2-phenyl-4-(3,4,5-trimethoxyphenyl)thiazole | 879424-69-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-phenyl-4-(3,4,5-trimethoxyphenyl)thiazole
• 英文别名: 2-phenyl-4-(3,4,5-trimethoxyphenyl)-1,3-thiazole
• CAS: 879424-69-8
• 化学式: C₁₈H₁₇NO₃S
• 分子量: 327.404
• InChiKey: JBOPRTWFFTWYIA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  68.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3',4',5'-三甲氧基苯乙酮 在 溴 作用下， 以 乙醇 为溶剂， 反应 2.0h， 生成 2-phenyl-4-(3,4,5-trimethoxyphenyl)thiazole
  参考文献：
  名称：

  4-取代甲氧基苯甲酰基-芳基-噻唑类似物的设计、合成和 SAR 研究作为有效和口服生物可利用的抗癌剂

  摘要：

  为了继续改进之前发表的 4-取代甲氧基苯甲酰基-芳基-噻唑 (SMART) 模板，我们探索了化学多样性的“B”环和“B”到“C”环的连接。此外，为了克服该系列试剂水溶性差的问题，我们引入了极性和可离子化的亲水基团以获得水溶性化合物。例如，基于体内药代动力学 (PK) 研究，设计并合成了一种口服生物可利用的苯基-氨基-噻唑 (PAT) 模板，其中在化合物1 的“A”和“B”环之间插入了一个氨基键. PAT 模板通过抑制微管蛋白聚合保持了对癌细胞系的纳摩尔 (nM) 范围效力，并且在体外不易受到 P-糖蛋白介导的多药耐药性的影响，与 SMART 模板相比，溶解度和生物利用度显着提高 ( 45a – c (PAT)与1（智能））。

  DOI：

  10.1021/jm2003427

文献信息

• [EN] COMPOUNDS FOR TREATMENT OF CANCER<br/>[FR] COMPOSÉS DESTINÉS AU TRAITEMENT DU CANCER
  申请人：GTX INC

  公开号：WO2011109059A1

  公开（公告）日：2011-09-09

  The present invention relates to novel compounds having anti-cancer activity, methods of making these compounds, and their use for treating cancer and drug-resistant tumors, e.g. melanoma, metastatic melanoma, drug resistant melanoma, prostate cancer and drug resistant prostate cancer.

  本发明涉及具有抗癌活性的新化合物，制备这些化合物的方法，以及它们用于治疗癌症和耐药肿瘤的用途，例如黑色素瘤、转移性黑色素瘤、耐药黑色素瘤、前列腺癌和耐药前列腺癌。
• Drug Metabolism and Pharmacokinetics of 4-Substituted Methoxybenzoyl-aryl-thiazoles
  作者：Chien-Ming Li、Yan Lu、Ramesh Narayanan、Duane D. Miller、James T. Dalton

  DOI：10.1124/dmd.110.034348

  日期：2010.11

  Tubulins are some of the oldest and most extensively studied therapeutic targets for cancer. Although many tubulin polymerizing and depolymerizing agents are known, the search for improved agents continues. We screened a class of tubulins targeting small molecules and identified 4-(3,4,5-trimethoxybenzoyl)-2-phenyl-thiazole (SMART-H) as our lead compound. SMART-H inhibited the proliferation of a variety of cancer cells in vitro, at subnanomolar IC50, and in vivo, in nude mice xenografts, with near 100% tumor growth inhibition. Metabolic stability studies with SMART-H in liver microsomes of four species (mouse, rat, dog, and human) revealed half-lives between <5 and 30 min, demonstrating an interspecies variability. The clearance predicted based on in vitro data correlated well with in vivo clearance obtained from mouse, rat, and dog in vivo pharmacokinetic studies. SMART-H underwent four major metabolic processes, including ketone reduction, demethylation, combination of ketone reduction and demethylation, and hydroxylation in human liver microsomes. Metabolite identification studies revealed that the ketone and the methoxy groups of SMART-H were most labile and that ketone reduction was the dominant metabolism reaction in human liver microsomes. We designed and tested four derivatives of SMART-H to improve the metabolic stability. The oxime and hydrazide derivatives, replacing the ketone site, demonstrated a 2- to 3-fold improved half-life in human liver microsomes, indicating that our prediction regarding metabolic stability of SMART-H can be extended by blocking ketone reduction. These studies led us to the next generation of SMART compounds with greater metabolic stability and higher pharmacologic potency.

  微管蛋白是癌症治疗中一些最古老、研究最广泛的靶点。虽然已知许多微管蛋白聚合和去聚合剂，但对改进剂量的搜索仍在继续。我们筛选了一类靶向微管蛋白的小分子，确定了4-(3,4,5-三甲氧基苯甲酰)-2-苯基噻唑（SMART-H）作为我们的主导化合物。SMART-H在体外以亚纳摩尔IC50抑制多种癌细胞的增殖，在裸鼠异种移植模型中则实现了近100%的肿瘤生长抑制。对SMART-H在四种物种（小鼠、老鼠、狗和人类）肝微粒体中的代谢稳定性研究显示其半衰期在<5到30分钟之间，表现出种间变异性。基于体外数据预测的清除率与从小鼠、老鼠和狗的体内药代动力学研究获得的体内清除率相关良好。SMART-H经历了四个主要代谢过程，包括酮还原、去甲基化、酮还原与去甲基化的结合以及在人体肝微粒体中的羟基化。代谢物鉴定研究表明，SMART-H的酮基和甲氧基是最易变的，其中酮还原是人体肝微粒体中主要的代谢反应。我们设计并测试了四种SMART-H的衍生物以提高其代谢稳定性。取代酮位的肟和氢肼衍生物在人体肝微粒体中显示出2到3倍的半衰期改善，表明我们关于SMART-H代谢稳定性的预测可以通过阻止酮还原来延伸。这些研究为我们带来了下一代SMART化合物，具有更大的代谢稳定性和更高的药效。
• COMPOUNDS FOR TREATMENT OF CANCER
  申请人：Lu Yan

  公开号：US20120071524A1

  公开（公告）日：2012-03-22

  The present invention relates to novel compounds having anti-cancer activity, methods of making these compounds, and their use for treating cancer and drug-resistant tumors, e.g. melanoma, metastatic melanoma, drug resistant melanoma, prostate cancer and drug resistant prostate cancer.

  本发明涉及具有抗癌活性的新化合物，制备这些化合物的方法以及它们用于治疗癌症和耐药肿瘤的应用，例如黑色素瘤、转移性黑色素瘤、耐药性黑色素瘤、前列腺癌和耐药性前列腺癌。
• Compounds for treatment of cancer
  申请人：ONCTERNAL THERAPEUTICS, INC.

  公开号：US11084811B2

  公开（公告）日：2021-08-10

  The present invention relates to novel compounds having anti-cancer activity, methods of making these compounds, and their use for treating cancer and drug-resistant tumors, e.g. melanoma, metastatic melanoma, drug resistant melanoma, prostate cancer and drug resistant prostate cancer.

  本发明涉及具有抗癌活性的新型化合物、制造这些化合物的方法及其用于治疗癌症和耐药性肿瘤（如黑色素瘤、转移性黑色素瘤、耐药性黑色素瘤、前列腺癌和耐药性前列腺癌）的用途。
• US8822513B2
  申请人：——

  公开号：US8822513B2

  公开（公告）日：2014-09-02