) have been prepared via chromone-2-carboxylic acids, which, in turn, were prepared from the corresponding o-hydroxyacetophenones. The N,N-dimethylchromone-2-carboxamides were prepared by reacting the appropriate chromone-2-carbonyl chlorides with dimethylammonium chloride in pyridine, in an approach which resolved various problems encountered in the preparation of these compounds. Substituent effects on the conformation of chromone-2-carboxamides have been explored using dynamic NMR spectroscopy, and the observed splitting of the N-alkyl signals has been attributed to slow site-exchange of the N-alkyl substituents. Dynamic NMR frequency separations and coalescence temperatures have been used to calculate rotational energy barriers, and substituent effects on these rotational energy barriers have been analysed. The possible implication of ring-opening of chromones in chromone pharmacology has also been examined. A range of 3-(2-hydroxybenzoyl)acrylamides has been prepared via the dimethylamine-mediated ring-opening of N,N-dimethylchromone-2-carboxamides and the E-double-bond configuration of the ring-opened products has been unambiguously established by single crystal analysis of the parent system. The configuration and conformation of the crystal structure of the parent system have been shown, using IR and NMR spectroscopic, and molecular graphics techniques, to be maintained in solution and to characterise the whole series. ¹H and ¹³C NMR spectroscopy have also been used to study the dimethylamine-mediated ring-opening of disodium cromoglycate. The kinetics of the dimethylamine-mediated ring-opening of N,N-dimethylchromone-2-carboxamides have been studied using UV spectroscopy. These reactions have been shown to follow third-order kinetics overall and a mechanism accommodating the observed third-order kinetics has been proposed. Substituent effects have been further investigated by the potentiometric determination of the pKa (pK [subscript a]) values for a series of chromone-2-carboxylic acids. The relationship between acidity and the observed rate constants has been explored and has verified that the observed rate constants are sensitive to the influence of meta-substituents on the stability of the phenoxide ion "leaving group" rather than C-2 electrophilicity.

Indiana University-Purdue University Indianapolis (IUPUI) / Asthma, a chronic inflammatory disease of the airways, affects nearly 25 million Americans. The vast majority of these patients suffer from exercise-induced bronchoconstriction (EIB), a complication of asthma. Although traditionally treated pharmacologically, nutritional strategies provide a promising alternative for managing EIB as the prevalence of asthma may be due in part to changes in diet. Our objective was to determine the effects of novel nutritional strategies on hyperpnea-induced bronchoconstriction (HIB) in asthmatic individuals. HIB uses rapid breathing to identify EIB in a research or clinical setting. Fish oil, a combination of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docsahexaenoic acid (DHA), has been shown to be effective in suppressing EIB. However, its use in combination with other nutritional supplements, the optimal fish oil formula, and its effect on smooth muscle contractility have not been fully explored. An in vivo study (study 1) was conducted in individuals with both asthma and HIB to determine whether a combination of fish oil and vitamin C was more effective than either one alone in alleviating HIB. Pulmonary function was significantly improved with both fish oil and the combination treatment but not with vitamin C alone. In study 2, individuals with both asthma and HIB were supplemented with DHA alone since the optimal formula for fish oil has yet to be ascertained; previous in vitro studies have suggested DHA may be the more potent omega-3 fatty acid in fish oil. However, no significant changes in pulmonary function or airway inflammation were seen with DHA supplementation. For study 3, canine airway smooth muscle tissue was treated with fish oil to determine the in vitro effect of fish oil on smooth muscle contractility. Acute treatment with fish oil relaxed smooth muscle strips that had been contracted with 5-hydroxytryptamine. These minor relaxations in smooth muscle tension with fish oil may represent significant changes at the level of the smaller airways. These studies have confirmed that fish oil represents a viable treatment modality for asthmatic individuals with EIB and suggest that fish oil may influence airway smooth muscle contractility.