Design and Synthesis of 4-N-Alkanoyl and 4-N-Alkyl Gemcitabine Analogues Suitable for Positron Emission Tomography

Gemcitabine is a highly potent chemotherapeutic nucleoside agent used in the treatment of several cancers and solid tumors. However, it is therapeutically limitated because of toxicity to normal cells and its rapid intracellular deamination by cytidine deaminase into the inactive uracil derivative. Modification at the 4-(N) position of gemcitabine's exocyclic amine to an -amide functionality is a well reported prodrug strategy which has been that confers a resistance to intracellular deamination while also altering pharmacokinetics of the parent drug. Coupling of gemcitabine to carboxylic acids with varying terminal moieties afforded the 4-N-alkanoylgemcitabines whereas reaction of 4-N-tosylgemcitabine with the corresponding alkyl amines gave the 4-N-alkylgemcitabines. The 4-N-alkanoyl and 4-N-alkyl gemcitabine analogues with a terminal hydroxyl group on the 4-N-alkanoyl or 4-N-alkyl chain were efficiently fluorinated either with diethylaminosulfur trifluoride or under conditions that are compatible with the synthetic protocols for 18F labeling, such as displacement of the corresponding mesylate with KF/Kryptofix 2.2.2. The 4-N-alkanoylgemcitabine analogues displayed potent cytostatic activities against murine and human tumor cell lines with 50% inhibitory concentration (IC50) values in the range of low nM, whereas cytotoxicity of the 4-N-alkylgemcitabine derivatives were in the low to modest µM range. The cytostatic activity of the 4-N-alkanoylgemcitabines was reduced by several orders of magnitude in the 2'-deoxycytidine kinase (dCK)-deficient CEM/dCK- cell line while the 4-N-alkylgemcitabines were only lowered by 2-5 times. None of the 4-N-modified gemcitabines were found to be substrates for cytosolic dCK, however all were found to inhibit DNA synthesis. As such, the 4-N-alkanoyl gemcitabine derivatives likely need to be converted to gemcitabine prior to achieving their significant cytostatic potential, whereas the 4-N-alkylgemcitabines reach their modest activity without "measurable" conversion to gemcitabine. Thus, the 4-N-alkylgemcitabines provide valuable insight on the metabolism of 4-N-modified gemcitabine prodrugs.

The Effects on Students' Self-Efficacy Beliefs Regarding Their Comprehension of American Literature When Aesthetic Reading and Reader Response Strategy are Implemented

High-stakes testing and accountability have infiltrated the education system in the United States; the top priority for all teachers must be student progress on standardized tests. This has resulted in the predominance of reading for test-taking, (efferent reading), in the English, language arts, and reading classrooms. Authentic uses of print activities, like aesthetic reading, that encourage students to engage individually with a text, have been pushed aside. During a 3-week time period, regular level, English 3/American literature students in a Title I magnet high school, participated in this quasi-experimental study (N = 62). It measured the effects of an intervention of reading American literature texts aesthetically and writing aesthetically-evoked reader responses on students’ self-efficacy beliefs regarding their comprehension of American literature. One trained teacher and the researcher participated in the study: student participants were pre- and post- tested using the Confidence in Reading American Literature Survey which examined their self-efficacy beliefs regarding their comprehension of American literature. Several statistical analyses were performed. The results of the linear regression analyses partially supported a positive relationship between aesthetically-evoked reader responses and students’ self-efficacy beliefs regarding their comprehension of American literature. Additionally, the results of the 2 (sex) x 2 (treatment) ANCOVAs conducted to test group differences in self-efficacy beliefs regarding the comprehension of American literature between treatment and control groups indicated a main effect for treatment (but not sex; nor was there a significant sex x treatment interaction), suggesting the treatment was partially effective in increasing students’ self-efficacy beliefs. Seven of the twelve ANCOVAs indicated a statistically significant increase in the treatment group’s adjusted group mean self-efficacy belief scores as a result of being exposed to the intervention. In six of these seven analyses, increases in self-efficacy beliefs occurred in tasks that required three or more higher-order levels of thinking/learning. The results are discussed in terms of theoretical, empirical and practical significance. Future research is recommended to extend the intervention beyond the narrow confines of a Title I magnet school to settings where the intervention could be tested longitudinally, e. g., honors and gifted students, elementary and middle schools.