Synthesis of Nucleoside-Based Antiprotozoan Compounds and Total Synthesis of Cylindricine C and its 2,13-Di-epi Stereoisomer
Date
2023-07
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Abstract
Parasitic protozoa employ a salvage pathway to synthesize purines and generate essential active nucleosides and nucleotides, whereas mammals are capable of their de novo biosynthesis. This difference provides opportunity for the design of potential new antiprotozoan compounds. A series of adenosine analogues was prepared by members of our group with modifications at the 2-, 6- and 5'-positions, based on the hypothesis that such compounds would serve as substrates for protozoan nucleoside salvage enzymes, while remaining refractory in mammalian cells. The altered nucleosides were designed to produce toxic metabolites upon cleavage to the corresponding purine base and uptake by the parasite. One adenosine derivative that is described in this thesis proved highly effective against Plasmodium falciparum (malaria): IC50 = 110 nM and selectivity index (SI) versus a mammalian cell line of 1010. Consequently, its synthesis was optimized and several new analogues containing different amino groups were prepared and assayed. Furthermore, one 7-deazaguanosine derivative proved effective against Leishmania donovani (leishmaniasis): IC50 = 60 nM and SI = 2720, as well as against several other pathogenic protozoa. Therefore, a new synthesis leading to the antileishmaniasis compound was also designed and optimized. Cylindricine alkaloids possess a rather uncommon tricyclic pyrrolo[2,1-j]quinoline framework containing a cis-fused azadecalin skeleton, making them unique molecules. They are difficult to isolate from natural sources and novel approaches to synthesize these compounds are thus required. Our research group has synthesized 2,13-di-epi-cylindricine C and cylindricine C via a tandem conjugate addition and intramolecular cyclization of a key intermediate ß-amino ester and an acetylenic sulfone. Following consecutive desulfonylation and reduction of the resulting enaminone double bond moiety yielded 2,13-di-epi-cylindricine C and cylindricine C in a diastereomeric ratio of 3:1. The former molecule appears to be novel, and its spectroscopic data failed to match those of any existing stereoisomers in the literature. Crystallization methods were attempted and 2D NMR techniques, as well as computational calculations, were employed in order to fully characterize the proposed structure of 2,13-di-epi-cylindricine C. Furthermore, an enhancement of the 3:1 d.r. was attempted by means of chiral selenium electrophiles in another key cyclization step.
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Keywords
bioactive, organic, molecules, total, synthesis
Citation
Pastor, A. M. D. (2023). Synthesis of nucleoside-based antiprotozoan compounds and total synthesis of cylindricine C and its 2,13-Di-epi stereoisomer (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.