A novel class of Cathepsin B inhibitors has been developed with a 1,2,4-thiadiazole heterocycle a... more A novel class of Cathepsin B inhibitors has been developed with a 1,2,4-thiadiazole heterocycle as the thiol trapping pharmacophore. Several compounds with different dipeptide recognition sequence (i.e., P1'-P2'=Leu-Pro-OH or P2-P1=Cbz-Phe-Ala) at the C5 position and with different substituents (i.e., OMe, Ph, or COOH) at the C3 position of the 1,2,4-thiadiazole ring have been synthesized and tested for their inhibitory activities. The substituted thiadiazoles 3a-h inhibit Cat B in a time dependent, irreversible manner. A mechanism based on active-site directed inactivation of the enzyme by disulfide bond formation between the active site cysteine thiol and the sulfur atom of the heterocycle is proposed. Compound 3a (K(i)=2.6 microM, k(i)K(i)=5630 M(-1)s(-1)) with a C3 methoxy moiety and a Leu-Pro-OH dipeptide recognition sequence, is found to be the most potent inhibitor in this series. The enhanced inhibitory potency of 3a is a consequence of its increased enzyme binding affinity (lower K(i)) rather than its increased intrinsic reactivity (higher k(i)). In addition, 3a is inactive against Cathepsin S, is a poor inhibitor of Cathepsin H and is >100-fold more selective for Cat B over papain.
This paper examines the effects of three different types of support for Japanese students studyin... more This paper examines the effects of three different types of support for Japanese students studying English writing. Students were required to make weekly visits to either the Writing Center or a student tutor or were given cards with simple reminder checklists that they were to review before and after completing each stage of writing an essay (pre-writing, first draft, and final draft). Due to the small sample size, we cannot address how these support structures affected improvement of students' writing; however, we did see an impact on students' awareness of support services. Students generally believed that the help they received was worth the effort. Instructor-mandated visits, to a limited degree, are likely to nudge the students to make the important first visit to the writing center or tutors. It is still not clear why utilization of the Writing Center decreases in the second semester.
A novel class of Cathepsin B inhibitors has been developed with a 1,2,4-thiadiazole heterocycle a... more A novel class of Cathepsin B inhibitors has been developed with a 1,2,4-thiadiazole heterocycle as the thiol trapping pharmacophore. Several compounds with different dipeptide recognition sequence (i.e., P1'-P2'=Leu-Pro-OH or P2-P1=Cbz-Phe-Ala) at the C5 position and with different substituents (i.e., OMe, Ph, or COOH) at the C3 position of the 1,2,4-thiadiazole ring have been synthesized and tested for their inhibitory activities. The substituted thiadiazoles 3a-h inhibit Cat B in a time dependent, irreversible manner. A mechanism based on active-site directed inactivation of the enzyme by disulfide bond formation between the active site cysteine thiol and the sulfur atom of the heterocycle is proposed. Compound 3a (K(i)=2.6 microM, k(i)K(i)=5630 M(-1)s(-1)) with a C3 methoxy moiety and a Leu-Pro-OH dipeptide recognition sequence, is found to be the most potent inhibitor in this series. The enhanced inhibitory potency of 3a is a consequence of its increased enzyme binding affinity (lower K(i)) rather than its increased intrinsic reactivity (higher k(i)). In addition, 3a is inactive against Cathepsin S, is a poor inhibitor of Cathepsin H and is >100-fold more selective for Cat B over papain.
This paper examines the effects of three different types of support for Japanese students studyin... more This paper examines the effects of three different types of support for Japanese students studying English writing. Students were required to make weekly visits to either the Writing Center or a student tutor or were given cards with simple reminder checklists that they were to review before and after completing each stage of writing an essay (pre-writing, first draft, and final draft). Due to the small sample size, we cannot address how these support structures affected improvement of students' writing; however, we did see an impact on students' awareness of support services. Students generally believed that the help they received was worth the effort. Instructor-mandated visits, to a limited degree, are likely to nudge the students to make the important first visit to the writing center or tutors. It is still not clear why utilization of the Writing Center decreases in the second semester.
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