N-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoyl-L-glutamic acid | 112887-62-4

• 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-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoyl-L-glutamic acid
• 英文别名: N-<4--N-prop-2-ynylamino>benzoyl>-L-glutamic acid；2-desamino-2-methyl-N(10)-propargyl-5,8-dideazafolic acid；N-<4-prop-2-ynylamino>benzoyl>-L-glutamic acid；(2S)-2-[[4-[(2-methyl-4-oxo-1H-quinazolin-6-yl)methyl-prop-2-ynylamino]benzoyl]amino]pentanedioic acid；(2S)-2-[[4-[(2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]benzoyl]amino]pentanedioic acid
• CAS: 112887-62-4
• 化学式: C₂₅H₂₄N₄O₆
• 分子量: 476.489
• InChiKey: PMTUUSDTAKQWQJ-NRFANRHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  148
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoyl-L-glutamic acid 在 diethyl cyanophosphoridate 、 Tris buffer (tris(hydroxymethyl)aminomethane, ZnCl₂, aq. HCl, pH 7.3) 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.5h， 生成 (S)-2-((S)-4-tert-Butoxycarbonyl-4-{4-[(2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-prop-2-ynyl-amino]-benzoylamino}-butyrylamino)-pentanedioic acid di-tert-butyl ester
  参考文献：
  名称：

  Syntheses and thymidylate synthase inhibitory activity of the poly-.gamma.-glutamyl conjugates of N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl]-L-glutamic acid (ICI D1694) and other quinazoline antifolates

  摘要：

  Thirteen poly-gamma-glutamates derived from several novel antifolates have been synthesized by a convergent route. The syntheses of poly-gamma-glutamyl conjugates of N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl]-L-glutamic acid (8) (ICI D1694), 2-desamino-N10-propargyl-5,8-dideazafolic acid (6), 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (7), 2-desamino-2-methyl-N10-propargyl-2'-fluoro-5,8-dideazafolic acid (9), and 2-desamino-2-methyl-4-chloro-N10-propargyl-2'-fluoro-3,5,8-trideazafolic acid (11) are described. A key step in the route involves coupling of an alpha-tert-butyl-protected poly-gamma-glutamate of the required chain length to the appropriate 5,8-dideazapteroic acid, obtained by carboxypeptidase G2 cleavage of the parent monoglutamate, if available, or by chemical synthesis. Deprotection with trifluoroacetic acid in the final step gave the desired poly-gamma-glutamyl antifolates as their trifluoroacetate salts. As inhibitors of thymidylate synthase, these polyglutamates were more potent in every case than the corresponding non-polyglutamylated drug.

  DOI：

  10.1021/jm00083a008
• 作为产物：
  描述：

  (S)-2-{4-[(4-Acetylamino-3-carboxy-benzyl)-prop-2-ynyl-amino]-benzoylamino}-pentanedioic acid diethyl ester 生成 N-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoyl-L-glutamic acid
  参考文献：
  名称：

  叶酸类似物。32.2-去氨基-2-甲基-N10-炔丙基-5，8-二氮杂萘甲酸和相关化合物的合成和生物学评价。

  摘要：

  描述了N10-炔丙基-5,8-二氮杂叶酸酯（PDDF）的三个紧密类似物（2-4）的化学合成。在非常温和的条件下，在合成的最后步骤中，由枢轴中间体9以新颖且明确的方式构造了2和4的喹唑啉环。2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolate（DMPDDF）（2）是人和干酪乳杆菌胸苷酸合酶的强抑制剂，而2-desamino-2-（三氟甲基）-N10-propargyl- 5,8-二脱氮叶酸酯（3）和2-脱氨基-2,3-二甲基-N10-炔丙基-5,8-二脱氮叶酸酯（4）只是该酶的弱抑制剂。DMPDDF对培养的Manca人淋巴白血病和H35肝癌细胞具有极好的生长抑制作用。在这些细胞系中，2的抑制剂活性分别比PDDF高43倍和65倍。由于运输缺陷而对甲氨蝶呤具有抗性的H35R细胞对DMPDDF具有交叉抗性，而对PDDF无交叉抗性。与H35N细胞相比

  DOI：

  10.1021/jm00126a023

文献信息

• Quinazoline antifolate thymidylate synthase inhibitors: alkyl, substituted alkyl, and aryl substituents in the C-2 position
  作者：Leslie R. Hughes、Ann L. Jackman、John Oldfield、Rodney C. Smith、Kenneth D. Burrows、Peter R. Marsham、Joel A. M. Bishop、Terence R. Jones、Brigid M. O'Connor、A. Hilary Calvert

  DOI：10.1021/jm00173a024

  日期：1990.11

  thymidylate synthase (TS) inhibitor N-[4-[N-[(2-amino-3,4-dihydro-4-oxo-6-quinazolinyl)methyl]-N-prop-2- ynylamino]benzoyl]-L-glutamic acid (1a) has led to the synthesis of quinazoline antifolates bearing alkyl, substituted alkyl, and aryl substituents at C2. In general the synthetic route involved the coupling of the appropriate diethyl N-[4-(alkylamino)benzoyl]-L-glutamate with a C2-substituted 6-(bromo-methyl)-3

  强大的胸苷酸​​合酶（TS）抑制剂N- [4- [N-[（2-氨基-3,4-二氢-4-氧代-6-喹唑啉基）甲基] -N-丙-2-炔基氨基]苯甲酰基的修饰] -L-谷氨酸（1a）导致合成在C2带有烷基，取代的烷基和芳基取代基的喹唑啉抗叶酸酯。通常，合成路线包括将合适的N- [4-（烷基氨基）苯甲酰基] -L-谷氨酸二乙酯与C2-取代的6-（溴甲基）-3,4-二氢-4-氧喹唑啉偶联，然后进行偶联。用弱碱脱保护。发现在C2位置含有小的非极性基团的化合物具有良好的酶抑制作用和细胞毒性，其中2-desamino-2-methyl类似物3a最有效。该酶可耐受较大的C2取代基，但降低了细胞毒性。在合成一系列类似的N10取代基的类似物之后，进行了一系列有力的后续工作。以这种方式，已经制备了许多有趣的TS抑制剂。尽管这些化合物对分离的酶均没有比1a更有效的作用，但所制备的化合物中有一半以上对培养的L1210
• Folate analogs. 35. Synthesis and biological evaluation of 1-deaza, 3-deaza, and bridge-elongated analogs of N10-propargyl-5,8-dideazafolic acid
  作者：Shu Wen Li、M. G. Nair、Donna M. Edwards、R. L. Kisliuk、Y. Gaumont、I. K. Dev、D. S. Duch、J. Humphreys、G. K. Smith、Robert Ferone

  DOI：10.1021/jm00113a011

  日期：1991.9

  Structural modifications at the pyrimidine ring and at the C-9,N-10-bridge region of the thymidylate synthase (TS) inhibitors N-10-propargyl-5,8-dideazafolate (1; PDDF; CB 3717), 2-desamino-N10-propargyl-5,8-dideazafolate (2, DPDDF), and 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolate (3, DMPDDF) have been carried out. Methods for the synthesis of 2-desamino-N-10-propargyl-1,5,8-trideazafolate (4), 2-desamino-2-methyl-N-10-propargyl-3,5,8-trideazafolate (5a), and 2-desamino-2-methyl-N10-propargyl-5,8-dideaza-1,2-dihydrofolate (6) have been developed. The bridge-extended analogues isohomo-PDDF (7) and isohomo-DMPDDF (8) contain an additional methylene group interposed between N-10 and the phenyl ring of 1 and 3, respectively. All new compounds were evaluated as inhibitors of TS and the growth of tumor cells in culture. Selected analogues were tested as substrates of folylpolyglutamate synthetase (FPGS) and striking differences in substrate activity were observed among these compounds, indicating that structural modifications at the pyrimidine ring of classical antifolates profoundly influence their polyglutamylation. Enzyme inhibition data established that both N1 and N3-H of the pyrimidine ring are essential for efficient binding of quinazoline-type antifolates to human TS.
• MARSHAM, PETER R.;JACKMAN, ANN L.;OKIDFIELD, JOHN;HUGHES, LESLIE R.;THORN+, J. MED. CHEM. , 33,(1990) N1, C. 3072-3078
  作者：MARSHAM, PETER R.、JACKMAN, ANN L.、OKIDFIELD, JOHN、HUGHES, LESLIE R.、THORN+

  DOI：——

  日期：——
• USE OF CYCLOPENTA[G]QUINAZOLINE DERIVATIVES FOR TREATING CANCER
  申请人：BTG International Limited

  公开号：EP1420809B1

  公开（公告）日：2011-09-28
• JPH01125373A
  申请人：——

  公开号：JPH01125373A

  公开（公告）日：1989-05-17