Part 1: Synthesis and Anti-HIV Activity of Novel CyclobutylNucleoside and Nucleotide Analogs, Part 2: Synthesis of FluorescentNucleoside Analogs, Part 3: Synthesis of Abacavir Open Access

Abstract

Part 1 of this dissertation describes the synthesis and anti-HIV activity of several novel four-membered ring nucleoside and nucleotide analogs as anti-HIV agents. The synthesis of these analogs features a [2+2] cycloaddition or [3+1] cycloaddition to construct the carbocyclic four-membered ring or thietane ring. An efficient SN2 strategy was used to couple the carbocyclic four-membered ring with a variety of nucleoside bases, including pyrimidine and purine bases. In addition, the Pummerer-type rearrangement was used to synthesize the thietanose nucleosides. The EC50 values of those compounds in human PBM cell lines ranged from 14.6 to 100 μM and some of them were shown toxicity in PBM, CEM and Vero cells. Interestingly, most of the cyclobutyl nucleoside analogs did not show any anti-HIV activity; however, some of the cyclobutyl phosphonate nucleoside analogs did show some mild anti-HIV activity and toxicity. For the thietanose nucleosides, some of them showed moderate activity and cytotoxicity. The other nucleosides showed neither anti-HIV activity nor cytotoxicity up to 100 μM.

Part 2 of this dissertation reported the synthesis of fluorescent nucleoside analogs with modified sugar moieties. Novel variants of fluorescent thymidine analog 6-methyl-3-(β-D-2'-deoxyribofuranosyl) furano-[2,3-d]pyrimidin-2-one were synthesized, such as, AZT, D4T and DDC, by a Sonogashira reaction and a copper catalyzed cycloaddition. These compounds can be used as promising tools to research metabolites inside living cells and study biochemical reactions in situ, such as the 5'-phosphorylation of the nucleosides by cellular deoxynucleoside kinases.

Part 3 of this dissertation discusses the improvement on the preparation of abacavir ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-enyl)methanol by utilizing commercially available and inexpensive starting materials and that proceeds with high regioselectivity and stereochemical control. After formation of a novel allylpalladium complex, the bicyclic precursor can be opened with complete regio- and stereo-specificity to yield the desired, biologically active anomeric nucleoside.

Table of Contents

1. PART 1: SYNTHESIS AND ANTI-HIV ACTIVITY OF NOVEL CYCLOBUTYL NUCLEOSIDE PRODRUG AND NUCLEOTIDE ANALOGS..........................................................1 1.1 Statement of purpose..........................................................................1 1.2 Introduction............................................................................................3 1.2.1 HIV Replication cycle........................................................................7 1.2.2 The mechanism of NRTIs...............................................................9 1.2.3 Challenges of NRTIs......................................................................10 1.3 Background.........................................................................................12 1.3.1 Synthesis of carbocyclic four- membered rings.......................12 1.3.1.1 [2+2] cycloaddition.......................................................................12 1.3.1.2 [3+1] cycloaddition.......................................................................16 1.3.2 Synthesis of nucleoside triphosphates........................................17 1.3.2.1 "One-pot, three-step" triphosphorylation....................................17 1.3.2.2 Monophosphate activation.........................................................18 1.3.3 Synthesis and anti-HIV activity of 3'-hydroxymethyl cyclobutyl nucleosides.................................................................................19 1.3.3.1 Synthesis...................................................................................19 1.3.3.2 Anti-HIV activity.........................................................................21 1.4 Design and synthesis of cyclobutyl nucleosides.........................24 1.4.1 Design and synthesis of 2'-methyl substituted cyclobutyl nucleosides.................................................................................27 1.4.1.1 Synthesis of 2'-α-methyl-3'-hydroxymethyl cyclobutyl nucleosides.................................................................................27 1.4.1.2 Synthesis of 2'-methyl-cyclobutyl nucleoside analogs...............28 1.4.2 Design and synthesis of cyclobutyl pyrimidine phosphonate analogs.......................................................................................31 1.4.3 Design and synthesis of cyclobutyl adenine phosphonate analogs.......................................................................................37 1.4.4 Design and synthesis of cyclobutyl guanidine phosphonate analogs.......................................................................................40 1.4.5 Design and synthesis of thietanose nucleoside..........................44 1.5 Anti-HIV activity..........................................................................50 1.6 Incorporation of CBN-TP (77) into DNA using reverse transcriptase...............................................................................51 1.7 Discussion..................................................................................52 2. PART 2: SYNTHESIS FLUROSCENT NUCLEOSIDE ANALOGS..............55 2.1 Statement of purpose.................................................................55 2.2 Introduction and background......................................................57 2.3 Novel fluorescent nucleoside analogs with ribose modification..60 2.4 Pyrimidine analogs.....................................................................61 2.5 Conclusion.................................................................................65 3. PART 3: SYNTHESIS OF ABACAVIR.........................................................67 3.1 Statement of purpose.................................................................67 3.2 Introduction and background......................................................69 3.3 Synthesis of abacavir.................................................................72 3.4 Conclusion.................................................................................77 4. EXPERIMENTAL SECTION.........................................................................80 4.1 Experimental section of part 1....................................................81 4.2 Experimental section of part 2..................................................142 4.3 Experimental section of part 3..................................................152 5. REFERENCES AND NOTES......................................................................162

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Keyword	Nucleoside, anti-HIV, abacavir
Committee Chair / Thesis Advisor	Liotta, Dennis C, Emory University
Committee Members	McDonald, Frank, Emory University Padwa, Albert, Emory University

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