硫代秋水仙碱 | 2730-71-4

• 分子结构分类: 有机化合物 - 碳氢化合物衍生物 - 环庚三烯酮
• 中文名称: 硫代秋水仙碱
• 英文名称: thiocolchicine
• 英文别名: 10-methylthiocolchicine；thiocolchicoside；Thiocholchicine；N-[(7S)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5H-benzo[a]heptalen-7-yl]acetamide
• CAS: 2730-71-4
• 化学式: C₂₂H₂₅NO₅S
• 分子量: 415.51
• InChiKey: CMEGANPVAXDBPL-INIZCTEOSA-N

物化性质

• 熔点：
  193℃
• 比旋光度：
  D20 -221°
• 沸点：
  729.1±60.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：可溶10mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  99.2
• 氢给体数：
  1
• 氢受体数：
  6

制备方法与用途

生物活性

Thiocolchicine 是秋水仙碱（HY-16569）的衍生物，是一种有效的微管蛋白聚合抑制剂（IC50=2.5 μM），能够以竞争性方式结合微管蛋白（Ki=0.7 μM）。此外，Thiocolchicine 可作为 ADC 的毒素分子。

体外研究

Thiocolchicine 对 MCF-7、LoVo、LoVo/DX、A-549 和 BALB/3T3 细胞的 IC50 值分别为 0.01 μM、0.021 μM、0.398 μM、0.011 μM 和 0.114 μM。Thiocolchicine 在 1 nM 至 100 μM 的浓度范围内（作用时间 24-72 小时）对乳腺癌细胞表现出细胞周期阻滞活性和生长抑制的关系。它能够以 IC50 值分别为 0.6 nM 和 400 nM 抑制 MDA-MB-231 和多药耐药（MDR）的 MCF-7 ADRr 乳腺癌细胞，以及 MDR CEM-VBL 白血病细胞（IC50 = 50 nM）。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	thiocolchicine	209810-39-9	C22H25NO5S	415.51
  (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	deacetylthiocolchicine	2731-16-0	C20H23NO4S	373.473
  ——	7-amino-1,2,3-trimethoxy-10-methylsulfanyl-6,7-dihydro-5H-benzo[a]-heptalen-9-one	2731-16-0	C20H23NO4S	373.473
  秋水仙碱	colchicine	64-86-8	C22H25NO6	399.444
  N-(1,2,3,10-四甲氧基-9-氧代-5,6,7,9-四氢苯并[a]庚搭烯-7-基)乙酰胺	N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl) acetamide	54192-66-4	C22H25NO6	399.444
  ——	(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid ((S)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl)-amide	203584-67-2	C30H35NO7S	553.676

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  3-去甲基硫代秋水仙碱	3-O-demethylthiocolchicine	87424-25-7	C21H23NO5S	401.483
  2-去甲基硫代秋水仙碱	2-demethylthiocolchicine	87424-26-8	C21H23NO5S	401.483
  ——	2,3-didemethylthiocolchicine	51296-12-9	C20H21NO5S	387.456
  ——	4-chloro-N-[(7S)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5H-benzo[a]heptalen-7-yl]butanamide	478361-73-8	C24H28ClNO5S	478.009
  ——	N-hexanoyl-N-deacetylthiocolchicine	147950-74-1	C26H33NO5S	471.618
  ——	N-decanoyldeacetylthiocolchicine	——	C30H41NO5S	527.725
  ——	N-palmitoyldeacetylthiocolchicine	——	C36H53NO5S	611.887
  ——	N-tricosanoyldeacetylthiocolchicine	——	C43H67NO5S	710.075
  ——	N-[(7S)-1,2-dimethoxy-10-methylsulfanyl-9-oxo-3-(prop(2-en)oxy)-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide	104158-08-9	C24H27NO5S	441.548
  ——	N-<5,6,7,9-tetrahydro-1,2,3-trimethoxy-9-oxo-10-(methylsulfinyl)benzoheptalen-7-yl>-(S)-acetamide	76189-03-2	C22H25NO6S	431.51

反应信息

• 作为反应物：
  描述：

  硫代秋水仙碱 在 盐酸 、 4-二甲氨基吡啶 、 sodium hydroxide 、 sodium dithionite 、 potassium carbonate 、 三乙胺 、 三氟乙酸 、 sodium nitrite 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 2.08h， 生成 4-<(2-diazo-3,3,3-trifluoropropanoyl)thio>thiocolchicine
  参考文献：
  名称：

  Synthesis, photochemical reactions, and tubulin binding of novel photoaffinity labeling derivatives of colchicine

  摘要：

  DOI：

  10.1021/jo00058a051
• 作为产物：
  描述：

  秋水仙碱 在 甲硫醇 、 对甲苯磺酸 作用下， 以80%的产率得到硫代秋水仙碱
  参考文献：
  名称：

  Photochemical Isomerization of Colchicine and Thiocolchicine

  摘要：

  The photochemical reactivity of colchicine and thiocolchicine is described. Although the irradiation of colchicine gave a well-known transposition reaction to beta- and gamma-lumicolchicines, thiocolchicine did not react. Femtosecond transient spectroscopy of colchicine showed a strong band with maximum at 510 nm appearing at tau = 0. It disappeared within few hundred femtoseconds, leaving a broad structureless band with a maximum around 470 urn. A second band is observed around 410 nm. The analysis in time showed that the 510-nm component appeared instantaneously and decayed following a biexponential low with time constants of 300 +/- 100 fs and 40 ps. The kinetics at 420 nm has a measurable rise lime of 300 +/- 150 fs. Quantum mechanical calculations on colchicine showed that this absorption is due to a S-1 --> S-11 transition. In thiocolchicine, the instantaneous formation of a structure with maxima out of the investigated spectral region was observed. A strong absorption around 650 nm indicated the presence of a band with a maximum at longer wavelengths (> 700 nm) and a peak around 380 nm, which partially coincides with the ground-state absorption and therefore strongly affected absorption around 650 nm and its rapid (similar to500 fs) decay by its bleaching. The instantaneous formation of an absorption was observed. At shorter wavelengths (400 nm), the t decay was fitted with a biexponential curve with the first time constant of about 80 ps. The second part of,the decay had a very long tail up to 500 ps. Transient spectroscopy and configuration interaction calculations are in agreement with a mechanism involving a disrotatory cyclization of colchicine in its first excited singlet state. The lack of reactivity observed in thiocolchicine was explained by considering the presence of efficient ISC to the triplet state.

  DOI：

  10.1021/jp035507l

文献信息

• Synthesis, antiproliferative activity and molecular docking of thiocolchicine urethanes
  作者：Urszula Majcher、Alicja Urbaniak、Ewa Maj、Mahshad Moshari、Magdalena Delgado、Joanna Wietrzyk、Franz Bartl、Timothy C. Chambers、Jack A. Tuszynski、Adam Huczyński

  DOI：10.1016/j.bioorg.2018.09.004

  日期：2018.12

  colchicine exert their therapeutic effect by changing the dynamics of tubulin and its polymer form, microtubules. The identification of tubulin as a potential target for anticancer drugs has led to extensive research followed by clinical development of numerous compounds from several families. In this paper we report on the design, synthesis and in vitro evaluation of a group of thiocolchicine derivatives

  许多天然存在的化合物（例如紫杉醇，长春碱，康维他汀和秋水仙碱）通过改变微管蛋白及其聚合物形式（微管）的动力学来发挥其治疗作用。将微管蛋白鉴定为抗癌药物的潜在靶标导致了广泛的研究，随后进行了来自多个家族的许多化合物的临床开发。在本文中，我们报告了一组在环B处修饰的硫代秋水仙碱衍生物的设计，合成和体外评估，该化合物在此处标记为化合物4 – 14。这些化合物是通过7-脱乙酰基-10-硫代秋水仙碱3的简单反应获得的在三光气存在下与十一种不同的醇一起使用。这些新型药物已针对四种人类癌细胞系进行了抗增殖活性检查，其作用方式已通过分子对接证实为秋水仙碱结合位点抑制（CBSI）。分子模拟为测试化合物提供了合理的微管蛋白结合模型。上的基础的体外试验中，衍生物4 - 8和14表现出对MCF-7，的LoVo和A549肿瘤细胞系（IC最高效力50值= 0.009–0.014μM）。与包括顺铂和阿霉素以及未修饰秋水
• [EN] TRICYCLIC INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE<br/>[FR] INHIBITEURS TRICYCLIQUES DE POLY(ADP-RIBOSE)POLYMÉRASE
  申请人：NEWGEN THERAPEUTICS INC

  公开号：WO2012166983A1

  公开（公告）日：2012-12-06

  The invention provides for compositions comprising phosphorous containing tricyclic compounds, including phthalazin-l(2H)-one derivatives. The compounds are potent inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), particularly PARP-1 and potentially PARP-2. The also show good cellular activity in inhibiting poly(ADP- ribose) oligomer formation. The compounds may be useful as mono-therapy or in combination with other therapeutic agents in the treatment conditions where PARP is implicated, such as cancer, inflammatory diseases and ischemic conditions. Thus, also provided are methods for the treatment of a condition where PARP is implicated comprising administering to an effective amount of a compound of the invention to an individual in need thereof.

  该发明提供了包含含磷三环化合物的组合物，包括邻苯二氮杂吲哚酮衍生物。这些化合物是酶聚(腺苷二磷酸核糖)聚合酶（PARP）的有效抑制剂，特别是PARP-1和潜在的PARP-2。它们还显示出在抑制聚(腺苷二磷酸核糖)寡聚物形成方面具有良好的细胞活性。这些化合物可能在单独治疗或与其他治疗剂联合治疗PARP参与的疾病条件中发挥作用，如癌症、炎症性疾病和缺血性疾病。因此，还提供了一种治疗PARP参与的疾病条件的方法，包括向需要的个体施用该发明化合物的有效量。
• Pyridine- and Pyrimidinecarboxamides as CXCR2 Modulators
  申请人：Maeda Dean Y.

  公开号：US20100210593A1

  公开（公告）日：2010-08-19

  There is disclosed pyridine- and pyrimidinecarboxamide compounds useful as pharmaceutical agents, synthesis processes, and pharmaceutical compositions which include pyridine- and pyrimidinecarboxamides compounds. More specifically, there is disclosed a genus of CXCR2 inhibitor compounds that are useful for treating a variety of inflammatory and neoplastic disorders.

  披露了作为药物剂的吡啶和嘧啶羧酰胺化合物，合成过程以及包括吡啶和嘧啶羧酰胺化合物的药物组合物。更具体地，披露了一类CXCR2抑制剂化合物，可用于治疗各种炎症和肿瘤性疾病。
• [EN] PI-3 KINASE INHIBITOR PRODRUGS<br/>[FR] PROMEDICAMENTS D'INHIBITEURS DE PI-3 KINASE
  申请人：SEMAFORE PHARMACEUTICALS INC

  公开号：WO2004089925A1

  公开（公告）日：2004-10-21

  The invention provides novel prodrugs of inhibitors of PI-3 kinase. The novel compounds are LY294002 and analogs thereof comprising a reversibly quaternized amine.

  这项发明提供了PI-3激酶抑制剂的新型前药。这些新型化合物是LY294002及其类似物，包括可逆性季铵化胺。
• [EN] CONJUGATES FOR TREATING DISEASES CAUSED BY PSMA EXPRESSING CELLS<br/>[FR] CONJUGUÉS POUR TRAITER LES MALADIES PROVOQUÉES PAR DES CELLULES EXPRIMANT PSMA
  申请人：ENDOCYTE INC

  公开号：WO2014078484A1

  公开（公告）日：2014-05-22

  The invention described herein pertains to the diagnosis, imaging, and/or treatment of pathogenic cell populations. In particular, the invention described herein pertains to the diagnosis, imaging, and/or treatment of diseases caused by PSMA expressing cells, such as prostate cancer cells, using compounds capable of targeting PSMA expressing cells.

  本发明涉及对病原细胞群体进行诊断、成像和/或治疗。具体来说，本发明涉及利用能够靶向PSMA表达细胞的化合物对由PSMA表达细胞引起的疾病，如前列腺癌细胞，进行诊断、成像和/或治疗。