Probing Binding Requirements of Type I and Type II Isoforms of Inosine Monophosphate Dehydrogenase with Adenine-Modified Nicotinamide Adenine Dinucleotide Analogues (original) (raw)
Related papers
Bioorganic & Medicinal Chemistry, 2005
Thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2 0 -MeAD (1) and T-3 0 -MeAD (2) containing, respectively, a methyl group at the ribose 2 0 -C-, and 3 0 -C-position of the adenosine moiety, were prepared as potential selective human inosine monophosphate dehydrogenase (IMPDH) type II inhibitors. The synthesis of heterodinucleotides was carried out by CDI-catalyzed coupling reaction of unprotected 2 0 -C-methyl-or 3 0 -C-methyl-adenosine 5 0 -monophosphate with 2 0 ,3 0 -O-isopropylidene-tiazofurin 5 0 -monophosphate, and then deisopropylidenation. Biological evaluation of dinucleotides 1 and 2 as inhibitors of recombinant human IMPDH type I and type II resulted in a good activity. Inhibition of both isoenzymes by T-2 0 -MeAD and T-3 0 -MeAD was noncompetitive with respect to NAD substrate. Binding of T-3 0 -MeAD was comparable to that of parent compound TAD, while T-2 0 -MeAD proved to be a weaker inhibitor. However, no significant difference was found in inhibition of the IMPDH isoenzymes. T-2 0 -MeAD and T-3 0 -MeAD were found to inhibit the growth of K562 cells (IC 50 30.7 and 65.0 lM, respectively).
Bioorganic & Medicinal Chemistry, 2011
Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinamide adenine dinucleotide (NAD) binding domain of the enzyme are modular in nature. They interact with the three sub-sites of the cofactor binding domain; the nicotinamide monophosphate (NMN) binding subsite (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Mycophenolic acid (MPA) shows high affinity to the N sub-site of human IMPDH mimicking NMN binding. We found that the attachment of adenosine to the MPA through variety of linkers afforded numerous mycophenolic adenine dinucleotide (MAD) analogues that inhibit the two isoforms of the human enzyme in low nanomolar to low micromolar range. An analogue 4, in which 2-ethyladenosine is attached to the mycophenolic alcohol moiety through the difluoromethylenebis(phosphonate) linker, was found to be a potent inhibitor of hIMPDH1 (K i = 5 nM), and one of the most potent, sub-micromolar inhibitor of leukemia K562 cells proliferation (IC 50 = 0.45 lM). Compound 4 was as potent as Gleevec (IC 50 = 0.56 lM) heralded as a 'magic bullet' against chronic myelogenous leukemia (CML). MAD analogues 7 and 8 containing an extended ethylenebis(phosphonate) linkage showed low nanomolar inhibition of IMPDH and low micromolar inhibition of K562 cells proliferation. Some novel MAD analogues described herein containing linkers of different length and geometry were found to inhibit IMPDH with K i 's lower than 100 nM. Thus, such linkers can be used for connection of other molecular fragments with high affinity to the N-and A-sub-site of IMPDH.
Journal of Medicinal Chemistry, 1997
Methylene-BAD (8), a nonhydrolyzable analogue of benzamide adenine dinucleotide (BAD), was synthesized as potential inhibitor of human inosine monophosphate dehydrogenase (IMPDH). Treatment of 2′,3′-O-isopropylideneadenosine 5′-methylenebisphosphonate (15) with DCC afforded P 1 ,P 4-bis(2′,3′-O-isopropylideneadenosine) 5′-P 1 ,P 2 :P 3 ,P 4-dimethylenetetrakisphosphonate (17). This compound was further converted with DCC to an active intermediate 18 which upon reaction with 3-(2′,3′-O-isopropylidene-D-ribofuranosyl)benzamide (19) gave, after hydrolysis and deisopropylidenation, the desired-methylene-BAD (8) in 95% yield. In a similar manner, treatment of 18 with 2′,3′-O-isopropylidenetiazofurin (21) followed by hydrolysis and deprotection afforded-methylene-TAD (5) in 91% yield. Compound 8 (IC 50) 0.665 µM) was found to be a 6-8 times less potent inhibitor of IMPDH than 5 (IC 50) 0.107 µM) and was almost equally potent against IMPDH type I and type II. Although TAD and-methylene-TAD were bound by LADH with the same affinity, the binding affinity of 8 toward LADH (K i) 333 µM) was found to be 50-fold lower than that of the parent pyrophosphate 7 (K i) 6.3 µM).
Journal of Medicinal Chemistry, 2002
Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats. Introduction. Inosine monophosphate dehydrogenase (IMPDH) is an enzyme that catalyzes the nicotinamide adenosine dinucleotide (NAD) dependent conversion of inosine 5′-monophosphate (IMP) to xanthosine 5′-monophosphate (XMP). 1 The reaction is irreversible and is the first step in the de novo synthesis of guanine nucleotides. Rapidly proliferating cells such as lymphocytes are dependent on the availability of the nucleotide pool to meet their metabolic requirement, and it is known that the activity of IMPDH is higher in proliferating cells. 2 Because of these cell requirements, IM-PDH is an attractive target for immunosuppressive, anticancer, and antiviral therapies. 3 Two isoforms of the IMPDH enzyme are known to exist: type I and type II. Human types I and II IMPDH cDNAs encode the same-size proteins (514 amino acids) and show 84% sequence identity. 4 It was initially thought that because type II expression is upregulated in neoplastic and replicating cells, it is this isoform that is responsible for cell differentiation and neoplastic transformation. 5 However, more recent work has indicated that induction of types I and II isoforms contributes significantly to the T-cell proliferation response. 6 The mechanism of IMPDH reaction has been studied in detail (Figure 1). 7 The oxidation of IMP to XMP is an irreversible reaction and utilizes NAD as the cofac
Advances in Enzyme Regulation, 1983
DAVID A. COONEY, et al. (EC 3.1.3.6), inorganic pyrophosphatase from baker's yeast (EC 3.6.1.1), Type III alkaline phosphatase from Escherichia coli (EC 3.1.3.1), and acid phosphatase from potato (EC 3.1.3.2) were the products of Sigma Chemical Co., St. Louis, MO. NAD pyrophosphorylase (EC2.7.7.1), phosphodiesterase from beef hearts (EC 3.1.4.17), phosphodiesterase from calf spleen (EC3.1.16.1) and phosphodiesterase from Crotalus durissus terrificus (EC3.1.4.1) were obtained from Boehringer Mannheim Biochemicals, Indianapolis, IN. Ribonuclease B (EC 3.1.4.23), snake venum phosphodiesterase (EC3.1.4.1) and NAD nucleosidase from Neurospora erassa (EC 3.2.2.5) were purchased from Worthington Biochemical Corp., Freehold, NJ. Tiazofurin, (2-/3-D-ribofuranosylthiazole-4-carboxamide, NSC 286193) and its 5'-monophosphate (NSC 343494) were kindly provided by Dr. Ven Narayanan of the National Cancer Institute, NIH, Bethesda, MD. [2-3 H]Inosinic acid (4.9 and 6.2 Ci/mmole) was prepared in our laboratory from Amersham's [2-3H]hypoxanthine.
Novel inhibitors of inosine monophosphate dehydrogenase (IMPDH)
2002
Inosine monophosphate dehydrogenase (IMPDH), an NAD-dependent enzyme that controls de novo synthesis of guanine nucleotides, has received considerable interest in recent years as an important target enzyme, not only for the discovery of anticancer drugs, but also for antiviral, antiparasitic, and immunosuppressive chemotherapy. The field of IMPDH inhibitor research is highly important for providing potential therapeutics against a validated target for disease intervention. This patent review examines the chemical structures and biological activities of recently reported IMPDH inhibitors. Patent databases SciFinder and Espacenet and Delphion were used to locate patent applications that were published between January 2002 and July 2012, claiming chemical structures for use as IMPDH inhibitors. From 2002 to 2012, around 47 primary patent applications have claimed IMPDH inhibitors, which we analyzed by target and applicant. The level of newly published patent applications covering IMPDH inhibitors remains high and a diverse range of scaffolds has been claimed.
Proceedings of the National Academy of Sciences, 1999
Inosine monophosphate dehydrogenase (IMPDH) controls a key metabolic step in the regulation of cell growth and differentiation. This step is the NAD-dependent oxidation of inosine 5′ monophosphate (IMP) to xanthosine 5′ monophosphate, the rate-limiting step in the synthesis of the guanine nucleotides. Two isoforms of IMPDH have been identified, one of which (type II) is significantly up- regulated in neoplastic and differentiating cells. As such, it has been identified as a major target in antitumor and immunosuppressive drug design. We present here the 2.9-Å structure of a ternary complex of the human type II isoform of IMPDH. The complex contains the substrate analogue 6-chloropurine riboside 5′-monophosphate (6-Cl-IMP) and the NAD analogue selenazole-4-carboxamide adenine dinucleotide, the selenium derivative of the active metabolite of the antitumor drug tiazofurin. The enzyme forms a homotetramer, with the dinucleotide binding at the monomer–monomer interface. The 6 chloro-subs...
Current Medicinal Chemistry, 2004
IMP dehydrogenase, the key enzyme in de novo synthesis of purine nucleotides, is an important therapeutic target. Three inhibitors of IMP dehydrogenase reached the market; ribavirin (Rebetol) a broadspectrum antiviral agent, which in combination with interferon-α is now used for treatment of hepatitis C virus infections, mizoribine (Bredinin) and mycophenolic mofetil (CellCept) have been introduced as immunosuppressants. Numerous novel inhibitors are under development. This review describes recent progress in the development of new drugs based on inhibition of IMP dehydrogenase.