Syntheses and evaluation of putative enzyme inhibitor of isoprenoid biosynthesis Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/6h440w75n

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  • The discovery of the methylerythritol phosphate pathway (the MEP pathway) as an alternate pathway for isoprenoid biosynthesis in some organisms including most bacteria, malarial parasites and plants, but not in animals, has stimulated extensive studies in this area. Research has revealed the potential of finding novel antibacterials, antimalarial drugs, and herbicides from enzyme inhibitors of this pathway. The natural products fosmidomycin and FR900098 appear to be very promising antibacterial and antimalarial compounds. Both compounds have inhibition activities against the second enzyme in the MEP pathway, deoxyxylulose- 5-phosphate reductoisomerase (DXR), which mediates the conversion of deoxyxylulose-5-phosphate (DXP) into methylerythritol-4-phosphate (MEP). This thesis presents one aspect of the MEP pathway studies. Six different analogs of DXP were designed based on the structural features of DXP to understand the requirements of the DXR-substrate binding. Compounds with the trivial names 1-Me-DXP (containing an ethyl ketone moiety), DX-phosphonate (DXP having a phosphonate group rather than a phosphate group), 4-epi-DXP (possessing the opposite stereochemistry at the C₄ position compared to DXP), 4-deoxy-DXP (lacking the hydroxyl group at the C₄ position), 3-deoxy-DXP (lacking the hydroxyl group at the C₃ position), and DXP carboxamide (having a primary amide group rather than the methyl ketone) were synthesized and tested as alternate substrates and enzyme inhibitors against DXR. The compound DX-phosphonate was the only alternate substrate among the synthesized compounds. The remaining analogs of DXP acted as weak competitive inhibitors against DXR. Kinetic studies of these compounds provided an overall picture of how the substrate DXP binds to DXR. Further studies of the compound 1-Me-DXP, using the published X-ray crystal structures of DXR and DXR mutagenesis demonstrated more detail of the DXR active site. The results present useful information for designing better enzyme inhibitors. The mechanism for the rearrangement of DXP to MEP by DXR was also studied. Two possible mechanisms for this rearrangement have been proposed, the α-ketol rearrangement and the retroaldol/aldol rearrangement. Several approaches including the use of the potential alternate substrates, 4-deoxy-DXP and 3-deoxy-DXP were tried. Unfortunately none of the results obtained can definitively rule out either of the mechanisms. Further studies are needed to completely understand this mechanism and establish additional strategies for inhibition of DXR. Syntheses of an intermediate from the DXR reaction, methylerythrose-4-phosphate, were also attempted in order to better understand the chemistry mediated by DXR. Even though the target compound was not successfully obtained, several synthetic approaches to this compound were useful for the syntheses of the different DXP analogs mentioned above.
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