Biomimetic modeling of the nitrogen-centered radical postulated to occur during the inhibition of ribonucleotide reductases by 2'-azido-2'-deoxynucleotides

Ribonucleotide reductases (RNR) are essential enzymes that catalyze the reduction of ribonucleotides to 2'-deoxyribonucleotides, which is a critical step that produces precursors for DNA replication and repair. The inactivation of RNR, logically, would discontinue producing the precursors of the DNA of viral or cancer cells, which then would consequently end the cycle of DNA replication. Among different compounds that were found to be inhibitors of RNR, 2'-azido-2'-deoxynucleotide diphosphates (N3NDPs) have been investigated in depth as potent inhibitors of RNR. Decades of investigation has suggested that the inactivation of RNR by N3NDPs is a result of the formation of a nitrogen-centered radical (N·) that is covalently attached to the nucleotide at C3' and cysteine molecule C225 [3'-C(R-S-N·-C-OH)]. Biomimetic simulation reactions for the generation of the nitrogen-centered radicals similar to the one observed during the inactivation of the RNR by azionuclotides was investigated. The study included several modes: (i) theoretical calculation that showed the feasibility of the ring closure reaction between thiyl radicals and azido group; (ii) synthesis of the model azido nucleosides with a linker attached to C3' or C5' having a thiol or vicinal dithiol functionality; (iii) generation of the thiyl radical under both physiological and radiolysis conditions whose role is important in the initiation on RNR cascades; and (iv) analysis of the nitrogen-centered radical species formed during interaction between the thiyl radical and azido group by electron paramagnetic resonance spectroscopy (EPR). Characterization of the aminyl radical species formed during one electron attachment to the azido group of 2'-azido-2'-deoxyuridine and its stereospecifically labelled 1'-, 2'-, 3'-, 4'- or 5,6-[2H 2]-analogues was also examined. This dissertation gave insight toward understanding the mechanism of the formation of the nitrogen-centered radical during the inactivation of RNRs by azidonucleotides as well as the mechanism of action of RNRs that might provide key information necessary for the development of the next generation of antiviral and anticancer drugs.

An Analysis on the Decline in the Authoritative Powers of the Papacy and its Application to Challenges to Authoritative Powers Faced By the Permanent Membership of the UN Security Council

The organizational authority of the Papacy in the Roman Catholic Church and the permanent membership of the UN Security Council are unique from institutions that are commonly compared with the UN, like the Concert of Europe and the League of Nations, in that these institutional organs possessed strong authoritative and veto powers. Both organs also owe their strong authority during their founding to a need for stability: The Papacy after the crippling of Western Roman Empire and the P-5 to deal with the insecurities of the post-WWII world. While the P-5 still possesses similar authoritative powers within the Council as it did after WWII, the historical authoritative powers of the Papacy within the Church was debilitated to such a degree that by the time of the Reformation in Europe, condemnations of practices within the Church itself were not effective. This paper will analyze major challenges to the authoritative powers of the Papacy, from the crowning of Charlemagne to the beginning of the Reformation, and compare the analysis to challenges affecting the authoritative powers of the P-5 since its creation. From research conducted thus far, I hypothesize that common themes affecting the authoritative powers of the P-5 and the Papacy would include: major changes in the institutions organization (i.e. the Avignon Papacy and Japan’s bid to become a permanent member); the decline in power of actors supporting the institutional organ (i.e. the Holy Roman Empire and the P-5 members); and ideological clashes affecting the institution’s normative power (i.e. the Great Western Schism and Cold War politics).

An Analysis on the Decline in the Authoritative Powers of the Papacy and its Application to Challenges to Authoritative Powers Faced By the Permanent Membership of the UN Security Council

The organizational authority of the Papacy in the Roman Catholic Church and the permanent membership of the UN Security Council are unique from institutions that are commonly compared with the UN, like the Concert of Europe and the League of Nations, in that these institutional organs possessed strong authoritative and veto powers. Both organs also owe their strong authority during their founding to a need for stability: The Papacy after the crippling of Western Roman Empire and the P-5 to deal with the insecurities of the post-WWII world. While the P-5 still possesses similar authoritative powers within the Council as it did after WWII, the historical authoritative powers of the Papacy within the Church was debilitated to such a degree that by the time of the Reformation in Europe, condemnations of practices within the Church itself were not effective. This paper will analyze major challenges to the authoritative powers of the Papacy, from the crowning of Charlemagne to the beginning of the Reformation, and compare the analysis to challenges affecting the authoritative powers of the P-5 since its creation. From research conducted thus far, I hypothesize that common themes affecting the authoritative powers of the P-5 and the Papacy would include: major changes in the institutions organization (i.e. the Avignon Papacy and Japan’s bid to become a permanent member); the decline in power of actors supporting the institutional organ (i.e. the Holy Roman Empire and the P-5 members); and ideological clashes affecting the institution’s normative power (i.e. the Great Western Schism and Cold War politics).