[(4aR,9aS,10aS,10bR)-10b-methoxy-6-methyl-7-oxo-1,4,4a,5,7,9,9a,10,10a,10b,11,12a-dodecahydroazireno[2',3':6,7]pyrrolizino[2,3-f][1,2]dithiino[4,5-b]quinoxalin-11-yl]methyl carbamate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: [(4aR,9aS,10aS,10bR)-10b-methoxy-6-methyl-7-oxo-1,4,4a,5,7,9,9a,10,10a,10b,11,12a-dodecahydroazireno[2',3':6,7]pyrrolizino[2,3-f][1,2]dithiino[4,5-b]quinoxalin-11-yl]methyl carbamate
• 英文别名: [(3S,4R,5S,7S,15R,20R)-4-methoxy-12-methyl-11-oxo-17,18-dithia-6,9,14,21-tetrazahexacyclo[11.8.0.02,10.04,9.05,7.015,20]henicosa-1(21),2(10),12-trien-3-yl]methyl carbamate
• 化学式: C₁₉H₂₃N₅O₄S₂
• 分子量: 449.555
• InChiKey: RXFTUADIBYUHFL-VDAREFTKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.0
• 重原子数：
  30.0
• 可旋转键数：
  3.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  128.19
• 氢给体数：
  3.0
• 氢受体数：
  10.0

反应信息

• 作为产物：
  描述：

  丝裂霉素 A 、 (4R,5R)-trans-4,5-diamino-1,2-dithiane bistrifluoroacetate 在 三乙胺 作用下， 以 甲醇 为溶剂， 反应 48.0h， 以71%的产率得到[(4aR,9aS,10aS,10bR)-10b-methoxy-6-methyl-7-oxo-1,4,4a,5,7,9,9a,10,10a,10b,11,12a-dodecahydroazireno[2',3':6,7]pyrrolizino[2,3-f][1,2]dithiino[4,5-b]quinoxalin-11-yl]methyl carbamate
  参考文献：
  名称：

  Cyclic Disulfide C(8) Iminoporfiromycin:  Nucleophilic Activation of a Porfiromycin

  摘要：

  The clinical success of mitomycin C (1) and its associated toxicities and resistance have led to efforts to prepare semisynthetic analogues (i.e., KW-2149 (3), BMS-181174 (4)) that have improved pharmacological profiles. In this study, we report the preparation and evaluation of the novel 7-N-(1'-amino-4',5'-dithian-2'-yl)porfiromycin C(8) cyclized imine (6) and its reference compound, 7-N-(1'-aminocyclohex-2'-yl)porfiromycin C(8) cyclized imine (13). Porfiromycin 6 contains a disulfide unit that, upon cleavage, may provide thiol(s) that affect drug reactivity. We demonstrated that phosphines dramatically accelerated 6 activation and solvolysis in methanolic solutions ("pH 7.4") compared with 13. Porfiromycins 6 and 13 efficiently cross-linked EcoRI-linearized pBR322 DNA upon addition of Et3P. We found enhanced levels of interstrand cross-link (ISC) adducts for 6 and 13 compared with porfiromycin (7) and that 6 was more efficient than 13. The large Et3P-mediated rate enhancements for the solvolysis of 6 compared with 13 and a N(7)-substituted analogue of 1, and the increased levels of ISC adducts for 6 compared with 13 and 7 are attributed to a nucleophile-assisted disulfide cleavage process that permits porfiromycin activation and nucleophile (MeOH, DNA) adduction. The in vitro antiproliferative activities of 6 and 13 using the A549 tumor cell line (lung adenocarcinoma) were determined under aerobic and hypoxic conditions and then compared with 7. Both 6 and 13 were more cytotoxic than 7, with 13 being more potent than 6. The C(8) iminoporfiromycins 6 and 13 displayed anticancer profiles similar to 3.

  DOI：

  10.1021/ja030577r

文献信息

• Cyclic Disulfide C(8) Iminoporfiromycin:  Nucleophilic Activation of a Porfiromycin
  作者：Sang Hyup Lee、Harold Kohn

  DOI：10.1021/ja030577r

  日期：2004.4.1

  The clinical success of mitomycin C (1) and its associated toxicities and resistance have led to efforts to prepare semisynthetic analogues (i.e., KW-2149 (3), BMS-181174 (4)) that have improved pharmacological profiles. In this study, we report the preparation and evaluation of the novel 7-N-(1'-amino-4',5'-dithian-2'-yl)porfiromycin C(8) cyclized imine (6) and its reference compound, 7-N-(1'-aminocyclohex-2'-yl)porfiromycin C(8) cyclized imine (13). Porfiromycin 6 contains a disulfide unit that, upon cleavage, may provide thiol(s) that affect drug reactivity. We demonstrated that phosphines dramatically accelerated 6 activation and solvolysis in methanolic solutions ("pH 7.4") compared with 13. Porfiromycins 6 and 13 efficiently cross-linked EcoRI-linearized pBR322 DNA upon addition of Et3P. We found enhanced levels of interstrand cross-link (ISC) adducts for 6 and 13 compared with porfiromycin (7) and that 6 was more efficient than 13. The large Et3P-mediated rate enhancements for the solvolysis of 6 compared with 13 and a N(7)-substituted analogue of 1, and the increased levels of ISC adducts for 6 compared with 13 and 7 are attributed to a nucleophile-assisted disulfide cleavage process that permits porfiromycin activation and nucleophile (MeOH, DNA) adduction. The in vitro antiproliferative activities of 6 and 13 using the A549 tumor cell line (lung adenocarcinoma) were determined under aerobic and hypoxic conditions and then compared with 7. Both 6 and 13 were more cytotoxic than 7, with 13 being more potent than 6. The C(8) iminoporfiromycins 6 and 13 displayed anticancer profiles similar to 3.