2',3'-O-isopropylidene-2-ethylinosine | 13591-93-0

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 2',3'-O-isopropylidene-2-ethylinosine
• 英文别名: 2-ethyl-9-(tri-O-acetyl-β-D-ribofuranosyl)-1,9-dihydro-purin-6-one；9-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-ethyl-1H-purin-6-one
• CAS: 13591-93-0
• 化学式: C₁₅H₂₀N₄O₅
• 分子量: 336.348
• InChiKey: MSQYCJGDBMUYHJ-FRJWGUMJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  107
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2',3'-O-isopropylidene-2-ethylinosine 在 吡啶 、 四乙基氯化铵 、 氨 、 水 、 N,N-二甲基苯胺 、 三氯氧磷 作用下， 以 异丙醇 、 乙腈 为溶剂， 反应 29.0h， 生成
  参考文献：
  名称：

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

  摘要：

  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-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 (IC50 = 0.45 mu M). Compound 4 was as potent as Gleevec (IC50 = 0.56 mu M) 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. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.01.042

文献信息

• NAD-based inhibitors with anticancer potential
  作者：Krzysztof Felczak、Robert Vince、Krzysztof W. Pankiewicz

  DOI：10.1016/j.bmcl.2013.11.005

  日期：2014.1

  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 to be potent inhibitors of IMPDH (K-i's in range of 0.6-82 nM) and sub-mu M inhibitors of leukemic K562 cell proliferation. (2) Mycophenolic adenosine (D and L) esters (20 and 21) showed a potent inhibition of IMPDH2 (K-i = 102 and K-i = 231 nM, respectively) and inhibition of K562 cell growth (IC50 = 0.5 and IC50 = 1.6 mu M). 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 (K-i = 84 nM), did not inhibit cancer cell proliferation. (3) Mycophenolic-(L)-and (D)-valine adenine diamide derivatives 25 (K-i = 9 nM) and 28 (K-i = 3 nM) were found to be very potent enzymatically, but did not inhibit proliferation of cancer cells. (C) 2013 Elsevier Ltd. All rights reserved.