Design, Synthesis, and Biological Studies of Flavone-Based Esters and Acids as Potential P450 2A6 Inhibitors.

As a potential means for smoking cessation and consequently prevention of smoking-related diseases and mortality, in this study, our goal was to investigate the inhibition of nicotine metabolism by P450 2A6. Smoking is the main cause of many diseases and disabilities and harms nearly every organ of the body. As reported by the Centers for Disease Control and Prevention (CDC), more than 16 million Americans are living with diseases caused by smoking. On average, the life expectancy of a smoker is about 10 years less than a nonsmoker. Smoking cessation can substantially reduce the incidence of smoking-related diseases, including cancer. At least, 70 of the more than 7000 cigarette smoke components, including polycyclic aromatic hydrocarbons, N-nitrosamines, and aromatic amines, are known carcinogens. Nicotine is the compound responsible for the addictive and psychopharmacological effects of tobacco. Cytochrome P450 enzymes are responsible for the phase I metabolism of many tobacco components, including nicotine. Nicotine is mainly metabolized by cytochrome P450s 2A6 and 2A13 to cotinine. This metabolism decreases the amount of available nicotine in the bloodstream, leading to increased smoking behavior and thus exposure to tobacco toxicants and carcinogens. Here, we report the syntheses and P450 2A6 inhibitory activities of a number of new flavone-based esters and acids. Three of the flavone derivatives studied were found to be potent competitive inhibitors of the enzyme. Docking studies were used to determine the possible mechanisms of the activity of these inhibitors.

DESIGN AND SYNTHESIS OF DIBENZYLFURAN BASED ETHER AND ESTER DERIVATIVES AS POTENTIAL P450 INHIBITORS.

Cytochrome P450 enzymes are a superfamily of hemoproteins involved in the metabolism and detoxification of endogenous and exogenous compounds. P450s are involved in the bioactivation of certain procarcinogens leading to the production of carcinogenic species. This has resulted in P450s' popularity as targets in cancer research. Developing selective and potent mechanism-based inhibitors for these enzymes is expected to be the key to understanding their mechanisms of action, as well as, developing potential anticancer agents. Our group has shown that certain aryl and aryl-alkyl acetylenes act as inhibitors of these enzymes. In an attempt to increase the number of selective P450 inhibitors available for enzymatic studies, five novel dibenzofuran ethers and esters have been designed and synthesized successfully.

A dibenzofuran derivative: 2-(pentyloxy)dibenzo[b,d]furan.

The title compound, C17H18O2, crystallizes in two-dimensional sheets, in which the 2-(pentyloxy)dibenzo[b,d]furan molecules are arranged in a head-to-head and tail-to-tail fashion that enables hydrophobic interactions between fully extended 2-pentoxy chains and π-π stacking between dibenzofuran rings in adjacent rings. Nearest intermolecular π-π stacking contacts are 3.3731 (12) Å. The molecule is nearly planar with an r.m.s. deviation of 0.0803 Å from the mean plane defined by the nineteen non-hydrogen atoms.

Who's not driving among U.S. high school seniors: A closer look at race/ethnicity, socioeconomic factors, and driving status.

OBJECTIVES: We examined associations among race/ethnicity, socioeconomic factors, and driving status in a nationally representative sample of >26,000 U.S. high school seniors. METHODS: Weighted data from the 2012 and 2013 Monitoring the Future surveys were combined and analyzed. We imputed missing values using fully conditional specification multiple imputation methods. Multivariate logistic regression modeling was conducted to explore associations among race/ethnicity, socioeconomic factors, and driving status, while accounting for selected student behaviors and location. Lastly, odds ratios were converted to prevalence ratios. RESULTS: 23% of high school seniors did not drive during an average week; 14% of white students were nondrivers compared to 40% of black students. Multivariate analysis revealed that minority students were 1.8 to 2.5 times more likely to be nondrivers than their white counterparts, and students who had no earned income were 2.8 times more likely to be nondrivers than those earning an average of ≥$36 a week. Driving status also varied considerably by student academic performance, number of parents in the household, parental education, census region, and urbanicity. CONCLUSIONS: Our findings suggest that resources-both financial and time-influence when or whether a teen will learn to drive. Many young people from minority or lower socioeconomic families who learn to drive may be doing so after their 18th birthday and therefore would not take advantage of the safety benefits provided by graduated driver licensing. Innovative approaches may be needed to improve safety for these young novice drivers.

Brief report: feasibility of social cognition and interaction training for adults with high functioning autism.

The goal of this study was to evaluate the feasibility and utility of a group-based cognitive behavioral intervention to improve social-cognitive functioning in adults with high-functioning autism (HFA). We modified the treatment manual of a previously validated intervention, Social Cognition and Interaction Training (SCIT), for optimal use with HFA adults (SCIT-A). We then conducted a pilot study to compare SCIT-A (n = 6) to treatment as usual (TAU) (n = 5) for adults with HFA. Feasibility was supported; attendance was high (92%) and satisfaction reports were primarily positive. Participants in SCIT-A showed significant improvement in theory-of-mind skills and trend level improvements in social communication skills; TAU participants did not show these improvements. Findings indicate SCIT-A shows promise as an intervention for adults with HFA.

Social services: the Navajo way.

The development of child welfare services in Indian Country followed enactment of the 1975 Indian Education and Self-Determination Act and the 1978 Indian Child Welfare Act. These acts allow tribal contracting with the Bureau of Indian Affairs (BIA) to provide social services. Because the BIA model has not fit well with Navajo needs, the Navajo Nation Division of Social Services is creating a more holistic case management paradigm for child and family services, which is more congruent with its culture and its rural, sparsely populated land.