Anthraquinone-xanthone heterodimeric natural products are a diverse family of polyketides highlighted by a unique bicyclo [3.2.2] ring system which links both anthraquinone and xanthone moieties. Both the connectivity of the unique bicyclic ring system and the oxidation state of the two heterocycles vary among the members of this family of natural products. These molecules have been generally isolated as fungal metabolites but also have shown anticoccidial (xanthoquinodin A:0.02 μg/mL), antibiotic (acremonidins A and C; 32 μM and acremoxanthone, MIC; 12.5 μg/mL), and cytotoxicity against various human cancer cell lines. Both anthraquinone and xanthone heterocycles are derived from the anthraquinone chrysophanol, a common biosynthetic intermediate for polyketide synthesis. To date, there have been no reported synthetic efforts or total syntheses of the anthraquinone-xanthone heterodimeric natural products. Related synthetic examples include complex anthraquinone-xanthone biaryls, anthraquinone dimers, and monomeric xanthone and benzophenone-derived natural products. We describe an initial proposed synthesis wherein we aimed to prepare the unique bicyclo [3.2.2] ring system in a late stage operation of functionalized anthraquinone and xanthone units through a photo-mediated cycloaddition. We achieved synthesis of both an anthraquinone-derived oxanthrone ester fragment and the synthesis of several xanthone related natural products, namely graphisin A, sydowinin B, acremonidin E, and pinselin. Key steps involve aryl anion addition to substituted benzaldehyde derivatives, subsequent methyl ester installation, and dehydrative cyclization. Although we have not yet achieved the desired cycloaddition, we contributed to this area by developing efficient, reliable syntheses of various benzophenone and xanthone natural products. We will also describe an alternative strategy to access the bicyclo [3.2.2] core of these natural products via various proposed rearrangements of an anthraquinone-xanthone biaryl intermediate. Cross-coupling of substituted xanthone and naphthalene fragments established the desired biaryl linkage which was further elaborated to afford anthraquinone-xanthone biaryl structures. Attempts to rearrange these biaryls are ongoing to produce the unique core structure of the parent natural products. Initially discovered as a byproduct of the aforementioned cross-coupling reaction, we have achieved homo-coupling of substituted naphthalene fragments. The resulting naphthalene dimers could be further advanced to a series of novel 2,2'-linked anthraquinone dimers including the natural product chrysotalunin.

<p>The central dogma of molecular biology relies on the correct Watson-Crick (WC) geometry of canonical deoxyribonucleic acid (DNA) dG•dC and dA•dT base pairs to replicate and transcribe genetic information with speed and an astonishing level of fidelity. In addition, the Watson-Crick geometry of canonical ribonucleic acid (RNA) rG•rC and rA•rU base pairs is highly conserved to ensure that proteins are translated with high fidelity. However, numerous other potential nucleobase tautomeric and ionic configurations are possible that can give rise to entirely new pairing modes between the nucleotide bases. Very early on, James Watson and Francis Crick recognized their importance and in 1953 postulated that if bases adopted one of their less energetically disfavored tautomeric forms (and later ionic forms) during replication it could lead to the formation of a mismatch with a Watson-Crick-like geometry and could give rise to “natural mutations.” </p><p>Since this time numerous studies have provided evidence in support of this hypothesis and have expanded upon it; computational studies have addressed the energetic feasibilities of different nucleobases’ tautomeric and ionic forms in siico; crystallographic studies have trapped different mismatches with WC-like geometries in polymerase or ribosome active sites. However, no direct evidence has been given for (i) the direct existence of these WC-like mismatches in canonical DNA duplex, RNA duplexes, or non-coding RNAs; (ii) which, if any, tautomeric or ionic form stabilizes the WC-like geometry. This thesis utilizes nuclear magnetic resonance (NMR) spectroscopy and rotating frame relaxation dispersion (R1ρ RD) in combination with density functional theory (DFT), biochemical assays, and targeted chemical perturbations to show that (i) dG•dT mismatches in DNA duplexes, as well as rG•rU mismatches RNA duplexes and non-coding RNAs, transiently adopt a WC-like geometry that is stabilized by (ii) an interconnected network of rapidly interconverting rare tautomers and anionic bases. These results support Watson and Crick’s tautomer hypothesis, but additionally support subsequent hypotheses invoking anionic mismatches and ultimately tie them together. This dissertation shows that a common mismatch can adopt a Watson-Crick-like geometry globally, in both DNA and RNA, and whose geometry is stabilized by a kinetically linked network of rare tautomeric and anionic bases. The studies herein also provide compelling evidence for their involvement in spontaneous replication and translation errors.</p> / Dissertation

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This thesis describes a computational investigation of the mutagenicity of 5-bromouracil (BrU). In Chapter 1, three models of spontaneous and BrU-induced base mispairing (rare tautomer, wobble pair, and ion) are reviewed. Chapter 2 presents the computational techniques used: electronic structure methods (Hartree–Fock-based and density functional theory) and molecular dynamics. Chapter 3 presents optimisations of the keto and enol tautomers of BrU and uracil (U) in water clusters. The enol tautomer of BrU is found to be more stable than that of U. Chapter 4 is a molecular dynamics study of the keto-enol tautomerism of BrU and U in a periodic water box. The pKₐ of BrU at N3 is found to be lower than that of U. Chapter 5 is a study of stacked base dimers containing BrU, U, or thymine (T) stacking with natural bases. Some structures were taken from the Protein Data Bank, while others were generated using an in-house methodology. BrU is found to stack more strongly than T in vacuo, but solvation and thermal effects nullify this difference. Chapter 6 discusses the significance of the results in Chapters 3–5 in terms of BrU-induced mutagenesis. Appendices A and B–D provide supplementary material to Chapters 2 and 5, respectively. Appendix E is an investigation of the “base flipping” pathway of 2-aminopurine (2AP). Both 2AP/N and A/N dinucleosides (N = thymine or guanine) are found to adopt a wide range of energy-minimum conformations – not only stacked and “flipped”, but also intermediate – and the stacked are not the most favourable by free energy. Appendix F is a list of publications and papers in preparation. One publication concerns BrU stacking. The other is a conformational study of the dipeptide tyrosine-glycine: the theoretical results are shown to be consistent with experiment (R2PI spectra) if thermal effects are taken into account.