1-(3-methyl-4-(1H-pyrazol-4-yl)phenyl)-3-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)urea | 1459140-49-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(3-methyl-4-(1H-pyrazol-4-yl)phenyl)-3-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)urea
• 英文别名: 1-[3-methyl-4-(1H-pyrazol-4-yl)phenyl]-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea
• CAS: 1459140-49-8
• 化学式: C₁₈H₁₅N₇OS
• 分子量: 377.429
• InChiKey: PWMMEGBMFSUOKK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  137
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-氨基-5-(4-吡啶基)-1,3,4-噻重氮 在 potassium phosphate 、 [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl) palladium(II) dichloride 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 1-(3-methyl-4-(1H-pyrazol-4-yl)phenyl)-3-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)urea
  参考文献：
  名称：

  Synthesis and SAR studies of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine derivatives as potent inhibitors of Bloom helicase

  摘要：

  Human cells utilize a variety of complex DNA repair mechanisms in order to combat constant mutagenic and cytotoxic threats from both exogenous and endogenous sources. The RecQ family of DNA helicases, which includes Bloom helicase (BLM), plays an important function in DNA repair by unwinding complementary strands of duplex DNA as well as atypical DNA structures such as Holliday junctions. Mutations of the BLM gene can result in Bloom syndrome, an autosomal recessive disorder associated with cancer predisposition. BLM-deficient cells exhibit increased sensitivity to DNA damaging agents indicating that a selective BLM inhibitor could be useful in potentiating the anticancer activity of these agents. In this work, we describe the medicinal chemistry optimization of the hit molecule following a quantitative high-throughput screen of >355,000 compounds. These efforts lead to the identification of ML216 and related analogs, which possess potent BLM inhibition and exhibit selectivity over related helicases. Moreover, these compounds demonstrated cellular activity by inducing sister chromatid exchanges, a hallmark of Bloom syndrome. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2013.08.025

文献信息

• Synthesis and SAR studies of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine derivatives as potent inhibitors of Bloom helicase
  作者：Andrew S. Rosenthal、Thomas S. Dexheimer、Opher Gileadi、Giang H. Nguyen、Wai Kit Chu、Ian D. Hickson、Ajit Jadhav、Anton Simeonov、David J. Maloney

  DOI：10.1016/j.bmcl.2013.08.025

  日期：2013.10

  Human cells utilize a variety of complex DNA repair mechanisms in order to combat constant mutagenic and cytotoxic threats from both exogenous and endogenous sources. The RecQ family of DNA helicases, which includes Bloom helicase (BLM), plays an important function in DNA repair by unwinding complementary strands of duplex DNA as well as atypical DNA structures such as Holliday junctions. Mutations of the BLM gene can result in Bloom syndrome, an autosomal recessive disorder associated with cancer predisposition. BLM-deficient cells exhibit increased sensitivity to DNA damaging agents indicating that a selective BLM inhibitor could be useful in potentiating the anticancer activity of these agents. In this work, we describe the medicinal chemistry optimization of the hit molecule following a quantitative high-throughput screen of >355,000 compounds. These efforts lead to the identification of ML216 and related analogs, which possess potent BLM inhibition and exhibit selectivity over related helicases. Moreover, these compounds demonstrated cellular activity by inducing sister chromatid exchanges, a hallmark of Bloom syndrome. Published by Elsevier Ltd.