(Z)-1,1,1-trifluoro-4-hydroxy-4-(4-methoxyphenyl)but-3-en-2-one | 910303-55-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: (Z)-1,1,1-trifluoro-4-hydroxy-4-(4-methoxyphenyl)but-3-en-2-one
• 英文别名: (Z)-1,1,1-trifluoro-4-hydroxy-4-(4-methoxyphenyl)-3-buten-2-one；(2Z)-1,1,1-Trifluoro-4-(4-methoxyphenyl)-4-oxobut-2-en-2-olate
• CAS: 910303-55-8
• 化学式: C₁₁H₉F₃O₃
• 分子量: 246.186
• InChiKey: XTRRSNPVYBZKEW-TWGQIWQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (Z)-1,1,1-trifluoro-4-hydroxy-4-(4-methoxyphenyl)but-3-en-2-one 在 盐酸 、 氯化亚砜 作用下， 以 乙醇 为溶剂， 反应 23.5h， 生成 methyl 4-(5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate
  参考文献：
  名称：

  Structure–Activity Relationships of UTX-121 Derivatives for the Development of Novel Matrix Metalloproteinase-2/9 Inhibitors

  摘要：

  塞来昔布是一种非甾体抗炎药，据报道具有抗肿瘤和抗转移活性，有潜力应用于癌症治疗。基质金属蛋白酶（MMP）-2/9的表达与癌症恶性程度密切相关，抑制这些MMP被认为能有效增强药物的抗肿瘤和抗转移效果。我们之前揭示了UTX-121（将塞来昔布的磺酰胺转化为甲酯）比塞来昔布具有更强的MMP-2/9抑制活性。基于这些发现，我们以UTX-121为先导化合物，通过构效关系（SAR）研究鉴定出具有改善MMP抑制活性的化合物。其中，化合物9c和10c，将苯环上的甲基替换为氯或氟，显示出比UTX-121更显著的抗肿瘤活性，并抑制了MMP-2/9的表达以及前体MMP-2的激活。我们的发现表明，化合物9c和10c可能是开发针对MMP的更有效抗肿瘤药物的有力先导化合物。

  DOI：

  10.1248/cpb.c21-00549
• 作为产物：
  描述：

  三氟乙酸乙酯 、 对甲氧基苯乙酮 以 甲基叔丁基醚 、 mineral oil 为溶剂， 反应 3.5h， 以89%的产率得到(Z)-1,1,1-trifluoro-4-hydroxy-4-(4-methoxyphenyl)but-3-en-2-one
  参考文献：
  名称：

  Structure–Activity Relationships of UTX-121 Derivatives for the Development of Novel Matrix Metalloproteinase-2/9 Inhibitors

  摘要：

  塞来昔布是一种非甾体抗炎药，据报道具有抗肿瘤和抗转移活性，有潜力应用于癌症治疗。基质金属蛋白酶（MMP）-2/9的表达与癌症恶性程度密切相关，抑制这些MMP被认为能有效增强药物的抗肿瘤和抗转移效果。我们之前揭示了UTX-121（将塞来昔布的磺酰胺转化为甲酯）比塞来昔布具有更强的MMP-2/9抑制活性。基于这些发现，我们以UTX-121为先导化合物，通过构效关系（SAR）研究鉴定出具有改善MMP抑制活性的化合物。其中，化合物9c和10c，将苯环上的甲基替换为氯或氟，显示出比UTX-121更显著的抗肿瘤活性，并抑制了MMP-2/9的表达以及前体MMP-2的激活。我们的发现表明，化合物9c和10c可能是开发针对MMP的更有效抗肿瘤药物的有力先导化合物。

  DOI：

  10.1248/cpb.c21-00549

文献信息

• 2-Hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide (DRF-4367): an orally active COX-2 inhibitor identified through pharmacophoric modulation
  作者：Sunil Kumar Singh、Saibaba Vobbalareddy、Srinivasa Rao Kalleda、Shaikh Abdul Rajjak、Seshagiri Rao Casturi、Srinivasa Raju Datla、Rao N. V. S. Mamidi、Ramesh Mullangi、Ravikanth Bhamidipati、Rajagopalan Ramanujam、Venkateswarlu Akella、Koteswar Rao Yeleswarapu

  DOI：10.1039/b402787f

  日期：——

  Analogs of 1,5-diarylpyrazoles with a novel pharmacophore at N1 were designed, synthesized and evaluated for the in-vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The variations at/around position-4 of the C-5 phenyl ring in conjunction with a CF3 and CHF2 groups at C-3 exhibited a high degree of potency and selectivity index (SI) for COX-2 inhibition. The in-vivo evaluation of these potent compounds with a few earlier ones indicated the 4-OMe-phenyl analog 6 and the 4-NHMe-phenyl analog 9 with a CF3, and the 4-OEt-phenyl analog 19 with a CHF2 group at C-3 to possess superior potency than celecoxib. In addition to its impressive anti-inflammatory, antipyretic, analgesic and anti-arthritic properties, compound 6 (DRF-4367) was found to possess an excellent pharmacokinetic profile, gastrointestinal (GI) safety in the long-term arthritis study and COX-2 potency in human whole blood assay. Thus, compound 6 was selected as an orally active anti-inflammatory candidate for pre-clinical evaluation.

  在N1位含有新颖药效团的1,5-二芳基吡唑类类似物被设计、合成并对体外环氧合酶（COX-1/COX-2）抑制活性进行了评估。在C-5苯环的4位及其周围的变异与C-3位的CF3和CHF2基团结合，展现出高度的效力和选择性指数（SI），用于COX-2抑制。这些强效化合物的体内评估与先前的一些化合物相比，显示4-OMe-苯基类似物6和4-NHMe-苯基类似物9（C-3位含CF3），以及4-OEt-苯基类似物19（C-3位含CHF2）对COX-2的抑制效力超过了塞来昔布。除了出色的抗炎、解热、镇痛和抗关节炎特性外，化合物6（DRF-4367）被发现具有优秀的药代动力学特性，长期关节炎研究中的胃肠道安全性，以及在人体全血检测中的COX-2效力。因此，化合物6被选为口服活性的抗炎候选物进行临床前评估。
• Synthesis and Biological Evaluation of Salicylic Acid Analogues of Celecoxib as a New Class of Selective Cyclooxygenase-1 Inhibitor
  作者：Sung-Hwa Yoon、Duk-Yeon Cho、Seoung-ryoung Choi、Joo-young Lee、Dong-Kug Choi、Eunha Kim、Ju-Young Park

  DOI：10.1248/bpb.b20-00991

  日期：2021.9.1

  A series of salicylic acid analogues of celecoxib where the phenylsulfonamide moiety in the structure of celecoxib is replaced by salicylic acid moiety was synthesized and tested for in vitro cyclooxygenase (COX)-1 and COX-2 enzyme inhibition. Among the series, 5-substituted-2-hydroxy-benzoic acid analogues (7a–7h) generally showed better inhibitory activities on both enzymes than 4-substituted-2-hydroxy-benzoic acid analogues (12a–12h). In particular, the chloro analogue 7f which had the highest inhibitory effect (IC50 = 0.0057 µM) to COX-1 with excellent COX-1 selectivity (SI = 768) can be classified as a new potent and selective COX-1 inhibitor. The high inhibitory potency of 7f was rationalized through the docking simulation of this analogue in the active site of COX-1 enzyme.

  一系列塞来昔布的水杨酸类似物被合成并测试了它们对体外环氧合酶（COX）-1和COX-2酶的抑制作用，这些类似物在结构上用水杨酸部分替代了塞来昔布的苯磺酰胺部分。在这一系列化合物中，5-取代-2-羟基苯甲酸类似物（7a–7h）通常比4-取代-2-羟基苯甲酸类似物（12a–12h）对这两种酶显示出更好的抑制活性。特别是氯代类似物7f，它对COX-1的抑制效果最高（IC50 = 0.0057 µM），并具有极佳的COX-1选择性（SI = 768），可被归类为一种新型强效且选择性的COX-1抑制剂。7f的高抑制效力通过将该类似物对接模拟到COX-1酶的活性位点得到了合理解释。
• Singh, Sunil K.; Saibaba; Koteswar Rao, Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 5, p. 1115 - 1118
  作者：Singh, Sunil K.、Saibaba、Koteswar Rao

  DOI：——

  日期：——
• Modified reaction conditions to achieve high regioselectivity in the two component synthesis of 1,5-diarylpyrazoles
  作者：Sunil K. Singh、M. Srinivasa Reddy、S. Shivaramakrishna、D. Kavitha、R. Vasudev、J. Moses Babu、A. Sivalakshmidevi、Y. Koteswar Rao

  DOI：10.1016/j.tetlet.2004.08.100

  日期：2004.10

  The factors affecting regioselectivity during the formation of 1,5-diarylpyrazoles from aryl hydrazines and 1,3-diketones are identified and the regioisomers were characterized by 1D NOESY, LC-NMR and X-ray analyses. A simple alteration in the usual reaction conditions is reported, which allows the exclusive formation of 1,5-diarylpyrazoles. (C) 2004 Elsevier Ltd. All rights reserved.
• Structure–Activity Relationships of UTX-121 Derivatives for the Development of Novel Matrix Metalloproteinase-2/9 Inhibitors
  作者：Hirari Yamahana、Yuki Komiya、Takahisa Takino、Yoshio Endo、Hisatsugu Yamada、Chikako Asada、Yoshihiro Uto

  DOI：10.1248/cpb.c21-00549

  日期：2021.10.1

  Celecoxib, a nonsteroidal anti-inflammatory drug, has been reported to have antitumor and antimetastatic activities, and it has potential for application in cancer treatments. The expression of matrix metalloproteinase (MMP)-2/9 is strongly correlated with cancer malignancy, and inhibition of these MMPs is believed to be effective in improving the antitumor and antimetastatic effects of drugs. We have previously revealed that UTX-121, which converted the sulfonamide of celecoxib to methyl ester, has more potent MMP-2/9 inhibitory activity than celecoxib. Based on these findings, we identified compounds with improved MMP inhibitory activity through a structure–activity relationship (SAR) study, using UTX-121 as a lead compound. Among them, compounds 9c and 10c, in which the methyl group of the p-tolyl group was substituted for Cl or F, showed significantly higher antitumor activity than UTX-121, and suppressed the expression of MMP-2/9 and activation of pro MMP-2. Our findings suggest that compounds 9c and 10c may be potent lead compounds for the development of more effective antitumor drugs targeting MMP.

  塞来昔布是一种非甾体抗炎药，据报道具有抗肿瘤和抗转移活性，有潜力应用于癌症治疗。基质金属蛋白酶（MMP）-2/9的表达与癌症恶性程度密切相关，抑制这些MMP被认为能有效增强药物的抗肿瘤和抗转移效果。我们之前揭示了UTX-121（将塞来昔布的磺酰胺转化为甲酯）比塞来昔布具有更强的MMP-2/9抑制活性。基于这些发现，我们以UTX-121为先导化合物，通过构效关系（SAR）研究鉴定出具有改善MMP抑制活性的化合物。其中，化合物9c和10c，将苯环上的甲基替换为氯或氟，显示出比UTX-121更显著的抗肿瘤活性，并抑制了MMP-2/9的表达以及前体MMP-2的激活。我们的发现表明，化合物9c和10c可能是开发针对MMP的更有效抗肿瘤药物的有力先导化合物。