SIS3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: SIS3
• 英文别名: ((E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one)；6,7-dimethoxy-2-((2E)-3-(1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine-3-ylprop-2-enoyl))-1,2,3,4-tetrahydroisoquinoline；SIS3 free base；(E)-1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-3-(1-methyl-2-phenylpyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one
• 化学式: C₂₈H₂₇N₃O₃
• 分子量: 453.541
• InChiKey: IJYPHMXWKKKHGT-VAWYXSNFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  56.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  SIS3 在 palladium on activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 以55%的产率得到1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propan-1-one
  参考文献：
  名称：

  Discovery of a novel selective water-soluble SMAD3 inhibitor as an antitumor agent

  摘要：

  Targeting the SMAD3 protein is an attractive therapeutic strategy for treating cancer, as it avoids the potential toxicities due to targeting the TGF-beta signaling pathway upstream. Compound SIS3 was the first selective SMAD3 inhibitor developed that had acceptable activity, but its poor water solubility limited its development. Here, a series of SIS3 analogs was created to investigate the structure-activity relationship for inhibiting the activation of SMAD3. On the basis of this SAR, further optimization generated a water-soluble compound, 16d, which was capable of effectively blocking SMAD3 activation in vitro and had similar NK cell-mediated anticancer effects in vivo to its parent SIS3. This study not only provided a preferable lead compound, 16d, for further drug discovery or a potential tool to study SMAD3 biology, but also proved the effectiveness of our strategy for water-solubility driven optimization.

  DOI：

  10.1016/j.bmcl.2020.127396
• 作为产物：
  描述：

  [3-(2,2-dichlorovinyl)pyridin-2-yl]carbamic acid tert-butyl ester 在 palladium diacetate 2-双环己基膦-2',6'-二甲氧基联苯 、 盐酸 、 potassium phosphate 、 N-碘代丁二酰亚胺 、 四丁基氯化铵 、 sodium hydride 、 sodium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 8.58h， 生成 SIS3
  参考文献：
  名称：

  A General Modular Method of Azaindole and Thienopyrrole Synthesis via Pd-Catalyzed Tandem Couplings of gem-Dichloroolefins

  摘要：

  A palladium-catalyzed reaction of gem-dichloroolefins and a boronic acid via a tandem intramolecular C-N and intermolecular Suzuki coupling process gave corresponding substituted azaindoles or thienopyrroles. This method is a very modular protocol to synthesize all four isomers of azaindole and two isomers of thienopyrroles in good to excellent yield.

  DOI：

  10.1021/jo070460b

文献信息

• One-Pot Coupling–Cyclization–Alkylation Synthesis of 1,2,5-Trisubstituted 7-Azaindoles in a Consecutive Three-component Fashion
  作者：Timo Lessing、Thomas Müller

  DOI：10.1055/s-0036-1590837

  日期：2017.9

  rapidly and efficiently prepared in a one-pot, copper-free alkynylation–cyclization–alkylation sequence starting from unprotected 2-aminopyridyl halides in a consecutive three-component fashion. By extension to a consecutive four-component coupling–cyclization–iodination–alkylation synthesis of 3-iodo-1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, a concise synthesis of SIS3, a selective TGF-β1 and signaling

  1,2,5-三取代的 7-氮杂吲哚可以在一锅无铜的炔基化-环化-烷基化序列中以连续的三组分方式从未保护的 2-氨基吡啶基卤化物开始快速有效地制备。通过扩展到 3-iodo-1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine 的连续四组分偶联-环化-碘化-烷基化合成，SIS3 的简明合成，选择性 TGF -β1 和信号抑制剂，实现了。
• Amide derivatives and drugs
  申请人：Maruyama Yasufumi

  公开号：US20050014942A1

  公开（公告）日：2005-01-20

  The present invention provides an amide derivative represented by the following formula [1]: wherein n represents 0 or 1; X represents CR 4 or N; Y represents CR 6 or N; Z represents CR 7 or N; R 1 and R 2 may be the same or different and each represents hydrogen, optionally substituted alkyl, acyl, optionally substituted aryl, or an optionally substituted aromatic heterocyclic group; R 4 , R 5 , R 6 and R 7 may be the same or different and each represents hydrogen, halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy, monoalkylamino, dialkylamino, arylalkyl, cyano, or nitro; and R 3 represents optionally substituted alkylamino, optionally substituted arylamino, or optionally substituted cyclic amino, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising them as an active ingredient. The compound of the present invention is useful as a TGF-β inhibitor.

  本发明提供了一种由以下式[1]表示的酰胺衍生物：其中n代表0或1；X代表CR4或N；Y代表CR6或N；Z代表CR7或N；R1和R2可以相同或不同，并且每个代表氢，可选择取代的烷基，酰基，可选择取代的芳基或可选择取代的芳香族杂环基；R4，R5，R6和R7可以相同或不同，并且每个代表氢，卤素，羟基，氨基，烷基，卤代烷基，烷氧基，单烷基氨基，双烷基氨基，芳基烷基，氰基或硝基；R3代表可选择取代的烷基氨基，可选择取代的芳基氨基或可选择取代的环状氨基，或其药学上可接受的盐，并且其中包括以其为活性成分的制药组合物。本发明的化合物可用作TGF-β抑制剂。
• AMIDE DERIVATIVES AND DRUGS
  申请人：Nippon Shinyaku Co., Ltd.

  公开号：EP1452525A1

  公开（公告）日：2004-09-01

  The present invention provides an amide derivative represented by the following formula [1]: wherein n represents 0 or 1; X represents CR4 or N; Y represents CR6 or N; Z represents CR7 or N; R1 and R2 may be the same or different and each represents hydrogen, optionally substituted alkyl, acyl, optionally substituted aryl, or an optionally substituted aromatic heterocyclic group; R4, R5, R6 and R7 may be the same or different and each represents hydrogen, halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy, monoalkylamino, dialkylamino, arylalkyl, cyano, or nitro; and R3 represents optionally substituted alkylamino, optionally substituted arylamino, or optionally substituted cyclic amino, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising them as an active ingredient. The compound of the present invention is useful as a TGF-β inhibitor.

  本发明提供了由下式[1]表示的酰胺衍生物： 其中n代表0或1；X代表CR4或N；Y代表CR6或N；Z代表CR7或N；R1和R2可以相同或不同，各自代表氢、任选取代的烷基、酰基、任选取代的芳基或任选取代的芳杂环基团；R4、R5、R6 和 R7 可以相同或不同，各自代表氢、卤素、羟基、氨基、烷基、卤代烷基、烷氧基、单烷基氨基、二烷基氨基、芳基烷基、氰基或硝基；以及 R3 代表任选取代的烷基氨基、任选取代的芳基氨基或任选取代的环氨基，或其药学上可接受的盐，以及包含它们作为活性成分的药物组合物。 本发明的化合物可用作 TGF-β 抑制剂。
• CELL AGGREGATION INCLUDING OLFACTORY NEURON OR PRECURSOR CELL THEREOF, AND METHOD FOR PRODUCING SAME
  申请人：SUMITOMO CHEMICAL COMPANY LIMITED

  公开号：EP3842527A1

  公开（公告）日：2021-06-30

  A method for producing a cell cluster including an olfactory receptor neuron or a precursor cell thereof, comprising the following steps (1) to (3): step (1) of suspension-culturing a pluripotent stem cell in the presence of a Wnt signaling pathway inhibitory substance to form a cell aggregate; step (2) of suspension-culturing the cell aggregate obtained in the step (1) in the presence of a BMP signaling pathway-activating substance; and step (3) of suspension-culturing the cell aggregate obtained in the step (2) to obtain the cell cluster, wherein step (3) comprises at least one step selected from the group consisting of: step (3a) of suspension-culturing in the presence of an FGF signaling pathway-activating substance; step (3b) of suspension-culturing in the presence of a BMP signaling pathway inhibitory substance; and step (3c) of culturing in the presence of an FGF signaling pathway-activating substance and a BMP signaling pathway inhibitory substance.

  一种生产包括嗅觉受体神经元或其前体细胞的细胞团的方法，包括以下步骤(1)至(3)：步骤(1)在Wnt信号通路抑制物质存在下悬浮培养多能干细胞以形成细胞聚集体；步骤(2)在BMP信号通路激活物质存在下悬浮培养步骤(1)中获得的细胞聚集体；以及步骤(3)悬浮培养步骤(2)中获得的细胞聚集体以获得细胞簇，其中步骤(3)包括至少一个选自由以下组成的组的步骤：在 FGF 信号通路激活物质存在下进行悬浮培养的步骤(3a)； 在 BMP 信号通路抑制物质存在下进行悬浮培养的步骤(3b)；以及 在 FGF 信号通路激活物质和 BMP 信号通路抑制物质存在下进行培养的步骤(3c)。
• UCP-1 expression promoter
  申请人：Kao Corporation

  公开号：US10758519B2

  公开（公告）日：2020-09-01

  It is intended to provide a drug, a quasi-drug, a dermatological preparation for external use, or a material to be contained to drugs, quasi-drugs, dermatological preparations for external use, food products, or the like which has an excellent UCP-1 expression-promoting action and promotes conversion of adipose to brown adipose (browning). The present invention provides a UCP-1 expression promoter comprising a PPARγ activator and a Smad3 inhibitor in combination. The present invention also provides a UCP-1 expression promoter comprising a PPARγ activator, a Smad3 inhibitor, and a β3 adrenaline receptor activator or a TGR5 activator in combination.

  本发明旨在提供一种药物、准药物、外用皮肤病制剂，或一种可包含在药物、准药物、外用皮肤病制剂、食品或类似物中的材料，该材料具有良好的 UCP-1 表达促进作用，可促进脂肪向棕色脂肪转化（褐变）。本发明提供了一种由 PPARγ 激活剂和 Smad3 抑制剂组合而成的 UCP-1 表达促进剂。本发明还提供了一种由 PPARγ 激活剂、Smad3 抑制剂和 β3肾上腺素受体激活剂或 TGR5 激活剂组合而成的 UCP-1 表达启动子。