methyl 2-L-[4-[N-[(2,4-diaminopteridin-6-yl)methyl]amino]-1-naphthoyl]amino-5-phthalimidopentanoate | 272779-30-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 蒽
• 英文名称: methyl 2-L-[4-[N-[(2,4-diaminopteridin-6-yl)methyl]amino]-1-naphthoyl]amino-5-phthalimidopentanoate
• 英文别名: methyl (2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methylamino]naphthalene-1-carbonyl]amino]-5-(1,3-dioxoisoindol-2-yl)pentanoate
• CAS: 272779-30-3
• 化学式: C₃₂H₂₉N₉O₅
• 分子量: 619.64
• InChiKey: NHRKOKHMRXSXGO-DEOSSOPVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  46.0
• 可旋转键数：
  10.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  208.41
• 氢给体数：
  4.0
• 氢受体数：
  12.0

反应信息

• 作为反应物：
  描述：

  methyl 2-L-[4-[N-[(2,4-diaminopteridin-6-yl)methyl]amino]-1-naphthoyl]amino-5-phthalimidopentanoate 在 barium dihydroxide 作用下， 以 乙醇 为溶剂， 反应 24.0h， 以71%的产率得到N^α-2-L-[4-[N-[(2,4-diaminopteridin-6-yl)methyl]amino]-1-naphthoyl]-N^δ-hemiphthaloyl-L-ornithine
  参考文献：
  名称：

  Analogues of the Potent Nonpolyglutamatable Antifolate N^α-(4-Amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-l-ornithine (PT523) with Modifications in the Side Chain, p-Aminobenzoyl Moiety, or 9,10-Bridge:  Synthesis and in Vitro Antitumor Activity

  摘要：

  Seven N-alpha-(4-amino-4-deoxypteroyl)-N-sigma-hemiphtha (2, PT523) analogues were synthesized by modifications of the literature synthesis of the corresponding AMT (1) analogues and were tested as inhibitors of tumor cell growth. in growth assays against cultured CCRF-CEM human leukemic cells exposed to drug for 72 h, the IC50 values of analogues in which N-10 was replaced by CH2 and CHMe were found to be 0.55 +/- 0.07 and 0.63 +/- 0.08 nM, and thus these analogues are more potent than 1 (IC50 = 4.4 +/- 1.0 nM) or 2 (IC50 = 1.5 +/-: 0.39 nM). The 10-ethyl-10-deaza analogue of 2 (IC50 = 1.2 +/- 0.25 nM) was not statistically different from 2 but was more potent than edatrexate, the 10-ethyl-10-deaza analogue of 1, which had an IC50 of 3.3 +/- 0.36 nM. In contrast, the analogue of 2 with both an ethyl and a CO2Me group at the 10-position had an IC50 of 54 +/- 4.9 nM, showing this modification to be unfavorable. The 4-amino-1-naphthoic acid analogue of 2 had an IC50 Of 1.2 +/- 0.22 nM, indicating that replacement of the p-aminobenzoic acid (pABA) moiety does not diminish cytotoxicity. The analogues in which the (CH2)(3) Side chain was replaced by slightly longer CH2SCH2 and (CH2)(2)-SCH2 groups gave IC50 values of 4.4 +/- 1.1 and 5.0 +/- 0.56 nM and thus were somewhat less potent than the parent molecule. However the analogues in which the aromatic COOH group was at the meta and para positions of the phthaloyl ring had IC50 values of 7.5 +/- 0.47 and 55 +/- 0.07 nM, confirming the low potency we had previously observed with these compounds against other cell lines. Overall, the results in this study support the conclusion that, while the position of the phthaloyl COOH group and the length of the amino acid side chain in 2 are important determinants of cytotoxic potency, changes in the pABA region and 9,10-bridge are well-tolerated and can even increase potency.

  DOI：

  10.1021/jm990630f
• 作为产物：
  描述：

  4-nitro-1-nathphoyl chloride 在 ammonium formate 、 sodium carbonate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 144.5h， 生成 methyl 2-L-[4-[N-[(2,4-diaminopteridin-6-yl)methyl]amino]-1-naphthoyl]amino-5-phthalimidopentanoate
  参考文献：
  名称：

  Analogues of the Potent Nonpolyglutamatable Antifolate N^α-(4-Amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-l-ornithine (PT523) with Modifications in the Side Chain, p-Aminobenzoyl Moiety, or 9,10-Bridge:  Synthesis and in Vitro Antitumor Activity

  摘要：

  Seven N-alpha-(4-amino-4-deoxypteroyl)-N-sigma-hemiphtha (2, PT523) analogues were synthesized by modifications of the literature synthesis of the corresponding AMT (1) analogues and were tested as inhibitors of tumor cell growth. in growth assays against cultured CCRF-CEM human leukemic cells exposed to drug for 72 h, the IC50 values of analogues in which N-10 was replaced by CH2 and CHMe were found to be 0.55 +/- 0.07 and 0.63 +/- 0.08 nM, and thus these analogues are more potent than 1 (IC50 = 4.4 +/- 1.0 nM) or 2 (IC50 = 1.5 +/-: 0.39 nM). The 10-ethyl-10-deaza analogue of 2 (IC50 = 1.2 +/- 0.25 nM) was not statistically different from 2 but was more potent than edatrexate, the 10-ethyl-10-deaza analogue of 1, which had an IC50 of 3.3 +/- 0.36 nM. In contrast, the analogue of 2 with both an ethyl and a CO2Me group at the 10-position had an IC50 of 54 +/- 4.9 nM, showing this modification to be unfavorable. The 4-amino-1-naphthoic acid analogue of 2 had an IC50 Of 1.2 +/- 0.22 nM, indicating that replacement of the p-aminobenzoic acid (pABA) moiety does not diminish cytotoxicity. The analogues in which the (CH2)(3) Side chain was replaced by slightly longer CH2SCH2 and (CH2)(2)-SCH2 groups gave IC50 values of 4.4 +/- 1.1 and 5.0 +/- 0.56 nM and thus were somewhat less potent than the parent molecule. However the analogues in which the aromatic COOH group was at the meta and para positions of the phthaloyl ring had IC50 values of 7.5 +/- 0.47 and 55 +/- 0.07 nM, confirming the low potency we had previously observed with these compounds against other cell lines. Overall, the results in this study support the conclusion that, while the position of the phthaloyl COOH group and the length of the amino acid side chain in 2 are important determinants of cytotoxic potency, changes in the pABA region and 9,10-bridge are well-tolerated and can even increase potency.

  DOI：

  10.1021/jm990630f