6-[2'-Formyl-2'-(4-carbomethoxy phenyl)-ethyl]-2-pivaloylamino-4(3H)-oxo-quinazoline | 182217-62-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 6-[2'-Formyl-2'-(4-carbomethoxy phenyl)-ethyl]-2-pivaloylamino-4(3H)-oxo-quinazoline
• 英文别名: methyl 4-[1-[2-(2,2-dimethylpropanoylamino)-4-oxo-3H-quinazolin-6-yl]-3-oxopropan-2-yl]benzoate
• CAS: 182217-62-5
• 化学式: C₂₄H₂₅N₃O₅
• 分子量: 435.48
• InChiKey: WKZJRZBJEORKPY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-[2'-Formyl-2'-(4-carbomethoxy phenyl)-ethyl]-2-pivaloylamino-4(3H)-oxo-quinazoline 在 sodium tetrahydroborate 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 0.25h， 生成 4-{2-[2-(2,2-Dimethyl-propionylamino)-4-oxo-3,4-dihydro-quinazolin-6-yl]-1-methanesulfonyloxymethyl-ethyl}-benzoic acid methyl ester
  参考文献：
  名称：

  Functionalized analogues of 5,8,10-trideazafolate: Development of an enzyme-assembled tight binding inhibitor of GAR Tfase and a potential irreversible inhibitor of AICAR Tfase

  摘要：

  A set of inhibitors 3 and 4 of GAR and AICAR Tfase based on the TDAF core which contain an sp(2) C-10 carbon atom replacing N-10 of the natural cofactor are detailed. Both possess electrophilic olefins and the potential of trapping the reacting amine of the substrates GAR and AICAR by a Michael addition at the enzyme active site to provide an enzyme-assembled tight binding inhibitor. While these agents did not display such characteristics and served as simple competitive inhibitors of GAR Tfase and AICAR Tfase, inhibitor 15 prepared in the conversion of 3 to 4 may provide an enzyme-assembled tight binding inhibitor of GAR Tfase upon reaction with the substrate GAR and may inactivate AICAR Tfase by virtue of alkylation of an active site residue. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0968-0896(97)00122-3
• 作为产物：
  描述：

  4-(2-氧代乙基)苯甲酸甲酯 在 phosphate buffer 、 magnesium sulfate 、 copper dichloride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 9.5h， 生成 6-[2'-Formyl-2'-(4-carbomethoxy phenyl)-ethyl]-2-pivaloylamino-4(3H)-oxo-quinazoline
  参考文献：
  名称：

  10-甲酰基-5,8,10-三氮杂af酸（10-甲酰基-TDAF）：甘氨酰胺核糖核苷酸转化酶的有效抑制剂。

  摘要：

  据报道，可合成10-甲酰基-5,8,10-三氮杂3酸（3）作为潜在的甘氨酰胺核糖核苷酸转化酶（GAR Tfase）抑制剂。通过utilizing的合成，利用5与苄基溴6的烷基化以构建核心杂环7，制备目标化合物。将醛3和相关试剂评估为purN GAR Tfase和禽类AICAR Tfase的抑制剂。化合物3显示出对GAR Tfase的有效抑制，Ki为0.26 +/- 0.05 microM。相比之下，3表现出对氨基咪唑羧酰胺核糖核苷酸转化酶（AICAR Tfase）的中等抑制，Ki为7.6 +/- 1.5 microM。

  DOI：

  10.1016/s0968-0896(97)00120-x

文献信息

• Non-classical folate analogue inhibitors of glycinamide ribonucleotide
  申请人：——

  公开号：US05593999A1

  公开（公告）日：1997-01-14

  Several new 10-formyl and 10-hydroxymethyl derivatives of 5,8,10-trideazapteroic acid are provided, as well as procedures for their preparation. These compounds were shown to be powerful inhibitors of glycinamide ribonucleotide formyltransferase (GARFT), an enzyme that mediates the de novo biosynthesis of purine nucleotides that are required for DNA synthesis and cell division. Due to their ability to interfere with nucleotide biosynthesis and to penetrate microbial cells they are potential anti-microbial agents and are useful for the treatment of opportunistic infections in AIDS and other infections caused by micro-organisms that are resistant to conventional anti-bacterial and anti-fungal agents.

  提供了几种5,8,10-三去氨基蝶酸的新的10-甲酰基和10-羟甲基衍生物的制备方法。这些化合物被证明是甘氨酰核苷酸甲酰转移酶（GARFT）的强力抑制剂，该酶介导嘌呤核苷酸的新生物质，这些核苷酸是DNA合成和细胞分裂所必需的。由于它们干扰核苷酸的生物合成并能够渗透入微生物细胞，因此它们是潜在的抗微生物药物，并且对于治疗艾滋病和其他由对传统抗菌和抗真菌药物具有抗药性的微生物引起的机会性感染非常有用。
• US5593999A
  申请人：——

  公开号：US5593999A

  公开（公告）日：1997-01-14
• [EN] NOVEL NON-CLASSICAL FOLATE ANALOGUE INHIBITORS OF GLYCINAMIDE RIBONUCLEOTIDE FORMYLTRANSFERASE (GARFT)<br/>[FR] NOUVEAUX ANALOGUES NON CLASSIQUES DE FOLATE INHIBITEURS DE LA GLYCINAMIDE RIBONUCLEOTIDE FORMYLTRANSFERASE
  申请人：NAIR, Madhavan, G.

  公开号：WO1996040680A1

  公开（公告）日：1996-12-19

  (EN) Several new 10-formyl and 10-hydroxymethyl derivatives of 5,8,10-trideazapteroic acid are provided, as well as procedures for their preparation. These compounds were shown to be powerful inhibitors of glycinamide ribonucleotide formyltransferase (GARFT), an enzyme that mediates the $i(de novo) biosynthesis of purine nucleotides that are required for DNA synthesis and cell division. Due to their ability to interfere with nucleotide biosynthesis and to penetrate microbial cells they are anti-microbial agents and are useful for the treatment of $i(Pneumocystis carinii) infection in AIDS and other infections responding to folate based antimicrobial agents.(FR) L'invention se rapporte à plusieurs nouveaux dérivés 10-formyle et 10-hydroxyméthyle de l'acide 5,8,10-trideazaptéroïque, ainsi qu'à leurs procédés de préparation. Ces composés sont censés être de puissants inhibiteurs de la glycinamide ribonucléotide formyltransférase (GARFT), une enzyme qui induit la biosynthèse $i(de novo) de nucléotides de purine nécessaires à la synthèse de l'ADN et à la division cellulaire. Du fait de leur capacité à interférer avec la biosynthèse des nucléotides et à pénétrer dans les cellules microbiennes, ces composés agissent comme agents antimicrobiens et sont utiles dans le traitement des infections par $i(Pneumocystis carinii) chez les malades du SIDA et à d'autres infections réagissant aux agents antimicrobiens à base de folate.
• 10-formyl-5,8,10-trideazafolic acid (10-formyl-TDAF): A potent inhibitor of glycinamide ribonucleotide transformylase
  作者：Dale L. Boger、Nancy-Ellen Haynes、Paul A. Kitos、Mark S. Warren、Joseph Ramcharan、Ariane E. Marolewski、Stephen J. Benkovic

  DOI：10.1016/s0968-0896(97)00120-x

  日期：1997.9

  10-trideazafolic acid (3) as a potential inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) is reported. The target compound was prepared by a convergent synthesis utilizing the alkylation of hydrazone 5 with benzylic bromide 6 to construct the core heterocycle 7. The aldehyde 3 and related agents were evaluated as inhibitors of purN GAR Tfase and avian AICAR Tfase. Compound 3 exhibited potent

  据报道，可合成10-甲酰基-5,8,10-三氮杂3酸（3）作为潜在的甘氨酰胺核糖核苷酸转化酶（GAR Tfase）抑制剂。通过utilizing的合成，利用5与苄基溴6的烷基化以构建核心杂环7，制备目标化合物。将醛3和相关试剂评估为purN GAR Tfase和禽类AICAR Tfase的抑制剂。化合物3显示出对GAR Tfase的有效抑制，Ki为0.26 +/- 0.05 microM。相比之下，3表现出对氨基咪唑羧酰胺核糖核苷酸转化酶（AICAR Tfase）的中等抑制，Ki为7.6 +/- 1.5 microM。
• Functionalized analogues of 5,8,10-trideazafolate: Development of an enzyme-assembled tight binding inhibitor of GAR Tfase and a potential irreversible inhibitor of AICAR Tfase
  作者：Dale L. Boger、Nancy-Ellen Haynes、Mark S. Warren、Joseph Ramcharan、Paul A. Kitos、Stephen J. Benkovic

  DOI：10.1016/s0968-0896(97)00122-3

  日期：1997.9

  A set of inhibitors 3 and 4 of GAR and AICAR Tfase based on the TDAF core which contain an sp(2) C-10 carbon atom replacing N-10 of the natural cofactor are detailed. Both possess electrophilic olefins and the potential of trapping the reacting amine of the substrates GAR and AICAR by a Michael addition at the enzyme active site to provide an enzyme-assembled tight binding inhibitor. While these agents did not display such characteristics and served as simple competitive inhibitors of GAR Tfase and AICAR Tfase, inhibitor 15 prepared in the conversion of 3 to 4 may provide an enzyme-assembled tight binding inhibitor of GAR Tfase upon reaction with the substrate GAR and may inactivate AICAR Tfase by virtue of alkylation of an active site residue. (C) 1997 Elsevier Science Ltd.