Synthesis of C-2 and C-6 functionalized ribofuranosylpurine analogues as potential antiviral agents targeting inhibition of inosine monophosphate dehydrogenase [electronic resource] /
Abstract (Summary)IMPDH is a key enzyme in the de novo biosynthesis of purine nucleotides. It catalyzes the conversion of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) using NAD as a cofactor. XMP is successively converted to deoxyguanosine triphosphate (substrate for DNA synthesis) by GMP synthetase, phosphorylating enzymes and ribonucleotide reductase. IMPDH exists in two isoforms, type I and type II. These isoforms have the same size and share 84% homology. The type I isoform is expressed in both normal and rapidly proliferating cells, whereas type II is preferentially upregulated in proliferating cells. Inhibition of IMPDH has anticancer, antiviral, antibacterial and immunosuppressive effects. Three inhibitors of IMPDH are currently in clinical use: ribavirin (a broad spectrum antiviral), mizoribine (immunosuppressant used in Japan) and mycophenolic mofetil (prodrug of mycophenolic acid, US approved immunosuppressant). None of these inhibitors possess significant selectivity against the type II isoform over the type I, hence there are severe side effects. The quest for specific isozyme inhibitors led to the discovery of the potential antiviral activity of certain C-2 functionalized hypoxanthine and C-2, C-6 modified purine systems against HSV1, HSV2, VV, VSV and RSV. Nair and coworkers have synthesized similar congeners, including 2-vinylinosine (broad spectrum antiviral), which is active due to its C-2 vinyl moiety acting as a Michael Acceptor. This dissertation elucidates the design and synthesis of new Michael Acceptor-type nucleosides. These novel compounds were designed mechanistically as transition-state analogues similar to mizoribine 5'-monophosphate and "Fat base" nucleotide (two potent IMPDH inhibitors). The structural design was fashioned to mimic the hydrogen bonding interactions observed in the crystal structure of the E-XMP* adduct of human IMPDH II and IMP. The C-2 functionalized hypoxanthine nucleosides were synthesized via a newly developed reproducible, efficient and high-yielding non-enzymatic methodology, whereas the C-2 and C-6 functionalized ribofuranosylpurine nucleosides were synthesized by Stille coupling from either the 2-I, 6-Cl or 2-I, 6-I ribofuranosylpurine intermediate. Both methodologies represent a significant improvement over previous methodologies. The modifications involved moities such as 2-furyl, 2-thienyl, vinyl, thio, methoxy and thiomethyl. These compounds were designed and synthesized as potential antiviral compounds targeting IMPDH inhibition.
School:The University of Georgia
School Location:USA - Georgia
Source Type:Master's Thesis
Date of Publication: