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(biochemistry) purine base found in DNA and RNA; pairs with thymine in DNA and with uracil in RNA (同)A

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アデニン(肝臓・茶の葉から採れる塩基の一種)

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1. 1型糖尿病の予防 prevention of type 1 diabetes mellitus
2. 心臓移植における免疫抑制療法の導入および維持 induction and maintenance of immunosuppressive therapy in cardiac transplantation
3. 重症筋無力症に対する長期免疫療法 chronic immunomodulating therapies for myasthenia gravis
4. 小児に対する腎移植における免疫抑制 immunosuppression in renal transplantation in children
5. 成人における肝移植：免疫抑制の概要 liver transplantation in adults overview of immunosuppression

English Journal

NAD-based inhibitors with anticancer potential.

Felczak K1, Vince R1, Pankiewicz KW2.Author information 1Center for Drug Design, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA.2Center for Drug Design, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA. Electronic address: panki001@umn.edu.AbstractThree classes of novel inhibitors of inosine monophosphate dehydrogenase have been prepared and their anti-proliferative properties were evaluated against several cancer cell lines. (1) Mycophenolic adenine dinucleotide analogues (8-13) containing a substituent at the C2 of adenine ring were found to be potent inhibitors of IMPDH (Ki's in range of 0.6-82nM) and sub-μM inhibitors of leukemic K562 cell proliferation. (2) Mycophenolic adenosine (d and l) esters (20 and 21) showed a potent inhibition of IMPDH2 (Ki=102 and Ki=231nM, respectively) and inhibition of K562 cell growth (IC50=0.5 and IC50=1.6μM). These compounds serve both as inhibitors of the enzyme and as a depot form of mycophenolic acid. The corresponding amide analogue 22, also a potent inhibitor of IMPDH (Ki=84nM), did not inhibit cancer cell proliferation. (3) Mycophenolic-(l)- and (d)-valine adenine di-amide derivatives 25 (Ki=9nM) and 28 (Ki=3nM) were found to be very potent enzymatically, but did not inhibit proliferation of cancer cells.
Bioorganic & medicinal chemistry letters.Bioorg Med Chem Lett.2014 Jan 1;24(1):332-6. doi: 10.1016/j.bmcl.2013.11.005. Epub 2013 Nov 14.
Three classes of novel inhibitors of inosine monophosphate dehydrogenase have been prepared and their anti-proliferative properties were evaluated against several cancer cell lines. (1) Mycophenolic adenine dinucleotide analogues (8-13) containing a substituent at the C2 of adenine ring were found t
PMID 24269162

Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: targeting the pyrophosphate binding sub-domain.

Felczak K, Chen L, Wilson D, Williams J, Vince R, Petrelli R, Jayaram HN, Kusumanchi P, Kumar M, Pankiewicz KW.Author information Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA.AbstractCofactor-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 sub-site (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 μM). Compound 4 was as potent as Gleevec (IC(50)=0.56 μM) 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.
Bioorganic & medicinal chemistry.Bioorg Med Chem.2011 Mar 1;19(5):1594-605. doi: 10.1016/j.bmc.2011.01.042. Epub 2011 Jan 27.
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 sub-
PMID 21324702

Triazole-linked inhibitors of inosine monophosphate dehydrogenase from human and Mycobacterium tuberculosis.

Chen L, Wilson DJ, Xu Y, Aldrich CC, Felczak K, Sham YY, Pankiewicz KW.Author information Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, Minnesota 55455, USA. chenx462@umn.eduAbstractThe modular nature of nicotinamide adenine dinucleotide (NAD)-mimicking inosine monophsophate dehydrogenase (IMPDH) inhibitors has prompted us to investigate novel mycophenolic adenine dinucleotides (MAD) in which 1,2,3-triazole linkers were incorporated as isosteric replacements of the pyrophosphate linker. Synthesis and evaluation of these inhibitors led to identification of low nanomolar inhibitors of human IMPDH and more importantly the first potent inhibitor of IMPDH from Mycobacterium tuberculosis (mtIMPDH). Computational studies of these IMPDH enzymes helped rationalize the observed structure-activity relationships. Additionally, the first cloning, expression, purification and characterization of mtIMPDH is reported.
Journal of medicinal chemistry.J Med Chem.2010 Jun 24;53(12):4768-78. doi: 10.1021/jm100424m.
The modular nature of nicotinamide adenine dinucleotide (NAD)-mimicking inosine monophsophate dehydrogenase (IMPDH) inhibitors has prompted us to investigate novel mycophenolic adenine dinucleotides (MAD) in which 1,2,3-triazole linkers were incorporated as isosteric replacements of the pyrophosphat
PMID 20491506