Nanostructures, molecular assemblies at the nanometer scale, are currently influencing diagnostics, imaging, and therapeutics. Many nanostructures are built using supramolecular chemistry principles, where hydrogen bonding between simple building blocks causes the formation of specific morphologies. Here we hypothesize that a six stranded DNA nanotube can be generated by tethering triaminopyrimidine and cyanuric acid building blocks as bases on the natural DNA backbone. We also hypothesize that cyanuric acid, a secondary oxidation product of guanine, will form complex architectures with adenine, its natural hydrogen bond complement. To test these hypotheses, we used multi-step synthetic strategies to generate DNA strands of cyanuric acid and triaminopyrimidine. The synthesis of the cyanuric acid DNA strand is complete and preliminary self-assembly studies with adenine DNA strands have been performed. The synthesis of the triaminopyrimidine DNA strand is ongoing. This thesis provides the groundwork for incorporating supramolecular building blocks into DNA to generate complex DNA architectures.

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As a first generation of compounds, the nucleosides adenosine 8, cytidine 11, guanosine 9, inosine 116 and uridine 12, as well as the sugar ᴅ-(-)-ribose 100, were transformed into the corresponding 5’-O-(tert-butyldiphenylsilyl)- and 5’-O-(4,4’-dimethoxytrityl)-derivatives. These were subsequently protected as acetyl, benzoyl and allyl derivatives at various positions on the molecules, to give a range of twenty five unique compounds for biological testing. The nucleoside and corresponding ᴅ-(-)-ribose derivatives were evaluated for their antibacterial activity against two Gram-positive (Staphylococcus aureus ATCC 25923 and Bacillus cereus DL5) and two Gram-negative bacteria (Pseudomonas aeruginosa ATCC 27853 and Escherichia coli ATCC 25922), for their anti-HIV activity against strain HLTVIIIB as well as for their anticancer properties, by evaluating inhibition of cell proliferation in two adherent (HT-29 and Caco-2) and three suspension (HL-60, Jurkat and K-562) cell lines. From these screens, and based on the 2,3,5-triphenyltetrazolium chloride (TTC) assay, it was found that 5’-O-(tert-butyldiphenylsilyl)uridine 107, 5’-O-(tert-butyldiphenylsilyl)-1'-O-methoxy-ᴅ-(-)-ribose 102 and tert-butyldiphenylsilyl alcohol 145 exhibited antimicrobial activity towards only the Gram-positive bacteria when compared to the ciprofloxacin 153 control. None of the compounds tested showed any antiviral activity when assayed against HIV; however, all compounds indicated some form of toxicity to the uninfected cells. Subsequent cell proliferation studies indicated pronounced activity against both the adherent and suspension cancer cell lines for 5’-O-(tert-butyldiphenylsilyl)uridine 107, 5’-O-(tert-butyldiphenylsilyl)cytidine 134, tert-butyldiphenylsilyl alcohol 145, 5’-O-(4,4’-dimethoxytrityl)uridine 126 and 4,4’-dimethoxytrityl alcohol 147. Our initial screen indicated that ᴅ-(-)-ribose derivatives do not show any significant general biological activity; whereas (tert-butyldiphenylsilyl)-protected nucleoside derivatives and the corresponding tert-butyldiphenylsilyl alcohol control are intrinsically more bio-active. From the data reported for the anti-bacterial and the cell proliferation studies, we concluded that the nucleoside showing the most promising results was uridine 12 and our mini structure- activity study on the uridine derivatives found that the best position for performing modifications to the nucleoside was at the 5'-OH position on the sugar ring. As such, this would become the initial focus for the synthesis of the second generation compounds. The second generation compounds included a series of ten uridine 12 and five 5-methyluridine 233 derivatives which were protected on the primary alcohol with a range of different silicon-containing protecting groups. At the same time, we used a general procedure to synthesize a series of fourteen silanols for use as control compounds. The uridine 12, 5-methyluridine 233 and corresponding silanol derivatives were screened for their antibacterial activity against the same two Gram-positive and two Gram-negative bacteria as above, as well as for their anticancer properties, by evaluating inhibition of cell proliferation in a series of six adherent cell lines (five human: Hs683, MCF-7, PC-3, SKMEL-28, U373, and one murine: B16F10) cell lines. The data obtained for our TTC assay showed that converting the base in 1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,-2,4]trioxadisilocin-8-yl]-pyrimidine-2,4(1H,-3H)dione 234 to the 5-methyl derivative 254 caused a corresponding loss in antibacterial activity for the compound, whereas oxidising the secondary alcohol on the 2'-position of the sugar ring to give compound 239 caused a corresponding increase in antibacterial activity. As such, we concluded that 1-[(6aR,8R,9aR)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6H-furo[3,2-f][1,3,5,-2,4]trioxadisilo-cin-8-yl]pyrimidine-2,4(1H,3H)dione 239 was the compound with the best antibacterial activity out all of the first and second generations of nucleoside derivatives assayed. The results obtained in the TTC assay, were supported by our scanning electron (SEM) and confocal scanning electron (CSLM) microscopy studies. Interestingly, the CSLM study suggests that the synthetic compound 239 is bacteriocidal and is inactivating cells, not simply inhibiting their growth. From the inhibition of cell proliferation assay performed on the fifty combined first and second generation derivatives and their corresponding controls, we found that the six most active compounds (5'-O-(tert-butyldiphenylsilyl)adenosine 142, 5'-O-(tert-butyldiphenyl-silyl)cytidine 134, 5'-O-(tert-butyldiphenylsilyl)uridine 107, 2',3'-O-diacetyl-5'-O-(tert-butyl-diphenylsilyl)uridine 123, 2',3'-O-diacetyl-5'-O-(4,4'-dimethoxytrityl)uridine 127 and 3-benzoyl-1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,-5,2,4]trioxa-disilocin-8-yl]pyrimidine-2,4(1H,3H)-dione 235) had mean IC50 values of approximately 24-28 μM.

Copies of author's previously published works inserted. / Bibliography: leaves 230-282. / 291 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Covers clinical data relating to trials with two antiretroviral agents, didanosine and foscarnet, conducted at St Stephen's clinic, London, discussing aspects of their therapetic efficacy, effect on survival, clinical and laboratory tolerability. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1995