N-[N-[(phenylmethoxy)carbonyl]-L-γ-glutamyl]-D-glutamic acid tris(1,1-dimethylethyl) ester | 1445098-26-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-[N-[(phenylmethoxy)carbonyl]-L-γ-glutamyl]-D-glutamic acid tris(1,1-dimethylethyl) ester
• 英文别名: benzylcarbonyl-gGlu(OtBu)-D-Glu(OtBu)-OtBu；ditert-butyl (2R)-2-[[(4S)-5-[(2-methylpropan-2-yl)oxy]-5-oxo-4-[(2-phenylacetyl)amino]pentanoyl]amino]pentanedioate
• CAS: 1445098-26-9
• 化学式: C₃₀H₄₆N₂O₈
• 分子量: 562.704
• InChiKey: XQOPFRALVVLLBI-FCHUYYIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  40
• 可旋转键数：
  18
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  137
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-[N-[(phenylmethoxy)carbonyl]-L-γ-glutamyl]-D-glutamic acid tris(1,1-dimethylethyl) ester 在 5%-palladium/activated carbon 、 氢气 作用下， 以 乙醇 为溶剂， 生成 (R)-2-((S)-4-氨基-5-叔丁氧基-5-氧代戊酰胺基)戊二酸二叔丁酯
  参考文献：
  名称：

  Development and Binding Mode Assessment of N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-d-glutamic Acid (BGC 945), a Novel Thymidylate Synthase Inhibitor That Targets Tumor Cells

  摘要：

  N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopent[g]quinazolin-6-yl]amino]benzoyl]-L-gamma-glutamyl-D-glutamic acid 1 (BGC 945, now known as ONX 0801); is a small molecule thymidylate synthase (TS) inhibitor discovered at the Institute of Cancer Research in London. It is licensed by Onyx Pharmaceuticals and is in phase,1 clinical studies. It is a novel antifolate drug resembling TS inhibitors plevitrexed and raltitrexed that combines enzymatic inhibition of thymidylate synthase with alpha-folate receptor-mediated targeting of tumor cells. Thus, it has potential for efficacy with lower toxicity due to selective intracellular accumulation through alpha-folate receptor (alpha-FR) transport. The alpha-FR, a cell-surface receptor glycoprotein, which is overexpressed mainly in ovarian and lung cancer tumors, has an affinity for 1 similar to that for its natural ligand, folic acid. This study describes a novel synthesis of 1, an X-ray crystal structure of its complex with Escherichia coli TS and 2'-deoxyuridine-5'-monophosphate, and a model for a similar complex with human TS.

  DOI：

  10.1021/jm400490e

文献信息

• Development and Binding Mode Assessment of <i>N</i>-[4-[2-Propyn-1-yl[(6<i>S</i>)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3<i>H</i>-cyclopenta[<i>g</i>]quinazolin-6-yl]amino]benzoyl]-<scp>l</scp>-γ-glutamyl-<scp>d</scp>-glutamic Acid (BGC 945), a Novel Thymidylate Synthase Inhibitor That Targets Tumor Cells
  作者：Anna Tochowicz、Sean Dalziel、Oliv Eidam、Joseph D. O’Connell、Sarah Griner、Janet S. Finer-Moore、Robert M. Stroud

  DOI：10.1021/jm400490e

  日期：2013.7.11

  N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopent[g]quinazolin-6-yl]amino]benzoyl]-L-gamma-glutamyl-D-glutamic acid 1 (BGC 945, now known as ONX 0801); is a small molecule thymidylate synthase (TS) inhibitor discovered at the Institute of Cancer Research in London. It is licensed by Onyx Pharmaceuticals and is in phase,1 clinical studies. It is a novel antifolate drug resembling TS inhibitors plevitrexed and raltitrexed that combines enzymatic inhibition of thymidylate synthase with alpha-folate receptor-mediated targeting of tumor cells. Thus, it has potential for efficacy with lower toxicity due to selective intracellular accumulation through alpha-folate receptor (alpha-FR) transport. The alpha-FR, a cell-surface receptor glycoprotein, which is overexpressed mainly in ovarian and lung cancer tumors, has an affinity for 1 similar to that for its natural ligand, folic acid. This study describes a novel synthesis of 1, an X-ray crystal structure of its complex with Escherichia coli TS and 2'-deoxyuridine-5'-monophosphate, and a model for a similar complex with human TS.