phenanthro[9,10-g]pteridine-11,13-diamine

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: phenanthro[9,10-g]pteridine-11,13-diamine
• 英文别名: phenanthro[9,10-g]pteridine-11,13-diyldiamine；Phenanthro[9,10-g]pteridin-11,13-diyldiamin
• 化学式: C₁₈H₁₂N₆
• 分子量: 312.333
• InChiKey: MKPYEIIASNCWAT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  24
• 可旋转键数：
  0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,4,5,6-四氨基嘧啶硫酸盐 、 菲醌 在 sodium hydroxide 作用下， 以 水 、 乙醇 为溶剂， 反应 3.67h， 以79%的产率得到phenanthro[9,10-g]pteridine-11,13-diamine
  参考文献：
  名称：

  Designing Dihydrofolate Reductase Inhibitors as X-ray Radiosensitizers to Reverse Radioresistance of Cervical Cancer

  摘要：

  X-ray radiotherapy has been widely used in the treatment of cervical cancer, a common gynecologic malignant tumor. However, the therapeutic efficacy tends to be indistinctive. One major reason for this is amplification of the dihydrofolate reductase (DHFR) gene, which causes an increase in DHFR activity and attenuation of the treatment effect. To solve this problem, we synthesized a series of DHFR inhibitors derived from methotrexate (MTX) analogues as radiotherapy sensitizers. Activity screening revealed that compound 2a exerted the best inhibitory effect toward DHFR activity. In combination with X-ray radiotherapy (4 Gy), 2a showed much more prominent antiproliferative activity on cervical cancer cells than 2a or X-rays alone and revealed higher selectivity and radiosensitization than MTX. In vitro experiments showed that 2a + X-rays significantly induced cell apoptosis, as revealed by the increase in the Sub-G1 population and activation of caspase 3, 8, and 9. The in vivo antitumor effect demonstrated that in the presence of X-rays, 2a effectively suppressed tumor growth and did not cause obvious side effects. In conclusion, as a DHFR inhibitor, 2a successfully reversed the radioresistance problem induced by radiotherapy and greatly promoted the therapeutic effect. This is a promising candidate for tumor treatment that deserves further research and development. This study clearly demonstrates that DHFR inhibitors could be developed as promising radiosensitizers in the treatment of cervical cancer and that further research to improve their activity and potential in future clinical use is deserved.

  DOI：

  10.1021/acsmedchemlett.0c00105

文献信息

• Pyrimido [4,5-b] pyrazines. II. 2,4-Diaminopyrimido [4,5-b] pyrazine and Derivatives¹
  作者：M. F. Mallette、E. C. Taylor、C. K. Cain

  DOI：10.1021/ja01199a073

  日期：1947.7
• Designing Dihydrofolate Reductase Inhibitors as X-ray Radiosensitizers to Reverse Radioresistance of Cervical Cancer
  作者：Yuanwei Liang、Delong Zeng、Yuanyuan You、Bin Ma、Xiaoling Li、Tianfeng Chen

  DOI：10.1021/acsmedchemlett.0c00105

  日期：2020.7.9

  X-ray radiotherapy has been widely used in the treatment of cervical cancer, a common gynecologic malignant tumor. However, the therapeutic efficacy tends to be indistinctive. One major reason for this is amplification of the dihydrofolate reductase (DHFR) gene, which causes an increase in DHFR activity and attenuation of the treatment effect. To solve this problem, we synthesized a series of DHFR inhibitors derived from methotrexate (MTX) analogues as radiotherapy sensitizers. Activity screening revealed that compound 2a exerted the best inhibitory effect toward DHFR activity. In combination with X-ray radiotherapy (4 Gy), 2a showed much more prominent antiproliferative activity on cervical cancer cells than 2a or X-rays alone and revealed higher selectivity and radiosensitization than MTX. In vitro experiments showed that 2a + X-rays significantly induced cell apoptosis, as revealed by the increase in the Sub-G1 population and activation of caspase 3, 8, and 9. The in vivo antitumor effect demonstrated that in the presence of X-rays, 2a effectively suppressed tumor growth and did not cause obvious side effects. In conclusion, as a DHFR inhibitor, 2a successfully reversed the radioresistance problem induced by radiotherapy and greatly promoted the therapeutic effect. This is a promising candidate for tumor treatment that deserves further research and development. This study clearly demonstrates that DHFR inhibitors could be developed as promising radiosensitizers in the treatment of cervical cancer and that further research to improve their activity and potential in future clinical use is deserved.