methotrexate γ-hexadecyl ester | 88887-42-7

• 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: methotrexate γ-hexadecyl ester
• 英文别名: MTX-γ-hexadecyl ester；C16-MTX-ester；(2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]-5-hexadecoxy-5-oxopentanoic acid
• CAS: 88887-42-7
• 化学式: C₃₆H₅₄N₈O₅
• 分子量: 678.875
• InChiKey: XDUJULXISLBYOW-LJAQVGFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  49
• 可旋转键数：
  25
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  200
• 氢给体数：
  4
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  methotrexate γ-hexadecyl ester 、 2,6-二氯苄基溴 在 sodium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 以18%的产率得到(S)-2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-pentanedioic acid 1-(2,6-dichloro-benzyl) ester 5-hexadecyl ester
  参考文献：
  名称：

  Methotrexate analogs. 21. Divergent influence of alkyl chain length on the dihydrofolate reductase affinity and cytotoxicity of methotrexate monoesters

  摘要：

  n-Octyl, n-dodecyl, and n-hexadecyl alpha- and gamma-esters of methotrexate (MTX) were compared with the previously described alpha- and gamma-n-butyl esters and with MTX as inhibitors of dihydrofolate reductase (DHFR) and human leukemic lymphoblasts (CEM cells) in culture. The overall order of activity in both test systems was MTX greater than MTX gamma-esters greater than MTX alpha-esters. In the DHFR assay the activity of the alpha-esters followed the order C4 greater than C8 congruent to C12 greater than C16, whereas for the gamma-esters this order was C4 congruent to C8 greater than C12 greater than C16. On the other hand, the order of cytotoxic activity in culture in both series was C16 greater than C12 greater than C8 greater than C4. Increasing the alkyl chain length in the ester moiety therefore decreases DHFR affinity but increases cytotoxicity. The most potent member of the compounds tested was the gamma-n-hexadecyl ester, whose IC50 against CEM cells was 0.11 microM as compared with 0.025 microM for MTX. In a comparison of the effect of treatment with the gamma-n-hexadecyl ester (10(-5) M, 1 h) on DNA synthesis in CEM and CEM/MTX cells, the latter of which are 120-fold resistant to MTX by virtue of a transport defect, the ester produced only 4-fold less inhibition in the resistant line than in the parental line. These results suggest possible use of this compound or related derivatives in the treatment of MTX-resistant tumors with impaired transport.

  DOI：

  10.1021/jm00371a009
• 作为产物：
  描述：

  N-叔丁氧羰基-L-谷氨酸 1-苄酯 在 palladium on activated charcoal 吡啶 、 potassium fluoride 、 氰基磷酸二乙酯 、 四丁基氯化铵 、 氢气 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 、 异丙醇 、 乙腈 、 苯 为溶剂， 80.0 ℃ 、303.98 kPa 条件下， 反应 114.03h， 生成 methotrexate γ-hexadecyl ester
  参考文献：
  名称：

  Methotrexate analogs. 21. Divergent influence of alkyl chain length on the dihydrofolate reductase affinity and cytotoxicity of methotrexate monoesters

  摘要：

  n-Octyl, n-dodecyl, and n-hexadecyl alpha- and gamma-esters of methotrexate (MTX) were compared with the previously described alpha- and gamma-n-butyl esters and with MTX as inhibitors of dihydrofolate reductase (DHFR) and human leukemic lymphoblasts (CEM cells) in culture. The overall order of activity in both test systems was MTX greater than MTX gamma-esters greater than MTX alpha-esters. In the DHFR assay the activity of the alpha-esters followed the order C4 greater than C8 congruent to C12 greater than C16, whereas for the gamma-esters this order was C4 congruent to C8 greater than C12 greater than C16. On the other hand, the order of cytotoxic activity in culture in both series was C16 greater than C12 greater than C8 greater than C4. Increasing the alkyl chain length in the ester moiety therefore decreases DHFR affinity but increases cytotoxicity. The most potent member of the compounds tested was the gamma-n-hexadecyl ester, whose IC50 against CEM cells was 0.11 microM as compared with 0.025 microM for MTX. In a comparison of the effect of treatment with the gamma-n-hexadecyl ester (10(-5) M, 1 h) on DNA synthesis in CEM and CEM/MTX cells, the latter of which are 120-fold resistant to MTX by virtue of a transport defect, the ester produced only 4-fold less inhibition in the resistant line than in the parental line. These results suggest possible use of this compound or related derivatives in the treatment of MTX-resistant tumors with impaired transport.

  DOI：

  10.1021/jm00371a009

文献信息

• Liposomes containing alkylated methotrexate analogues for phospholipase A2 mediated tumor targeted drug delivery
  作者：Thomas Kaasgaard、Thomas L. Andresen、Simon S. Jensen、René O. Holte、Lotte T. Jensen、Kent Jørgensen

  DOI：10.1016/j.chemphyslip.2008.11.005

  日期：2009.2

  Two lipophilic methotrexate analogues have been synthesized and evaluated for cytotoxicity against KATO III and HT-29 human colon cancer cells. Both analogues contained a C-16-alkyl chain attached to the gamma-carboxylic acid and one of the analogues had an additional benzyl group attached to the alpha-carboxylic acid. The cytotoxicity of the gamma-alkylated compound towards KATO III (IC50 = 55 nM) and HT-29 (IC50 = 400 nM) cell lines, Was unaffected by the alkylation, whereas the additional benzyl group on the alpha-carboxyl group made the Compound nontoxic. The gamma-derivative with promising cytotoxicity was incorporated into liposomes that were designed to be particularly Susceptible to a liposome degrading enzyme, secretory phospholipase A(2) (sPLA(2)), which is found in high concentrations in tumors of several different cancer types. Liposome incorporation was investigated by differential scanning calorimetry (DSC), and sPLA(2) hydrolysis was examined by fluorescence spectroscopy and high performance liquid chromatography (HPLC). The results showed that the methotrexate (MTX)-analogue could be incorporated into liposomes that were degradable by sPLA(2). However, the in vitro cytotoxicity of the MTX-liposomes against KATO III and HT-29 cancer cells was found to be independent of sPLA(2) hydrolysis, indicating that the alkylated MTX-analogue was available for cancer cell uptake even in the absence of liposome hydrolysis. Using a DSC based method for assessing the anchoring stability of alkylated compounds in liposomes, it was demonstrated that the MTX-analogue partitioned into the water phase and thereby became available for cell uptake. It was concluded that liposomes containing alkylated MTX-analogues show promise as a drug delivery system, although the MTX-analogue needs to be more tightly anchored to the liposomal carrier. Also, the developed DSC-assay for Studying the anchoring stability of alkylated drugs will be a useful tool in the development of liposomal drug delivery Systems. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
• Methotrexate analogs. 21. Divergent influence of alkyl chain length on the dihydrofolate reductase affinity and cytotoxicity of methotrexate monoesters
  作者：Andre Rosowsky、Ronald A. Forsch、Cheng Sein Yu、Herbert Lazarus、G. Peter Beardsley

  DOI：10.1021/jm00371a009

  日期：1984.5

  n-Octyl, n-dodecyl, and n-hexadecyl alpha- and gamma-esters of methotrexate (MTX) were compared with the previously described alpha- and gamma-n-butyl esters and with MTX as inhibitors of dihydrofolate reductase (DHFR) and human leukemic lymphoblasts (CEM cells) in culture. The overall order of activity in both test systems was MTX greater than MTX gamma-esters greater than MTX alpha-esters. In the DHFR assay the activity of the alpha-esters followed the order C4 greater than C8 congruent to C12 greater than C16, whereas for the gamma-esters this order was C4 congruent to C8 greater than C12 greater than C16. On the other hand, the order of cytotoxic activity in culture in both series was C16 greater than C12 greater than C8 greater than C4. Increasing the alkyl chain length in the ester moiety therefore decreases DHFR affinity but increases cytotoxicity. The most potent member of the compounds tested was the gamma-n-hexadecyl ester, whose IC50 against CEM cells was 0.11 microM as compared with 0.025 microM for MTX. In a comparison of the effect of treatment with the gamma-n-hexadecyl ester (10(-5) M, 1 h) on DNA synthesis in CEM and CEM/MTX cells, the latter of which are 120-fold resistant to MTX by virtue of a transport defect, the ester produced only 4-fold less inhibition in the resistant line than in the parental line. These results suggest possible use of this compound or related derivatives in the treatment of MTX-resistant tumors with impaired transport.