Synthesis and anti-HIV activity of [d4U]-spacer-[HI-236] bifinctional HIV-1 reverse transcriptase inhibitors
Doctoral Thesis
2006
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University of Cape Town
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Abstract
This thesis describes the design and synthesis of bifunctional drugs combining anucleoside (d4U) and non-nucleoside (HI-236) reverse transcriptase inhibitor linkedvia different spacers between C-5 of the NRTI and 0-1 of the NNRTI. Three targets were successfully synthesized in a divergent manner from uridine in 13steps for the butyne target and 19 steps for targets bearing PEG-propyne units usingSonogashira coupling as a key step. The most challenging step of the synthesisinvolved Boc deprotection and thiourea condensation in the final step, which sufferedfrom anomeric cleavage with loss of the sugar moiety. As a result, the target with athree-carbon propynyl spacer could not be accessed. Progress towards the synthesis of a bifunctional system bearing a saturated andmore flexible tether is highlighted in Chapter 4. The key reactions includedSonogashira coupling of iodo nucleosides, 2',3'-dideoxygenation of the vicinol diol,phenolic alkylation and condensation of amine with thiourea reagent. The synthesissurmounted several challenges, with chemoselective distinction of unsaturation vialate introduction of the d4U double bond using Corey-Winter methodology as thehighlight.
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Includes bibliographical references (leaves 182-190).
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Muhanji, C. 2006. Synthesis and anti-HIV activity of [d4U]-spacer-[HI-236] bifinctional HIV-1 reverse transcriptase inhibitors. University of Cape Town.