Synthesis of 2-Substituted 9-Oxa-Guanines {5-Aminooxazolo 5,4-D Pyrimidin-7(6H)-Ones} and 9-Oxa-2-Thio-Xanthines{5-Mercaptooxazolo 5,4-D Pyrimidin-7(6H)-Ones}

Oxazolo[5,4-d] pyrimidines can be considered as 9-oxa-purine analogs of naturally occurring nucleic acid bases. Interest in this ring system has increased due to recent reports of biologically active derivatives. In particular, 5-aminooxazolo[5,4-d]pyrimidine-7(6H)-ones (9-oxa-guanines) have been shown to inhibit ricin. The preparation of a series of 2-substituted 5-aminooxazolo[5,4-d] pyrimidin-7(6H)-ones and related 5-thio-oxazolo[5,4-d] pyrimidines is described, including analogs suitable for further elaboration employing "click" chemistry utilizing copper-catalyzed Huisgen 1,3-dipolar cycloadditions. Two of the compounds prepared were found to inhibit ricin with IC(50) ca. 1-3 mM.Pharmac

Inhibition of human telomerase by a G-quadruplex-interaction compound

Certain non-nucleoside compounds that will selectively inhibit telomerase by targeting the nucleic add structures, such as G-quadruplexes, that may be associated with human telomeres or telomerase have been identified. Inhibition of human telomerase by two perylenetetracarboxylic acid diimides and a carbocyanine has been demonstrated. 1H-NMR studies have evidenced the stabilization of a G-quadruplex by the perylenetetracarboxylic acid diimide compounds and provided evidence that these and structurally related compounds inhibit the telomerase enzyme by a mechanism consistent with interaction with G-quadruplex structures.Board of Regents, University of Texas Syste

Methods for treating bone deficit conditions with benzothiazole

" Compounds containing two aromatic systems covalently linked through a linker containing one or more atoms, or ""linker"" defined as including a covalent bond per se so as to space the aromatic systems at a distance 1.5-15 .ANG., are effective in treating conditions associated with bone deficits. The compounds can be administered to vertebrate subjects alone or in combination with additional agents that promote bone growth or that inhibit bone resorption. They can be screened for activity prior to administration by assessing their ability to effect the transcription of a reporter gene coupled to a promoter associated with a bone morphogenetic protein and/or their ability to stimulate calvarial growth in model animal systems. "Board of Regents, University of Texas Syste

Synthesis and studying the antitumor activity of novel 5-(2-methylbenzimidazol-5-yl)-1,3,4-oxadiazole-2(3H)-thiones

The influence of the incorporation of 1,3,4-oxadiazole ring into 2-methyl-1H-benzimidazole derivatives producing a series of substituted 5(6)-(2-methylbenzimidazol-5-yl)-1,3,4-oxadiazoles on the antitumor activity was studied in this study. The antitumor activity of the new compounds was tested against breast cancer cell line MCF-7 and lung cancer cell line A549. S-5-(2-methyl-1H-benzo[d]imidazol-5-yl)-1,3,4-oxadiazol-2-yl 2-nitrobenzenesulfonothioate (9) showed potent activity against both MCF-7 and A549 cell lines. Whereas, compounds 7, 11-13 and 15-17 have moderate growth inhibitory activity on the two cell lines

Compositions and methods for treating bone deficit conditions

Compounds containing two aromatic systems covalently linked through a linker containing one or more atoms, or “linker” defined as including a covalent bond per se so as to space the aromatic systems at a distance 1.5-15 å, are effective in treating conditions associated with bone deficits. The compounds can be administered to vertebrate subjects alone or in combination with additional agents that promote bone growth or that inhibit bone resorption. They can be screened for activity prior to administration by assessing their ability to effect the transcription of a reporter gene coupled to a promoter associated with a bone morphogenetic protein and/or their ability to stimulate calvarial growth in model animal systems.Board of Regents, University of Texas Syste

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Preparation and Utility of <i>N</i>-Alkynyl Azoles in Synthesis

Heteroatom-substituted alkynes have attracted a significant amount of interest in the synthetic community due to the polarized nature of these alkynes and their utility in a wide range of reactions. One specific class of heteroatom-substituted alkynes combines this utility with the presence of an azole moiety. These N-alkynyl azoles have been known for nearly 50 years, but recently there has been a tremendous increase in the number of reports detailing the synthesis and utility of this class of compound. While much of the chemistry of N-alkynyl azoles mirrors that of the more extensively studied N-alkynyl amides (ynamides), there are notable exceptions. In addition, as azoles are extremely common in natural products and pharmaceuticals, these N-alkynyl azoles have high potential for accessing biologically important compounds. In this review, the literature reports of N-alkynyl azole synthesis, reactions, and uses have been assembled. Collectively, these reports demonstrate the growth in this area and the promise of exploiting N-alkynyl azoles in synthesis