5,6-dihydro-1,2,3-trimethoxy-10-(methylthio)benzo[a]heptalene-7,9-dione | 186769-46-0

• 分子结构分类: 有机化合物 - 碳氢化合物衍生物 - 环庚三烯酮
• 英文名称: 5,6-dihydro-1,2,3-trimethoxy-10-(methylthio)benzo[a]heptalene-7,9-dione
• 英文别名: 7-oxodeacetamidothiocolchicine；thiocolchicone；thiocolchicine；1,2,3-trimethoxy-10-methylsulfanyl-5,6-dihydrobenzo[a]heptalene-7,9-dione
• CAS: 186769-46-0
• 化学式: C₂₀H₂₀O₅S
• 分子量: 372.442
• InChiKey: LMBIHYWAZRMYEM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  87.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5,6-dihydro-1,2,3-trimethoxy-10-(methylthio)benzo[a]heptalene-7,9-dione 在 sodium tetrahydroborate 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 以80%的产率得到7-Hydroxy-1,2,3-trimethoxy-10-methylsulfanyl-6,7-dihydro-5H-benzo[a]heptalen-9-one
  参考文献：
  名称：

  抗肿瘤药。172.作为抗微管蛋白剂的新型脱乙酰氨基硫代秋水仙碱-7-醇和酯类似物的合成和生物学评估。

  摘要：

  已经合成了一系列新颖的7-O-取代的对乙酰氨基硫代秋水仙碱衍生物，并评估了它们对微管蛋白聚合的抑制活性，[3H]-秋水仙碱与微管蛋白的结合以及人类伯基特淋巴瘤细胞的生长。在这些新的衍生物中，通过席夫碱平衡和酸水解从脱乙硫基秋水仙碱（6）获得了硫代秋水仙碱（8），其中硫代秋水仙碱中的乙酰氨基被C（7）处的羰基氧取代。用硼氢化钠还原硫代秋水仙碱得到外消旋醇9，其结构通过X射线晶体学分析证实。光学纯醇9a，通过用光学纯试剂（1S）-（-）-樟脑氯化物处理9，然后色谱分离樟脑酸酯和非对映异构体水解，得到b。X射线晶体学分析确定了9a的aS，7S构型。外消旋和旋光酯11-15、11a，b，12a，14a和15a是通过将相应的醇酯化而获得的。在所有生物学测定中显示等于或大于（-）-thiocolchicione（2a）的活性的化合物为三种（-）-aS，7S光学纯对映异构体：醇9a，乙酸酯11a（硫代秋

  DOI：

  10.1021/jm960663k
• 作为产物：
  描述：

  秋水仙碱 在 盐酸 、 草酸 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成 5,6-dihydro-1,2,3-trimethoxy-10-(methylthio)benzo[a]heptalene-7,9-dione
  参考文献：
  名称：

  Discovery of structurally simplified analogs of colchicine as an immunosuppressant

  摘要：

  We have discovered a new class of colchicine-derived therapeutic agents for immune diseases including rejection of organ-transplantation and autoimmune disease. Compound 2, which had been developed to overcome poor pharmacokinetic properties of compound 1, a first-generation colchicine analog, turned out to show toxicity such as intestinal toxicity and loss of weight during in vivo tests. The deletion of 7-carboxamide group and middle ring-truncation in colchicine allowed us to have structurally simplified analogs with strong immunosuppressive activity. Herein, we report non-alkaloid tricyclic compound 7 and 12 as immunosuppressants which exhibited a strong immunosuppressive in vivo efficacy on the T-dependent antibody response, the Zymosan A-induced arthritis model and the Carrageenan-induced edema model. Compound 7 and 12 revealed less toxicity than the previous lead compound 2, and their minimum lethal doses (MLD) were proved to exceed 100 mg/kg. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.05.007

文献信息

• Antitumor Agents. Part 184. Syntheses and antitubulin activity of compounds derived from reaction of thiocolchicone with amines: Lactams, alcohols, and ester analogs of allothiocolchicinoids
  作者：Qian Shi、Ke Chen、Arnold Brossi、Pascal Verdier-Pinard、Ernest Hamel、Andrew T. McPhail、Kuo-Hsiung Lee

  DOI：10.1002/hlca.19980810516

  日期：——

  chemical resolution including a separation of the comphanate diastereoisomers 12a and 12b, followed by basic hydrolysis. The (aR,7R)-configuration of 12b was verified by X-ray crystallographic analysis. Almost all racemic and optically active 7-O-acyl or 7-O-aroyl compounds had strong inhibitory effects on the tubulin polymerization reaction, with IC50 values from 1.7 to 5.1 μM. A few agents, such as the

  合成了7- O-取代的脱氨基脱氧胆甾醇硫代甲基醚类似物，并评价了其对体外微管蛋白聚合的抑制作用。酮9是这项研究中的关键化合物，它是通过与苯胺反应而从噻吩酮6衍生而来的。化合物6与MeNH 2或BuNH 2的反应分别得到四环内酰胺7和8。旋光醇11a和11b是由外消旋体11通过化学拆分而获得的，包括分离出甲酸酯非对映异构体12a。和12b，然后进行碱性水解。通过X射线晶体学分析证实了12b的（a R，7 R）-构型。几乎所有外消旋和旋光的7- O-酰基或7- O-芳酰基化合物均对微管蛋白聚合反应具有强烈的抑制作用，IC 50值为1.7至5.1μM。一些试剂，例如内酰胺7和8，樟脑酸酯12a和12b，环己烷羧酸酯19a和19b，最值得注意的是（7 S）-苯甲酸酯15a，对聚合的影响可忽略不计，产生的IC 50值大于40μM。酮9表现出对微管蛋白聚合的强烈抑制作用，其程度可与硫代秋水仙烯（6）相
• Stereochemical variations on the colchicine motif. Part 2.1 Unexpected tetracyclic isoxazole derivatives
  作者：Ulf Berg、Håkan Bladh、Maria Hoff、Christer Svensson

  DOI：10.1039/a701400g

  日期：——

  Attempts to expand the colchicine B-ring in 7-oxodeacetamidothiocolchicine 1 by a Beckmann-type rearrangement lead to unexpected tetracyclic isoxazole derivatives 2 and 3. The syntheses, crystal and solution structures, conformational interconversions and binding properties to tubulin are reported. The molecules exist as mixtures of two enantiomeric conformations due to hindered rotation around the A and C rings, which are twisted by dihedral angles of 62° (1) and 46° (2) in the crystal. Solid, solution and gas phase (according to MM2) structures are compared. Dynamic 1H NMR analyses give the following thermodynamic parameters for the rotation around the A–C pivot bond: (1) ωG‡381K = 77.4; (2) ωG‡300K = 60.7; ωH‡ = 55.6 ± 1.6 kJ mol-1; ωS‡ = -16.7 ± 15 J mol-1 K-1; (3) ωG‡298K = 60.1, ωH‡ = 59.9 ± 2.0 J mol-1 and ωS‡ = -0.7 ± 15 J mol-1 K-1. The drugs 1 and 2 depolymerize microtubules by binding to tubulin according to both in vitro and in vivo studies, but 1 is considerably more active than 2. Compound 3 does not seem to bind notably to tubulin.

  尝试通过贝克曼式重排来扩展 7-oxodeacetamidothiocolchicine 1 中的秋水仙碱 B 环，结果产生了意想不到的四环异噁唑衍生物 2 和 3。报告了这些衍生物的合成、晶体和溶液结构、构象互变以及与小管蛋白的结合特性。由于围绕 A 环和 C 环的旋转受阻，这些分子以两种对映体构象的混合物形式存在，它们在晶体中的二面角分别为 62°（1）和 46°（2）。对固体、溶液和气相（根据 MM2）结构进行了比较。动态 1H NMR 分析得出了围绕 A-C 枢键旋转的热力学参数：(1) ωG‡381K = 77.4；(2) ωG‡300K = 60.7；ωH‡ = 55.6 ± 1.6 kJ mol-1；ωS‡ = -16.7 ± 15 J mol-1 K-1；(3) ωG‡298K = 60.1，ωH‡ = 59.9 ± 2.0 J mol-1，ωS‡ = -0.7 ± 15 J mol-1 K-1。根据体外和体内研究，1 号和 2 号药物通过与微管蛋白结合来解聚微管，但 1 号的活性比 2 号高得多。化合物 3 与微管蛋白的结合似乎并不明显。
• Stereochemical variations on the colchicine motif. Peracid oxidation of thiocolchicone. Synthesis, conformation and inhibition of microtubule assembly
  作者：Ulf Berg、H�kan Bladh、Konstantinos Mpampos

  DOI：10.1039/b402840f

  日期：——

  When 7-oxodesacetamidothiocolchicine (1) was treated with various peroxides in order to afford a Baeyer–Villiger rearrangement, a complex mixture of products was formed, which included the sulfoxide, (2) and sulfone, (3). When peracetic acid was used two additional products were formed; a C-ring lactone (4) and a ring-contracted allocolchicine derivative (5). The sulfoxide (2) was semi-preparatively resolved into enantiomers by chromatography on microcrystalline triacetylcellulose. Rotational barriers around the A–C pivot bond of 2, 4 and 5 were determined by dynamic 1H NMR analysis. The compounds 2, 3, 4 and 7a exhibit moderate inhibition of tubulin polymerization, according to in vitro turbidity studies, whereas 5 was inactive.

  7-oxodesacetamidothiocolchicine (1) 经各种过氧化物处理以进行拜耳-维利格重排后，生成了一种复杂的混合物，其中包括亚砜 (2) 和砜 (3)。当使用过乙酸时，会生成两种额外的产物：一种 C 环内酯（4）和一种环收缩的异小甘菊碱衍生物（5）。通过在微晶三乙酰纤维素上进行色谱分析，亚砜（2）被半分离成对映体。通过动态 1H NMR 分析确定了 2、4 和 5 的 A-C 枢键周围的旋转障碍。根据体外浑浊度研究，化合物 2、3、4 和 7a 对微管蛋白的聚合有中度抑制作用，而 5 则没有活性。
• Antitumor Agents. 183. Syntheses, Conformational Analyses, and Antitubulin Activity of Allothiocolchicinoids
  作者：Qian Shi、Ke Chen、Xin Chen、Arnold Brossi、Pascal Verdier-Pinard、Ernest Hamel、Andrew T. McPhail、Alexander Tropsha、Kuo-Hsiung Lee

  DOI：10.1021/jo980073p

  日期：1998.6.1

  7-O-Substituted analogues of allothiocochicine were synthesized and evaluated for their inhibitory effects on tubulin polymerization in vitro. Ketone 6, a key compound in this study, was derived from thiocolchicone 5 by ring contraction. The structure of 6 was determined from spectral data. Optically active alcohols 7a and 7b were obtained by reduction of ketone 6 followed by chemical resolution including a separation of the camphanate diastereomers 8a and 8b and basic hydrolysis. The aR,7R configuration of 8b was verified by X-ray crystallographic analysis. Almost all compounds had strong inhibitory effects on the tubulin polymerization reaction, with IC50 values from 1.7 to 9.0 mu M. The camphanates, cyclohexanates, and, most notably, the 7S-benzoate ester (10a), were inactive with IC50 values >40 mu M. Compounds 6 and 7a also showed potent antitumor activity with GI(50) values at nM concentration range for most cell lines in NCI's in vitro screening. Generally, the 7S enantiomers of colchicinoids with a troplone C-ring showed greater activity than the 7R enantiomers. In the current allothiocolchicinoid (with a benzenoid C-ring) study, only small differences occurred between the two active enantiomers of each pair. The acyl esters with a 7S configuration were slightly more active than the 7R isomers. However, the aroyl ester with a 7S configuration was less active than the 7R isomer. NMR, optical rotation, and molecular modeling studies revealed two conformers in a solvent-dependent equilibrium for both 7S and 7R isomers. In polar solvents, the molecular chirality in esters with a 7-O-aroyl substituent was reversed from aS to aR or from aR to aS at an intensified rate.
• Attempted Oxidative Deamination ofN-Deacetylcolchicinoids with 3,5-Di(tert-butyl)-1,2-benzoquinone: Synthesis of 2H-1,4-Benzoxazine-Type Adducts
  作者：Bruno Danieli、Giordano Lesma、Daniele Passarella、Davide Prosperi、Alessandra Silvani、Ezio Bombardelli

  DOI：10.1002/(sici)1522-2675(19990908)82:9<1502::aid-hlca1502>3.0.co;2-j

  日期：1999.9.8

  In an attempt to use 3,5-di(tert-butyl)-1,2-benzoquinone for the oxidative deamination of N-deacetylcolchicine (4) and N-deacetylthiocolchicine (= N-deacetyl-10-demethoxy-10-(methylthio)colchicine; 5) to give the corresponding ketones 2 and 3, the 2H-1,4-benzoxazine-type adducts 8/9 and 11/12. respectively, were formed instead, showing a new and unexpected behavior of Corey's reagent. The adducts were separated and spectroscopically characterized, and a plausible scheme of formation is reported.