5-(2-hydroxy-1-butyl)thio-3-isopropyl-7-[4-(2-pyridyl)-benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-(2-hydroxy-1-butyl)thio-3-isopropyl-7-[4-(2-pyridyl)-benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine
• 英文别名: 1-[[3-propan-2-yl-7-[(4-pyridin-2-ylphenyl)methylamino]-2H-pyrazolo[4,3-d]pyrimidin-5-yl]sulfanyl]butan-2-ol
• 化学式: C₂₄H₂₈N₆OS
• 分子量: 448.592
• InChiKey: NVIBOJMTRFBOFE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  125
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-isopropyl-5-sulfanyl-1(2)H-pyrazolo[4,3-d]pyrimidin-7-ol 在 吡啶 、 phosphorus pentasulfide 、 四甲基氢氧化铵 作用下， 以 甲醇 、 乙二醇乙醚 为溶剂， 反应 21.0h， 生成 5-(2-hydroxy-1-butyl)thio-3-isopropyl-7-[4-(2-pyridyl)-benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine
  参考文献：
  名称：

  [EN] 5-ALKYLTHIO-7-[(4-ARYLBENZYL)AMINO]-1(2)H-PYRAZOLO[4,3-D]PYRIMIDINES FOR TREATMENT OF LYMPHOMA
  [FR] 5-ALKYLTHIO-7-[(4-ARYLBENZYL) AMINO] -1 (2) H-PYRAZOLO [4,3-D] PYRIMIDINES POUR LE TRAITEMENT DU LYMPHOME

  摘要：

  本发明涉及式I的5-烷基硫基-7-[(4-芳基苄基)氨基]-1(2)H-吡唑并[4,3-d]嘧啶衍生物，它们是激酶的有效抑制剂，并在淋巴瘤细胞上表现出强烈的抗增殖和促凋亡特性。本发明还涉及利用这些衍生物治疗血液过度增殖性疾病，如非霍奇金淋巴瘤。

  公开号：

  WO2019149295A1

文献信息

• [EN] 5-ALKYLTHIO-7-[(4-ARYLBENZYL)AMINO]-1(2)H-PYRAZOLO[4,3-D]PYRIMIDINES FOR TREATMENT OF LYMPHOMA<br/>[FR] 5-ALKYLTHIO-7-[(4-ARYLBENZYL) AMINO] -1 (2) H-PYRAZOLO [4,3-D] PYRIMIDINES POUR LE TRAITEMENT DU LYMPHOME
  申请人：UNIV PALACKEHO

  公开号：WO2019149295A1

  公开（公告）日：2019-08-08

  The present invention relates to 5-alkylthio-7-[(4-arylbenzyl)amino]-1(2)H-pyrazolo[4,3-d]pyrimidine derivatives of formula I which are effective inhibitors of kinases and exhibit strong antiproliferative and proapoptotic properties on lymphoma cells. This invention further relates to use of said derivatives in the treatment of blood hyperproliferative diseases, such as Non-Hodgkin lymphomas.

  本发明涉及式I的5-烷基硫基-7-[(4-芳基苄基)氨基]-1(2)H-吡唑并[4,3-d]嘧啶衍生物，它们是激酶的有效抑制剂，并在淋巴瘤细胞上表现出强烈的抗增殖和促凋亡特性。本发明还涉及利用这些衍生物治疗血液过度增殖性疾病，如非霍奇金淋巴瘤。
• 3,5,7-Substituted Pyrazolo[4,3-<i>d</i>]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models
  作者：Radek Jorda、Libor Havlíček、Antonín Šturc、Diana Tušková、Lenka Daumová、Mahmudul Alam、Jana Škerlová、Michaela Nekardová、Miroslav Peřina、Tomáš Pospíšil、Jitka Široká、Lubor Urbánek、Petr Pachl、Pavlína Řezáčová、Miroslav Strnad、Pavel Klener、Vladimír Kryštof

  DOI：10.1021/acs.jmedchem.9b00189

  日期：2019.5.9

  Cyclin-dependent kinases are therapeutic targets frequently deregulated in various cancers. By convenient alkylation of the 5-sulfanyl group, we synthesized 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines with various substitutions at position 5 with potent antiproliferative activity in non-Hodgkin lymphoma cell lines. The most potent derivative 4.35 also displayed activities across more than 60 cancer cell lines. The kinase profiling confirmed high selectivity of 4.35 toward cyclin-dependent kinases (CDKs) 2, 5, and 9, and the cocrystal with CDK2/cyclin A2 revealed its binding in the active site. Cultured lymphoma cell lines treated with 4.35 showed dephosphorylation of CDK substrates, cleavage of PARP-1, downregulation of XIAP and MCL-1, and activation of caspases, which collectively confirmed ongoing apoptosis. Moreover, 4.35 demonstrated significant activity in various cell line xenograft and patient-derived xenograft mouse models in vivo both as a monotherapy and as a combination therapy with the BCL2-targeting venetoclax. These findings support further studies of combinatorial treatment based on CDK inhibitors.