Inhibition of the MEP pathway : design, synthesis and evaluation of IspF enzyme inhibitors; Synthesis of PDE4D partial inhibitors and exploration of atropisomeric analogs
Zhang, Zheng (Graduate student of chemistry)
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This dissertation contains two major projects. The first project focused on the design and synthesis of small molecule inhibitors of the methyl erythritol phosphate (MEP) pathway. Known as a non-mevalonate isoprenoid biosynthetic pathway, plants and apicomplexan protozoa such as malaria parasites use this to produce isoprenoids (terpenoids). Additionally, most bacteria, including pathogens such as Mycobacterium tuberculosis, synthesize IPP and DMAPP via the non-mevalonate pathway.1 Among the seven enzymes involved in this pathway, a highly conserved enzyme is 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF). Fragment screening hits on Burkholderia pseudomallei IspF (BpIspF) afforded the basis for our chemistry leads, allowing the design of new potential IspF inhibitors. Three major series of compounds were synthesized by efficient methods that allowed for exploration of the IspF binding site and modification of the physiochemical properties. Fragment based screening of the BpIspF enzymes performed by Dr. Darren Begley provided additional hits that significantly expanded the diversity of the chemical cores and additional leads for the design of novel inhibitors. Guided by the biophysical methods of surface plasma resonance (SPR), we are able to obtain the binding potencies of compounds and generate structure activity relationships (SAR) for the chemical series. Computational studies using the docking module in the program SYBYL-X assisted in the exploration and visualization of potential binding motifs and allowed the rational design of new potential BpIspF inhibitors. This work forms the foundation for further medicinal chemistry efforts on the optimization of MEP pathway inhibitors and the modification of existing IspF enzymatic assays.The second project involved the development of a concise synthesis of PDE4D allosteric modulators and applications toward the synthesis of new PDE4D inhibitors. Phosphodiesterases (PDEs) are responsible for the hydrolysis of cAMP and cGMP and are highly conserved in their catalytic domains of all super family members.2,3 Phosphodiesterase 4 (PDE4) is one of enzymes present in inflammatory and immune cells, which can be targeted as potential therapeutic agent for central nervous system (CNS) and respiratory disease. 4,5 As one of the four protein isoforms, PDE4D has been intensely investigated and a series of partial PDE4D inhibitors overcame the severe nausea side effects that were plaguing clinical PDE4 inhibitors.2 To improve the reported six step synthesis of the PDE4D inhibitor D159687 that had an 8% overall yield, a concise two step synthesis was developed using sequential Suzuki couplings that significantly increased the yield to 40% and provided a convergent synthesis that allows for rapid analog synthesis. The convergent synthetic route developed for the PDE4D inhibitors allowed for the synthesis of atropisomeric compounds. A method to separate the atropisomeric PDE4D inhibitors was developed using chiral HPLC. The atropisomeric PDE4D inhibitors will open an opportunity to study the binding modes and biological activity of these inhibitors.