ethyl 2-[(1S)-2-methyl-1-[[2-[(1S)-2-methyl-1-[(3,4,5-trimethoxybenzoyl)amino]propyl]-1,3-thiazole-4-carbonyl]amino]propyl]-1,3-thiazole-4-carboxylate | 1609138-38-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ethyl 2-[(1S)-2-methyl-1-[[2-[(1S)-2-methyl-1-[(3,4,5-trimethoxybenzoyl)amino]propyl]-1,3-thiazole-4-carbonyl]amino]propyl]-1,3-thiazole-4-carboxylate
• CAS: 1609138-38-6
• 化学式: C₂₈H₃₆N₄O₇S₂
• 分子量: 604.748
• InChiKey: GQDUQMLAECNHAG-VXKWHMMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  41
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  194
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  2,3,4-三甲氧基苯甲酰氯 、 (S)-2-(1-{[2-(1-amino-2-methylpropyl)thiazole-4-carbonyl]amino}-(S)-2-methylpropyl)thiazole-4-carboxylic acid ethyl ester 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 以72%的产率得到ethyl 2-[(1S)-2-methyl-1-[[2-[(1S)-2-methyl-1-[(3,4,5-trimethoxybenzoyl)amino]propyl]-1,3-thiazole-4-carbonyl]amino]propyl]-1,3-thiazole-4-carboxylate
  参考文献：
  名称：

  Design and Synthesis of Human ABCB1 (P-Glycoprotein) Inhibitors by Peptide Coupling of Diverse Chemical Scaffolds on Carboxyl and Amino Termini of (S)-Valine-Derived Thiazole Amino Acid

  摘要：

  P-glycoprotein (P-gp) serves as a therapeutic target for the development of multidrug resistance reversal agents. In this study, we synthesized 21 novel compounds by peptide coupling at corresponding carboxyl and amino termini of (S)-valine-based bis-thiazole and monothiazole derivatives with diverse chemical scaffolds. Using calcein-AM efflux assay, we identified compound 28 (IC50 = 1.0 mu M) carrying 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the monothiazole zwitter-ion. Compound 28 inhibited the photolabeling of P-gp with [I-125]-iodoarylazidoprazosin with IC50 = 0.75 mu M and stimulated the basal ATP hydrolysis of P-gp in a concentration-dependent manner (EC50 ATPase = 0.027 mu M). Compound 28 at 3 mu M reduced resistance in cytotoxicity assay to paclitaxel in P-gp-expressing SW620/Ad300 and HEK/ABCB1 cell lines. Biochemical and docking studies showed site-1 to be the preferable binding site for 28 within the drug-binding pocket of human P-gp.

  DOI：

  10.1021/jm401966m

文献信息

• Design and Synthesis of Human ABCB1 (P-Glycoprotein) Inhibitors by Peptide Coupling of Diverse Chemical Scaffolds on Carboxyl and Amino Termini of (<i>S</i>)-Valine-Derived Thiazole Amino Acid
  作者：Satyakam Singh、Nagarajan Rajendra Prasad、Eduardo E. Chufan、Bhargav A. Patel、Yi-Jun Wang、Zhe-Sheng Chen、Suresh V. Ambudkar、Tanaji T. Talele

  DOI：10.1021/jm401966m

  日期：2014.5.22

  P-glycoprotein (P-gp) serves as a therapeutic target for the development of multidrug resistance reversal agents. In this study, we synthesized 21 novel compounds by peptide coupling at corresponding carboxyl and amino termini of (S)-valine-based bis-thiazole and monothiazole derivatives with diverse chemical scaffolds. Using calcein-AM efflux assay, we identified compound 28 (IC50 = 1.0 mu M) carrying 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the monothiazole zwitter-ion. Compound 28 inhibited the photolabeling of P-gp with [I-125]-iodoarylazidoprazosin with IC50 = 0.75 mu M and stimulated the basal ATP hydrolysis of P-gp in a concentration-dependent manner (EC50 ATPase = 0.027 mu M). Compound 28 at 3 mu M reduced resistance in cytotoxicity assay to paclitaxel in P-gp-expressing SW620/Ad300 and HEK/ABCB1 cell lines. Biochemical and docking studies showed site-1 to be the preferable binding site for 28 within the drug-binding pocket of human P-gp.