7-benzyloxy-6-(2-hydroxyethyl)-5-methoxy-4-methylphthalan-1-one | 402731-06-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异香豆素
• 英文名称: 7-benzyloxy-6-(2-hydroxyethyl)-5-methoxy-4-methylphthalan-1-one
• 英文别名: 6-(2-hydroxyethyl)-5-methoxy-4-methyl-7-phenylmethoxy-3H-2-benzofuran-1-one
• CAS: 402731-06-0
• 化学式: C₁₉H₂₀O₅
• 分子量: 328.365
• InChiKey: CJYUNWXVHAUTDR-UHFFFAOYSA-N

物化性质

• 沸点：
  578.9±50.0 °C(Predicted)
• 密度：
  1.256±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  65
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  7-benzyloxy-6-(2-hydroxyethyl)-5-methoxy-4-methylphthalan-1-one 在 palladium on activated charcoal N-甲基咪唑 、 四氮唑 、 2,4,6-三异丙基苯磺酰氯 、 氢气 、 三乙基碳酸氢铵缓冲液 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 乙醇 、 乙腈 为溶剂， 反应 5.0h， 生成 P¹-(adenosin-5'-yl)methylenephospho-P²-[7-hydroxy-6-(ethyl-2-yl)-5-methoxy-4-methylphthalan-1-one]phosphonate bis(triethylamine)
  参考文献：
  名称：

  Novel Methylenephosphophosphonate Analogues of Mycophenolic Adenine Dinucleotide. Inhibition of Inosine Monophosphate Dehydrogenase

  摘要：

  Novel methylenephosphophosphonate analogues of mycophenolic adenine dinucleotide ( MAD) have been prepared as potential inhibitors of IMP dehydrogenase. A coupling of the mycophenolic (hydroxymethyl)phosphonate 6 with the phosphitylated adenosine analogue 11 followed by oxidation and deprotection afforded the phosphophosphonate 8. A similar coupling between adenosine ( hydroxymethyl) phosphonate 10 and phosphitylated mycophenolic alcohol 5 gave the corresponding phosphophosphonate 13. Both 8 and 13 (K-i = 20- 87 nM) were found to be the most potent cofactor type inhibitors of IMP dehydrogenase.

  DOI：

  10.1021/jm060479r
• 作为产物：
  描述：

  霉酚酸 在 sodium periodate 、 四氧化锇 、 四丁基氟化铵 、 N-甲基吗啉氧化物 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 6.5h， 生成 7-benzyloxy-6-(2-hydroxyethyl)-5-methoxy-4-methylphthalan-1-one
  参考文献：
  名称：

  新型麦考酚腺嘌呤双（膦酸酯）类似物可作为对抗人类白血病的潜在分化剂。

  摘要：

  新型霉酚酚腺嘌呤二核苷酸（MAD）类似物已被制备为肌苷单磷酸脱氢酶（IMPDH）的潜在抑制剂。MAD类似物类似于在IMPDH的辅因子结合域上的烟酰胺腺嘌呤二核苷酸结合。然而，它们不能参与氢化物转移，因此抑制了酶。亚甲基双（膦酸酯）类似物C2-MAD和C4-MAD是通过在二异丙基碳二亚胺存在下将2'，3'-O-异丙基亚氨腺苷5'-亚甲基双（膦酸酯）（22）与麦考酚醇20和21偶合而获得的。C2-MAD也可以通过将霉酚酚亚甲基双（膦酸酯）衍生物30与2'，3'-O-异丙基亚氨腺苷偶联来制备。在吉川氏反应条件下，用市售的亚甲基双（二氯化膦）处理苄基保护的霉酚醇27，可以方便地合成化合物30。发现C2-MAD和C4-MAD与霉酚酸（IC（50）= 0.3 microM）一样有效地抑制K562细胞的生长（IC（50）= 0.7 microM和IC（50）= 0.1 microM）。另外，C2-MAD

  DOI：

  10.1021/jm0104116

文献信息

• Mycophenolic anilides as broad specificity inosine-5’-monophosphate dehydrogenase (IMPDH) inhibitors
  作者：Seungheon Lee、Angela F. Ku、Mohana Rao Vippila、Yong Wang、Minjia Zhang、Xingyou Wang、Lizbeth Hedstrom、Gregory D. Cuny

  DOI：10.1016/j.bmcl.2020.127543

  日期：2020.12

  Inosine-5'-monophosphate dehydrogenase (IMPDH) is a potential target for microorganisms. However, identifying inhibitor design determinants for IMPDH orthologs continues to evolve. Herein, a series of mycophenolic anilide inhibitors of Cryptosporidium parvum and human IMPDHs are reported. Furthermore, molecular docking of 12 (e.g. SH-19; CpIMPDH Ki,app = 0.042 ± 0.015 µM, HsIMPDH2 Ki,app = 0.13 ± 0.05 µM) supports different binding modes with the two enzymes. For CpIMPDH the inhibitor extends into a pocket in an adjacent subunit. In contrast, docking suggests the inhibitor interacts with Ser276 in the NAD binding site in HsIMPDH2, as well as an adjacent pocket within the same subunit. These results provide further guidance for generating IMPDH inhibitors for enzymes found in an array of pathogenic microorganisms, including Mycobacterium tuberculosis.
• Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: Targeting the pyrophosphate binding sub-domain
  作者：Krzysztof Felczak、Liqiang Chen、Daniel Wilson、Jessica Williams、Robert Vince、Riccardo Petrelli、Hiremagalur N. Jayaram、Praveen Kusumanchi、Mohineesh Kumar、Krzysztof W. Pankiewicz

  DOI：10.1016/j.bmc.2011.01.042

  日期：2011.3

  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.
• Novel Mycophenolic Adenine Bis(phosphonate) Analogues As Potential Differentiation Agents against Human Leukemia
  作者：Krzysztof W. Pankiewicz、Krystyna B. Lesiak-Watanabe、Kyoichi A. Watanabe、Steven E. Patterson、Hiremagalur N. Jayaram、Joel A. Yalowitz、Michael D. Miller、Michael Seidman、Alokes Majumdar、Gerd Prehna、Barry M. Goldstein

  DOI：10.1021/jm0104116

  日期：2002.1.1

  Novel mycophenolic adenine dinucleotide (MAD) analogues have been prepared as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). MAD analogues resemble nicotinamide adenine dinucleotide binding at the cofactor binding domain of IMPDH; however, they cannot participate in hydride transfer and therefore inhibit the enzyme. The methylenebis(phosphonate) analogues C2-MAD and C4-MAD were

  新型霉酚酚腺嘌呤二核苷酸（MAD）类似物已被制备为肌苷单磷酸脱氢酶（IMPDH）的潜在抑制剂。MAD类似物类似于在IMPDH的辅因子结合域上的烟酰胺腺嘌呤二核苷酸结合。然而，它们不能参与氢化物转移，因此抑制了酶。亚甲基双（膦酸酯）类似物C2-MAD和C4-MAD是通过在二异丙基碳二亚胺存在下将2'，3'-O-异丙基亚氨腺苷5'-亚甲基双（膦酸酯）（22）与麦考酚醇20和21偶合而获得的。C2-MAD也可以通过将霉酚酚亚甲基双（膦酸酯）衍生物30与2'，3'-O-异丙基亚氨腺苷偶联来制备。在吉川氏反应条件下，用市售的亚甲基双（二氯化膦）处理苄基保护的霉酚醇27，可以方便地合成化合物30。发现C2-MAD和C4-MAD与霉酚酸（IC（50）= 0.3 microM）一样有效地抑制K562细胞的生长（IC（50）= 0.7 microM和IC（50）= 0.1 microM）。另外，C2-MAD
• Novel Methylenephosphophosphonate Analogues of Mycophenolic Adenine Dinucleotide. Inhibition of Inosine Monophosphate Dehydrogenase
  作者：Dominik Rejman、Magda Olesiak、Liqiang Chen、Steven E. Patterson、Daniel Wilson、Hiramagalur N. Jayaram、Lizbeth Hedstrom、Krzysztof W. Pankiewicz

  DOI：10.1021/jm060479r

  日期：2006.8.1

  Novel methylenephosphophosphonate analogues of mycophenolic adenine dinucleotide ( MAD) have been prepared as potential inhibitors of IMP dehydrogenase. A coupling of the mycophenolic (hydroxymethyl)phosphonate 6 with the phosphitylated adenosine analogue 11 followed by oxidation and deprotection afforded the phosphophosphonate 8. A similar coupling between adenosine ( hydroxymethyl) phosphonate 10 and phosphitylated mycophenolic alcohol 5 gave the corresponding phosphophosphonate 13. Both 8 and 13 (K-i = 20- 87 nM) were found to be the most potent cofactor type inhibitors of IMP dehydrogenase.