8-(4-bromophenyl)-5-methyl-8-octadecyloxy-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-one

• 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: 8-(4-bromophenyl)-5-methyl-8-octadecyloxy-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-one
• 英文别名: 8-(4-Bromophenyl)-5-methyl-8-octadecoxy-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one
• 化学式: C₃₀H₄₅BrN₂O₃S
• 分子量: 593.669
• InChiKey: OZIMIFBCZVAKHT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  11.8
• 重原子数：
  37
• 可旋转键数：
  19
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  76.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  硬脂醇 、 8-(4-bromophenyl)-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-one 在 对甲苯磺酸 作用下， 以 甲苯 为溶剂， 反应 3.0h， 以69%的产率得到8-(4-bromophenyl)-5-methyl-8-octadecyloxy-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-one
  参考文献：
  名称：

  A New Class of Selective Myocardial Calcium Channel Modulators. 2. Role of the Acetal Chain in Oxadiazol-3-one Derivatives

  摘要：

  In the framework of the continuing interest of this research group in the use of 8-aryl-8-hydroxy-8H-[1,4]thiazino[3,4-c] [1,2,4]-oxadiazol-3-ones (1) as calcium entry blockers, a number of acetals were synthesized and assayed "in vitro". All of them are structurally related to diltiazem and pyrrolobenzothiazines. The effect on the biological profile was measured by functional assays for a wide variety of acetal residues: saturated linear and branched chains, short and long unsaturated E and/or Z chains as well as benzyl and methylcyclohexyl residues. From selective assays on the most active derivative (5b) (EC50 = 0.04 mu M), which is 20 times more active than diltiazern (EC50 = 0.79 mu M), a muscarinic or adenosinic mechanism of action was excluded. A 3D QSAR model was obtained and validated with homologous literature data, and a virtual receptor scheme was derived for the unknown binding site. The following pharmacophoric features favorably affect the potency: one positively charged center, three lipophilic groups, and two hydrogen-bonding acceptor groups.

  DOI：

  10.1021/jm0493414

文献信息

• A New Class of Selective Myocardial Calcium Channel Modulators. 2. Role of the Acetal Chain in Oxadiazol-3-one Derivatives
  作者：Roberta Budriesi、Emanuele Carosati、Alberto Chiarini、Barbara Cosimelli、Gabriele Cruciani、Pierfranco Ioan、Domenico Spinelli、Raffaella Spisani

  DOI：10.1021/jm0493414

  日期：2005.4.1

  In the framework of the continuing interest of this research group in the use of 8-aryl-8-hydroxy-8H-[1,4]thiazino[3,4-c] [1,2,4]-oxadiazol-3-ones (1) as calcium entry blockers, a number of acetals were synthesized and assayed "in vitro". All of them are structurally related to diltiazem and pyrrolobenzothiazines. The effect on the biological profile was measured by functional assays for a wide variety of acetal residues: saturated linear and branched chains, short and long unsaturated E and/or Z chains as well as benzyl and methylcyclohexyl residues. From selective assays on the most active derivative (5b) (EC50 = 0.04 mu M), which is 20 times more active than diltiazern (EC50 = 0.79 mu M), a muscarinic or adenosinic mechanism of action was excluded. A 3D QSAR model was obtained and validated with homologous literature data, and a virtual receptor scheme was derived for the unknown binding site. The following pharmacophoric features favorably affect the potency: one positively charged center, three lipophilic groups, and two hydrogen-bonding acceptor groups.
• Inhibition of MDR1 Activity in Vitro by a Novel Class of Diltiazem Analogues: Toward New Candidates
  作者：Maurizio Viale、Cinzia Cordazzo、Barbara Cosimelli、Daniela de Totero、Patrizio Castagnola、Cinzia Aiello、Elda Severi、Giovanni Petrillo、Maurizio Cianfriglia、Domenico Spinelli

  DOI：10.1021/jm801195k

  日期：2009.1.22

  The reversal of multidrug resistance by 22 molecules [8-aryl-8-hydroxy-5-R'-8H-[1,4]thiazino[3,4-c]-[1,2,4]oxadiazol-3-ones (1a-i) and 8-aryl-8-alkoxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (2a-m)] related to myocardial-calcium-channel-modulator diltiazem was studied in multidrug resistant A2780/DX3 and their sensitive counterpart A2780 cells. MTT, cytofluorimetry assays, and fluorescence microscopy analyses were used to define activity and accumulation of doxorubicin with or without the diltiazem-like modulators. Of the 22 molecules, 1a, 2f, 2g, and 2m were able to overcome the established criteria for the selection in A2780/DX3 cells (IC50 reduction >= 25%), but only 2f, 2g, and 2m caused a significant increase of intracellular accumulation of doxorubicin. In conclusion, experiments lead to the identification of three diltiazem-like molecules able to increase the intracellular accumulation of doxorubicin by inhibiting the MDR1 function, thus potentiating its anti proliferative activity in multidrug resistant A2780/DX3 cells.