2,2,4,4-tetramethyl-6-aminothiochroman | 203856-19-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 硫铬烷
• 英文名称: 2,2,4,4-tetramethyl-6-aminothiochroman
• 英文别名: 3,4-Dihydro-2,2,4,4-tetramethyl-2h-1-benzothiopyran-6-amine；2,2,4,4-tetramethyl-3H-thiochromen-6-amine
• CAS: 203856-19-3
• 化学式: C₁₃H₁₉NS
• 分子量: 221.367
• InChiKey: PFDZUEWOUUBIFZ-UHFFFAOYSA-N

物化性质

• 熔点：
  57-59 °C
• 沸点：
  338.2±41.0 °C(Predicted)
• 密度：
  1.030±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  51.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-氰基苯异氰酸酯 、 2,2,4,4-tetramethyl-6-aminothiochroman 在 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 18.0h， 以87%的产率得到1-(4-cyanophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)urea
  参考文献：
  名称：

  SHetA2（NSC-721689）类似物的合成及其针对卵巢癌细胞系A2780的生物学评估

  摘要：

  合成了一系列的柔性杂芳类化合物（Flex-Het）类似物，并评估了它们对A2780卵巢癌细胞系的生物学活性。这项研究的目的是建立新的Flex-Het衍生物的结构-活性关系（SAR），这些衍生物以前由于芳基异硫氰酸酯前体的可用性有限而无法获得。当前的工作开发了异硫氰酸酯13的合成，并用于从多种商业胺中制备铅化合物SHetA2（1，NSC-721689）的14种不同的硫脲类似物。此外，还准备了五种新的尿素以及九种氮-苄硫脲，五种结合有肼或酰肼连接基的衍生物和四种脱甲基化合物。确定每种衍生物的效力和功效。一些新的Flex-Hets具有很高的活性，其IC 50值为1.86至4.70μM，效率为85.6–95.9％，与铅化合物相当或更好（IC 503.17μM，功效为84.3％）。尽管SHetA2计划在不久的将来进入临床试验，但这项工作中已经确定了备选的备用药物候选物。新药具有相似的药理特性，并保留

  DOI：

  10.1016/j.ejmech.2019.03.010
• 作为产物：
  描述：

  4-乙酰氨基苯硫酚 在 盐酸 、 aluminum (III) chloride 、 碳酸氢钠 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 二氯甲烷 、 氯仿 、 水 、 氯苯 为溶剂， 反应 22.5h， 生成 2,2,4,4-tetramethyl-6-aminothiochroman
  参考文献：
  名称：

  SHetA2（NSC-721689）类似物的合成及其针对卵巢癌细胞系A2780的生物学评估

  摘要：

  合成了一系列的柔性杂芳类化合物（Flex-Het）类似物，并评估了它们对A2780卵巢癌细胞系的生物学活性。这项研究的目的是建立新的Flex-Het衍生物的结构-活性关系（SAR），这些衍生物以前由于芳基异硫氰酸酯前体的可用性有限而无法获得。当前的工作开发了异硫氰酸酯13的合成，并用于从多种商业胺中制备铅化合物SHetA2（1，NSC-721689）的14种不同的硫脲类似物。此外，还准备了五种新的尿素以及九种氮-苄硫脲，五种结合有肼或酰肼连接基的衍生物和四种脱甲基化合物。确定每种衍生物的效力和功效。一些新的Flex-Hets具有很高的活性，其IC 50值为1.86至4.70μM，效率为85.6–95.9％，与铅化合物相当或更好（IC 503.17μM，功效为84.3％）。尽管SHetA2计划在不久的将来进入临床试验，但这项工作中已经确定了备选的备用药物候选物。新药具有相似的药理特性，并保留

  DOI：

  10.1016/j.ejmech.2019.03.010

文献信息

• Heteroarotinoids containing urea or thiourea linker
  申请人：The Board of Regents for Oklahoma State University

  公开号：US06586460B1

  公开（公告）日：2003-07-01

  Compounds, known as heteroarotinoids, having varying abilities to inhibit growth of certain cancerous cells, induce normal cell differentiation, and induce apoptosis or death of cancerous cells, of the general formula: in which: Ar and Ar′ denote aryl substituents, and wherein at least one of said aryl substituents comprises an aromatic ring having at least one heteroatom in a fused, partially saturated ring; W denotes O or S; and Q denotes H or i-C3H7.

  化合物，被称为杂环芳烃，具有不同的抑制某些癌细胞生长的能力，诱导正常细胞分化，并诱导癌细胞凋亡或死亡，其通式为：其中：Ar和Ar'表示芳基取代基，其中至少一个芳基取代基包括一个具有至少一个杂原子的融合、部分饱和的环的芳香环; W表示O或S; Q表示H或i-C3H7。
• Novel Heteroarotinoids as Potential Antagonists of <i>Mycobacterium</i> <i>b</i><i>ovis</i> BCG
  作者：Chad W. Brown、Shengquan Liu、Jozef Klucik、K. Darrell Berlin、Patrick J. Brennan、Devinder Kaur、Doris M. Benbrook

  DOI：10.1021/jm0303453

  日期：2004.2.1

  A series of 15 heteroarotinoids has been prepared and evaluated for activity against Mycobacterium bovis BCG with the thiourea-containing isoxyl (7) (0.5 mug/mL) as the standard. 2,2,4-Trimethyl-2H-chromen-7-yl 4-(methoxycarbonyl)benzoate (8) displayed the most significant activity (2.0-4.0 mug/mL) in terms of the lowest concentration (mug/mL) (MIC, minimum inhibitory concentration) required to produce a 99% reduction in the number of colonies on a plate as compared to that system free of the agent at the same dilution of the culture suspension. Ethyl 4-[N-(2,2,4,4-tetramethylchroman-6-yl)thiocarbamoyl] amino}benzoate (9) and [(1E,3Z,5E)-1-aza-4-methyl-6-(1,2,2,4-tetramethyl(1,2-dihydroquinolyl))hexa-1,3,5-trienyl]-amino}aminomethane-1-thione (10) exhibited activity at 5.0-10.0 and 10.0-20.0 mug/mL, respectively, while the other examples had MIC values of 20 mug/mL or greater. The inhibitory ability of 8 may occur via the inhibition of mycolic acid synthesis in a like manner as found with 7, but this requires further study. The heteroarotinoids are the first examples to exhibit inhibitory ability against the growth of Mycobacterium bovis BCB.
• Synthesis of Flexible Sulfur-Containing Heteroarotinoids That Induce Apoptosis and Reactive Oxygen Species with Discrimination between Malignant and Benign Cells
  作者：Shengquan Liu、Chad W. Brown、K. Darrell Berlin、Aridam Dhar、Suresh Guruswamy、David Brown、Ginger J. Gardner、Michael J. Birrer、Doris M. Benbrook

  DOI：10.1021/jm030346v

  日期：2004.2.1

  Regulation of growth, differentiation, and apoptosis by synthetic retinoids can occur through mechanisms that are dependent and independent of their ability to bind and activate nuclear retinoic acid receptors. The objective of this study was to determine if increasing flexibility of the heteroarotinoid structure would affect the specificity of the synthetic retinoids for the receptors and for their regulation of cancerous and nonmalignant cells. Methods were developed to produce the first examples of heteroarotinoids 15a-15h, which contain urea and/or thiourea linking groups between two aryl rings. Substituents at the para position of the single phenyl ring were either an ester, a nitro group, or a sulfonamide group. Ovarian cancer cell lines Caov-3, OVCAR-3, SK-OV-3, UCI-101, and 222 were utilized, and the inhibitory prowess of the heteroarotinoids was referenced to that of 4-HPR (25). Similar to 4-HPR (25), the heteroarotinoids inhibited growth of all cell lines at micromolar concentrations. Although the heteroarotinoids did not activate retinoic acid receptors, the agents induced potent growth inhibition against the cancer cells with weak activity against normal and benign cells. The growth inhibition was associated with cell loss and induction of reactive oxygen species.
• Heteroarotinoids Inhibit Head and Neck Cancer Cell Lines in Vitro and in Vivo Through Both RAR and RXR Retinoic Acid Receptors
  作者：David Zacheis、Arindam Dhar、Shennan Lu、Matora M. Madler、Jozef Klucik、Chad W. Brown、Shengquan Liu、Francis Clement、Shankar Subramanian、G. Mahika Weerasekare、K. Darrell Berlin、Michael A. Gold、John R. Houck,、Kenneth R. Fountain、Doris M. Benbrook

  DOI：10.1021/jm990292i

  日期：1999.10.1

  A class of less toxic retinoids, called heteroarotinoids, was evaluated for their molecular mechanism of growth inhibition of two head and neck squamous cell carcinoma (HNSCC) cell lines SCC-2 and SCC-38. A series of 14 heteroarotinoids were screened for growth inhibition activity in vitro. The two most active compounds, one that contained an oxygen heteroatom (6) and the other a sulfur heteroatom (16), were evaluated in a xenograph model of tumor establishment in nude mice. Five days after subcutaneous injection of 10(7) SCC-38 cells, groups of 5 nu / nu mice were gavaged daily (5 days/week for 4 weeks) with 20 mg/kg/day of all-trans-retinoic acid (t-RA, 1), 10 mg/kg/day of 6, 10 mg/kg/day of 16, or sesame oil. After a few days, the dose of t-RA (1) was decreased to 10 mg/kg/day to alleviate the side effects of eczema and bone fracture. No significant toxic effects were observed in the heteroarotinoid groups. All three retinoids caused a statistically significant reduction in tumor size as determined by the Student t-test (P < 0.05). Complete tumor regression was noted in 3 of 5 mice treated with t-RA (1), 4 of 5 mice treated with 16, 1 of 5 mice treated with 6, and 1 of 5 mice treated with sesame oil. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine that the expression levels of RAR alpha, RXR alpha, and RXR beta were similar in the two cell lines, while RAR beta expression was higher in SCC-2 over SCC-38, and RAR gamma expression was higher in SCC-38 over SCC-2. Receptor cotransfection assays in CV-1 cells demonstrated that 16 was a potent activator of both RAR and RXR receptors, while 6 was selective for the RXR receptors. Transient cotransfection assays in CV-1 cells using an AP-1 responsive reporter plasmid demonstrated that t-RA (1), 6, and 16 each inhibited AP-1-driven transcription in this cell line. In conclusion, the growth inhibition activity of the RXR-selective 6 and the more potent growth inhibition activity of the RAR/RXR pan-agonist 16 implicate both RARs and RXRs in the molecular mechanism of retinoid growth inhibition. Moreover, the chemoprevention activity and the lack of toxicity of heteroarotinoids demonstrate their clinical potential in head and neck cancer chemoprevention.
• US5498755A
  申请人：——

  公开号：US5498755A

  公开（公告）日：1996-03-12