Inosine monophosphate dehydrogenase and

The purine synthase inhibitor mizoribine is phosphorylated to the active form mizoribine 5 -monophosphate, which selectively inhibits inosine monophosphate dehydrogenase and guanosine monophosphate synthetase. Mizoribine has been used to treat systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, and other childhood diseases. 

Human type II inosine monophosphate dehydrogenase catalyses NAD-dependent conversion of inosine monophosphate (IMP) into xanthosine monophosphate (XMP) measurements of the primary kinetic isotope effect using [ H]IMP suggest that both substrates (IMP and NAD) can dissociate from the enzyme-substrate complex therefore, the kinetic mechanism is not ordered. NMR studies indicate hydride transfer to the B or pro-S face of the nicotinamide ring of NAD, while kinetic studies suggest... 

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

Mycophenolate mofetil (MMF, CellCept) is an ester prodrug of mycophenolic acid (MPA), a Penicillium-de-rived immunosuppressive agent (see Chapter 57) that blocks de novo purine synthesis by noncompetitively inhibiting the enzyme inosine monophosphate dehydrogenase. MPA preferentially suppresses the proliferation of cells, such as T and B lymphocytes, that lack the purine salvage pathway and must synthesize de novo... 

Mechanism of Action An immunologic agent that suppresses the immunologically mediated inflammatory response by inhibiting inosine monophosphate dehydrogenase, an enzyme that deprives lymphocytes of nucleotides necessary for DNA and RNA synthesis, thus inhibiting the proliferation of T and B lymphocytes. Therapeutic Effect Prevents transplant rejection. 

Unlike these nonspecific agents, mycophenolate mofetil (6.4) tends to be a lymphocyte-specific cytotoxic agent. Mycophenolate mofetil is a semisynthetic derivative of mycophe-nolic acid, isolated from the mold Penicillium glaucum. It inhibits both T and B lymphocyte action. Since it inhibits the enzyme inosine monophosphate dehydrogenase, which catalyses purine synthesis in lymphocytes, this agent has a more specific effect on lymphocytes than on other cell types. Mizoribine (6.5) is a closely related drug which inhibits nucleotide synthesis, preferentially in lymphocytes. 

Mechanism of Action Selectively inhibits inosine monophosphate dehydrogenase in the de novo pathway of purine synthesis, producing potent cytostatic effects on T and B lymphocytes... 

Mechanism of Action. Mycophenolate mofetil inhibits a specific enzyme (inosine monophosphate dehydrogenase) that is responsible for the synthesis of DNA precursors in T and B lymphocytes.39 50 Because these lymphocytes cannot synthesize adequate amounts of DNA, their ability to replicate and proliferate is impaired, thus blunting the immune response. This drug may also inhibit lymphocyte attraction and adhesion to the vascular endothelium, thereby impairing the lymphocytes ability to migrate to the site of the foreign (transplanted) tissues and to infiltrate from the bloodstream into these tissues.50... 

Selenazofurin (158), selenophenfurin (159), and dinucleosides such as 160 (Fig. 10), are potent inosine monophosphate dehydrogenase (IMPDH) inhibitors and have pronounced antitumor activity in animals and broad spectrum antiviral as well as maturation-inducing activities [262-264], The inhibitory effects of heterocyclic organoselenium compounds such as ebselen and some of its derivatives have been demonstrated on 15-LOXs [21, 265],... 

JT Beck, S Zhao, CC Wang. Cloning, sequencing, and structural analysis of the DNA encoding inosine monophosphate dehydrogenase (EC 1.1.1.205) from Tritrichomonas foetus. Exp Parasitol 78 101-112, 1994. 

In inosine monophosphate dehydrogenase, the monovalent metal ion accelerates the hydride transfer step of the reaction with apparently few other effects on the enzyme structure. Probably the monovalent cation is involved in helping position the nicotinamide cofactor. The active site and location of the potassium ion are shown in Figure 2. Mycophenolic acid in this diagram is an inhibitor that is thought to lock inosine monophosphate into the active site, as shown. Note the large distance between the inhibitor (in the active site) and the K+. 

G. D. Markham, Monovalent Cation Activation of IMP Dehydrogenase, Inosine Monophosphate Dehydrogenase A Major Therapeutic Target , K. W. Pankiewicz and B. M. Goldstein eds., ACS Symposium, series 839, Washington, DC, 2003, p. 169. 

Base-induced (KH or /-BuOK) cyclizations of o-alkynylanilines were utilized to prepare 2-substituted indoles and poly-substituted indoles. For example, treatment of alkynes 86 with KH gave the corresponding indoles 87 <03T1571>. Similar base-mediated cyclizations and related indole syntheses were utilized to prepare indole inhibitors of 5 -inosine monophosphate dehydrogenase <03BMCL1273>. Moreover, base-induced cyclizations of arylacetonitriles with oxalic acid bis(imidoyl)chlorides provide a route to 2-alkylidene-3-iminoindoles <03CEJ3951>. 

Inosine Monophosphate Dehydrogenase. Proliferative cells such as lymphocytes have high demands for the rapid supply of nucleotides to support DNA and RNA synthesis, as do viruses during their proliferative phase. The first dedicated step in the de novo biosynthesis of guanine nucleotides is conversion of inosinate to XMP, catalyzed by inosine monophosphate dehydrogenase (IMPDH). 

Mycophenolate mofetil is the 2-moiphohnoethyl ester of mycophenolic acid (MPA). It is a prodrug that is rapidly hydrolyzed to the active form, mycophenolic acid. Mycophenolic acid is a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of purine nucleotide synthesis. This pathway is very important in B and T lymphocytes for proliferation. Other cells can use salvage pathways. Therefore MPA inhibits lymphocyte proliferation and functions. The mofetil ester is first converted to MPA which then is metabolized to an inactive glucuronide (Alhson and Eugui, 2000). MPA has a half-hfe of about 16 hours (Fulton and Markham, 1996). 

B Mycophenoiate mofetil and other antiproiiferative agents fre-quentiy cause leukopenia and thrombocytopenia. Mycophenoiic acid (active form of mycophenoiate mofetil) inhibits the enzyme inosine monophosphate dehydrogenase, the key enzyme in the de novo pathway for purine biosynthesis. Activated T-lymphocytes cannot use the salvage pathway for purine biosynthesis, and therefore are sensitive to the effects of mycophenoiic acid. The caicineurin inhibitors, IL-2 receptor antagonists, and corticosteroids do not cause bone marrow suppression. 

This in situ generation of enamines and subsequent Heck cyclization to afford indoles has been adopted by several groups for the synthesis of indoles (and azaindoles) from 2-chloroanilines [337], tricyclic inhibitors of 5 -inosine monophosphate dehydrogenase [145], medium-ring fused indoles [338], and tetrahydrocarbazole in an Organic Synthesis preparation [339]. Some mechanistic insights have been offered [340]. The use of aryl-propynamides and rV-alkynyl-2-haloanilides under Heck conditions affords oxindoles [341] and 2-aminomdoles [342], respectively. An example of the latter is illustrated for 323 to 324. 

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