5,6-dihydro-6(S)-(hydroxymethyl)-1,2,3-trimethoxy-9-(methylthio)-8H-cycloheptanaphthalen-8-one | 146311-27-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 5,6-dihydro-6(S)-(hydroxymethyl)-1,2,3-trimethoxy-9-(methylthio)-8H-cycloheptanaphthalen-8-one
• 英文别名: (6S)-5,6-dihydro-6-(hydroxymethyl)-1,2,3-trimethoxy-9-(methylsulfanyl)-8H-cyclohepta[a]naphthalen-8-one；5,6-dihydro-6(S)-(hydroxymethyl)-1,2,3-trimethoxy-9-methylthio-8H-cyclo-hepta[a]naphthalen-8-one；5,6-dihydro-6(S)-(hydroxymethyl)-1,2,3-trimethoxy-9-(methylthio)-8H-cyclohepta[a]naphthalen-8-one；(6S)-6-(hydroxymethyl)-1,2,3-trimethoxy-9-methylsulfanyl-5,6-dihydrocyclohepta[a]naphthalen-8-one
• CAS: 146311-27-5
• 化学式: C₂₀H₂₂O₅S
• 分子量: 374.458
• InChiKey: GWQSWLMEYHNEJW-GFCCVEGCSA-N

物化性质

• 熔点：
  200 °C
• 沸点：
  640.0±55.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  90.3
• 氢给体数：
  1
• 氢受体数：
  6

SDS

反应信息

• 作为反应物：
  描述：

  5,6-dihydro-6(S)-(hydroxymethyl)-1,2,3-trimethoxy-9-(methylthio)-8H-cycloheptanaphthalen-8-one 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 对甲苯磺酰氯 作用下， 以 苯 为溶剂， 反应 11.0h， 以77%的产率得到5,6-dihydro-6(S)-(methylene)-1,2,3-trimethoxy-9-(methylthio)-8H-cycloheptanaphthalen-8-one
  参考文献：
  名称：

  Antitumor agents. 139. Synthesis and biological evaluation of thiocolchicine analogs 5,6-dihydro-6(S)-acyloxy)- and 5,6-dihydro-6(S)-[(aroyloxy)methyl]-1,2,3-trimethoxy-9-(methylthio)-8H-cyclohepta[a]naphthalen-8-ones as novel cytotoxic and antimitotic agents

  摘要：

  A series of novel thiocolchicine analogs, 5,6-dihydro-6(S)-(acyloxy)- and 5,6-dihydro-6(S)-[(aroyloxy)-methyl]-1,2,3-trimethoxy-9-(methylthio)-8H-cyclohepta[a]naphthalen-8-ones, possessing a six-membered ring B, have been synthesized and evaluated for their cytotoxicity against various tumor cell lines, including solid tumor cell lines, and for their interaction with tubulin. The configuration of the parent alcohol (compound 5) was established unequivocally as (aR,6S) by X-ray crystallographic analysis. The side chain at the C(6) position is in a pseudoaxial orientation. The optical properties and H-1 NMR data indicated that these compounds have the same conformations in solution as in the solid state. Biological results showed that compounds (5, 6, 14,15,17, and 18) bearing a small side chain at C(6) demonstrate high potency in inhibiting tubulin polymerization and binding of radiolabeled colchicine to tubulin. The most cytotoxic compounds were 14, 15, 17, and 18, with good activity against several solid tumor cell lines. To explain the strong antitubulin activity of compound 5 (with an aR configured biaryl system in contrast to the aS configuration previously described for colchicinoids, allocolchicinoids, and steganacin) we speculate that a rapid atropisomerism equilibrium must exist for 5 and its active derivatives. This equilibrium would yield adequate amounts of aS-configured conformers that interact strongly with tubulin. Since the optically inactive 18 is also a potent inhibitor of tubulin, the configuration of the side chain of these six-membered ring B analogs cannot be essential for their binding to tubulin. Instead we propose that the size of ring B and of its side chain play important roles in tubulin binding activity by affecting the rotation of the rings A and C along their linking C-C bond axis.

  DOI：

  10.1021/jm00057a004
• 作为产物：
  描述：

  (7S)-7-氨基-1,2,3-三甲氧基-10-甲硫基-6,7-二氢-5H-苯并[g]庚搭烯-9-酮 在 溶剂黄146 、 sodium nitrite 作用下， 反应 24.0h， 以42%的产率得到5,6-dihydro-6(S)-(hydroxymethyl)-1,2,3-trimethoxy-9-(methylthio)-8H-cycloheptanaphthalen-8-one
  参考文献：
  名称：

  Antitumor agents. 139. Synthesis and biological evaluation of thiocolchicine analogs 5,6-dihydro-6(S)-acyloxy)- and 5,6-dihydro-6(S)-[(aroyloxy)methyl]-1,2,3-trimethoxy-9-(methylthio)-8H-cyclohepta[a]naphthalen-8-ones as novel cytotoxic and antimitotic agents

  摘要：

  A series of novel thiocolchicine analogs, 5,6-dihydro-6(S)-(acyloxy)- and 5,6-dihydro-6(S)-[(aroyloxy)-methyl]-1,2,3-trimethoxy-9-(methylthio)-8H-cyclohepta[a]naphthalen-8-ones, possessing a six-membered ring B, have been synthesized and evaluated for their cytotoxicity against various tumor cell lines, including solid tumor cell lines, and for their interaction with tubulin. The configuration of the parent alcohol (compound 5) was established unequivocally as (aR,6S) by X-ray crystallographic analysis. The side chain at the C(6) position is in a pseudoaxial orientation. The optical properties and H-1 NMR data indicated that these compounds have the same conformations in solution as in the solid state. Biological results showed that compounds (5, 6, 14,15,17, and 18) bearing a small side chain at C(6) demonstrate high potency in inhibiting tubulin polymerization and binding of radiolabeled colchicine to tubulin. The most cytotoxic compounds were 14, 15, 17, and 18, with good activity against several solid tumor cell lines. To explain the strong antitubulin activity of compound 5 (with an aR configured biaryl system in contrast to the aS configuration previously described for colchicinoids, allocolchicinoids, and steganacin) we speculate that a rapid atropisomerism equilibrium must exist for 5 and its active derivatives. This equilibrium would yield adequate amounts of aS-configured conformers that interact strongly with tubulin. Since the optically inactive 18 is also a potent inhibitor of tubulin, the configuration of the side chain of these six-membered ring B analogs cannot be essential for their binding to tubulin. Instead we propose that the size of ring B and of its side chain play important roles in tubulin binding activity by affecting the rotation of the rings A and C along their linking C-C bond axis.

  DOI：

  10.1021/jm00057a004

文献信息

• New Tetracyclic Colchicinoids from the Reaction of N-Deacetylthiocolchicine and N-Deacetylcolchicine with Nitrous Acid and tert-Butyl Nitrite
  作者：Bruno Danieli、Giordano Lesma、Daniele Passarella、Davide Prosperi、Alessandro Sacchetti、Alessandra Silvani、Riccardo Destro、Emanuela May、Ezio Bombardelli

  DOI：10.1002/hlca.200390164

  日期：2003.6

  Reaction of N-deacetylthiocolchicine (3) and N-deacetylcolchicine (4) with nitrous acid (HONO) furnished the new tetracyclic colchicinoids 5 and 6, as well as the Demyanov-rearrangement products 7 and 8. Starting from 3, the pyrazole-containing tetracycle 9 was obtained. The novel compounds were characterized spectroscopically, and an X-ray crystal-structure analysis of 5 allowed us to establish the

  的反应Ñ -deacetylthiocolchicine（3）和Ñ -deacetylcolchicine（4）与亚硝酸（HONO）得到新的四环类秋水仙碱5和6，以及所述Demyanov -rearrangement制品7和8。从3开始，获得了含吡唑的四环9。光谱表征了该新型化合物，X射线晶体结构分析5使我们能够在立体发生中心建立绝对构型。
• Colchicine derivatives and the therapeutical use thereof
  申请人：Indena S.p.A.

  公开号：US05843910A1

  公开（公告）日：1998-12-01

  The present invention relates to novel colchicine derivatives of formula (1), where Y is a --CH.sub.2 --CH--NH--R.sub.3 group or a --CH--CH.sub.2 OR.sub.3 group and the other variables are as defined in claim 1, having antiproliferative, antitumoral and anti-inflammatory activities. The novel compounds have a cytotoxicity on human tumoral cell lines comparable with colchicine, but, in comparison with the latter, they are less toxic and more selective, particularly on cells resistant to the usual medicaments. Some compounds have a marked activity on TNF and interleukine 2, and therefore are very potent anti-inflammatory agents. They can be included in pharmaceutical formulations useful for the parenteral, oral and topical administrations.

  本发明涉及一种新的秋水仙碱衍生物，其化学式为(1)，其中Y是--CH.sub.2--CH--NH--R.sub.3基团或--CH--CH.sub.2OR.sub.3基团，其他变量如权利要求1所定义，具有抗增殖、抗肿瘤和抗炎活性。这些新化合物对人类肿瘤细胞系具有与秋水仙碱相当的细胞毒性，但与后者相比，它们毒性更小、更具选择性，特别是对于对常规药物具有耐药性的细胞。一些化合物对TNF和白细胞介素2具有显著的活性，因此它们是非常有效的抗炎药物。它们可以被包含在用于静脉、口服和局部给药的制剂中。
• Antitumor agents. 139. Synthesis and biological evaluation of thiocolchicine analogs 5,6-dihydro-6(S)-acyloxy)- and 5,6-dihydro-6(S)-[(aroyloxy)methyl]-1,2,3-trimethoxy-9-(methylthio)-8H-cyclohepta[a]naphthalen-8-ones as novel cytotoxic and antimitotic agents
  作者：Li Sun、Andrew T. McPhail、Ernest Hamel、Chii M. Lin、Susan B. Hastie、Jer Jang Chang、Kuo Hsiung Lee

  DOI：10.1021/jm00057a004

  日期：1993.3

  A series of novel thiocolchicine analogs, 5,6-dihydro-6(S)-(acyloxy)- and 5,6-dihydro-6(S)-[(aroyloxy)-methyl]-1,2,3-trimethoxy-9-(methylthio)-8H-cyclohepta[a]naphthalen-8-ones, possessing a six-membered ring B, have been synthesized and evaluated for their cytotoxicity against various tumor cell lines, including solid tumor cell lines, and for their interaction with tubulin. The configuration of the parent alcohol (compound 5) was established unequivocally as (aR,6S) by X-ray crystallographic analysis. The side chain at the C(6) position is in a pseudoaxial orientation. The optical properties and H-1 NMR data indicated that these compounds have the same conformations in solution as in the solid state. Biological results showed that compounds (5, 6, 14,15,17, and 18) bearing a small side chain at C(6) demonstrate high potency in inhibiting tubulin polymerization and binding of radiolabeled colchicine to tubulin. The most cytotoxic compounds were 14, 15, 17, and 18, with good activity against several solid tumor cell lines. To explain the strong antitubulin activity of compound 5 (with an aR configured biaryl system in contrast to the aS configuration previously described for colchicinoids, allocolchicinoids, and steganacin) we speculate that a rapid atropisomerism equilibrium must exist for 5 and its active derivatives. This equilibrium would yield adequate amounts of aS-configured conformers that interact strongly with tubulin. Since the optically inactive 18 is also a potent inhibitor of tubulin, the configuration of the side chain of these six-membered ring B analogs cannot be essential for their binding to tubulin. Instead we propose that the size of ring B and of its side chain play important roles in tubulin binding activity by affecting the rotation of the rings A and C along their linking C-C bond axis.