Synthesis, antibacterial action, and ribosome inhibition of deoxyspectinomycins

Spectinomycin, an aminocyclitol antibiotic, is subject to inactivation by aminoglycoside modifying enzymes (AMEs) through adenylylation or phosphorylation of the 6-hydroxy group position. In this study, the effects of deoxygenation of the 2- and 6-hydroxy group positions on the spectinomycin actinamine ring are probed to evaluate their relationship to ribosomal binding and the antimicrobial activities of spectinomycin, semisynthetic aminomethyl spectinomycins (amSPCs), and spectinamides. To generate these analogs, an improved synthesis of 6-deoxyspectinomycin was developed using the Barton deoxygenation reaction. 6-Dehydrospectinamide was also synthesized from spectinamide 4 to evaluate the H-bond acceptor character on the C-6 position. All the synthesized analogs were tested for antibacterial activity against a panel of Gram (+) and Gram (-) pathogens, plus Mycobacterium tuberculosis. The molecular contribution of the 2- and 6-hydroxy group and the aryl functionalities of all analogs were examined by measuring inhibition of ribosomal translation and molecular dynamics experiments with MM/GBSA analysis. The results of this work indicate that the 6-hydroxy group, which is the primary target of AMEs, is a required motif for antimicrobial activity in current analogs. Removal of the 6-hydroxy group could be partially rescued by offsetting ribosomal binding contributions made by the aryl side chains found in the spectinamide and amSPCs. This study builds on the knowledge of the structure-activity relationships of spectinomycin analogs and is being used to aid the design of next-generation spectinomycins

Tobacco Use in California: An Evaluation of the Tobacco Control Program, 1989-1993. A Report to the California Department of Health Services

TOBACCO USE IN CALIFORNIA DETAILED FINDINGS SUMMARIZED BY CHAPTER Chapter 4. ASSESSING PROGRESS TOWARD PROGRAM GOALS 1. Between 1990 and 1993, the proportion of California children and nonsmoking workers who were protected from ETS exposure increased substantially. 2. Cigarette consumption in California declined by an estimated 13.7% following the passage of Proposition 99 and the mandated increase in excise tax on cigarette products. This accelerated decline in consumption lasted approximately 5 months after the imposition of the 25-cent tax. 3. The introduction of Tobacco Control Program interventions was associated with an increase in the rate of decline in cigarette consumption. 4. Between 1988 and 1993, we observed a 27% decrease in per capita tobacco consumption and a 28% decline in smoking prevalence. Based on mUltiple surveys, the best estimate of smoking prevalence in 1993 among California adults is 19.1 %. 5. Following the passage of Proposition 99, smoking prevalence declined at twice the rate observed before Proposition 99. However, this new rate of decline must be increased by a further 50% in order to achieve the Program goal of a 75% reduction in prevalence by 1999. 6. Smoking prevalence among 16- to 18-year-old Californians appeared to be increasing sharply following the introduction of the "Joe Camel" tobacco advertising campaign. We were unable to identify a decline in prevalence associated with the imposition of the excise tax. No further increases in adolescent smoking prevalence were observed following the introduction of the Tobacco Control Program. 7. The decline in tobacco consumption and smoking prevalence in California appears to result from increases in successful smoking cessation among adults. 8. Popular support for a further increase in the excise tax on tobacco has grown. In 1993, 60% of Californians indicated support for an additional increase in the excise tax of at least 50 cents, provided that the money would be used for antitobacco and other health programs. Under these conditions, two thirds of current smokers favored an increase of at least 25 cents in the tobacco tax.Chapter 5. THE IMPACT OF THE ANTITOBACCO MASS MEDIA CAMPAIGN IN CALIFORNIA 1. A period of accelerated decline in per capita cigarette consumption in California began in April 1990, coinciding with the start of the mass media campaign. During a 12-month period, consumption declined by 12%. At this time, the media campaign was the only major tobacco control intervention in the field. 2. The proportion of Californians who attempted to quit smoking for more than 1 day increased whenever the mass media campaign was in the field and decreased during the period when the campaign was withdrawn. 3. More than half of California adults and more than two thirds of adolescents recalled seeing the antitobacco mass media campaign. 4. Adults who saw the media campaign were more likely than adults who did not see the campaign to believe that ETS is harmful to nonsmokers, especially to children. 5. Adults who saw the media campaign were more likely than adults who did not see the campaign to ask someone not to smoke. Almost 60% of smokers reported that they had been asked not to smoke on at least one occasion. 6. Half of Californians had voluntarily made their homes smokefree by 1993. The number of smokers reporting a smokefree home increased substantially between 1992 and 1993. Smokers who had young children in the home were more likely than smokers living without children to report a smokefree home. 7. Smokefree home policies were more likely if adults believed in the danger ofETS to nonsmokers. The spread of smokefree homes in California may be an indirect effect of the media campaign.Chapter 6. TOBACCO MARKETING AND SMOKING IN SCHOOLS AS BARRIERS TOEFFECTIVE ADOLESCENT PREVENTION PROGRAMS 1. Adolescents appear to be the most receptive audience for tobacco advertising. Awareness and liking of cigarette advertisements is higher among adolescents than among adults in California. Liking and awareness of the "Joe Camel" cigarette campaign was highest in the youngest agegroup studied (12 to 14 years). 2. Two thirds of adolescents have a favorite cigarette ad, and one quarter are willing to use products promoting tobacco