(3R)-3-[(4-methoxyphenyl)methoxy]-4-phenylmethoxybutanoic acid | 1160697-54-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (3R)-3-[(4-methoxyphenyl)methoxy]-4-phenylmethoxybutanoic acid
• CAS: 1160697-54-0
• 化学式: C₁₉H₂₂O₅
• 分子量: 330.381
• InChiKey: RLPQTAGVYAGVIH-GOSISDBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  24
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  65
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3R)-3-[(4-methoxyphenyl)methoxy]-4-phenylmethoxybutanoic acid 在 咪唑 、 potassium permanganate 、 sodium periodate 、 2,4,6-三氯苯甲酰氯 、 水 、 氟化氢吡啶 、 三乙胺 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 、 叔丁醇 为溶剂， 反应 37.0h， 生成 (1R,3R,4R,5S,9R,13R)-9-((benzyloxy)methyl)-3-(4-(3-(benzyloxy)phenyl)butyl)-4,16,16-trimethyl-2,6,10,17-tetraoxatricyclo[11.3.1.1^1,5]octadecane-7,11-dione
  参考文献：
  名称：

  Structure–Activity Studies on the Spiroketal Moiety of a Simplified Analogue of Debromoaplysiatoxin with Antiproliferative Activity

  摘要：

  Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (delta, eta and theta) with subnanomolar K-i values, approximately 10-20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryostatins.

  DOI：

  10.1021/jm300566h
• 作为产物：
  描述：

  (3R)-4-benzyloxy-3-(4-methoxy-benzyloxy)-butyraldehyde 在 sodium chlorite 、 2-甲基-2-丁烯 作用下， 以 水 、 叔丁醇 为溶剂， 反应 0.25h， 以62%的产率得到(3R)-3-[(4-methoxyphenyl)methoxy]-4-phenylmethoxybutanoic acid
  参考文献：
  名称：

  Nakagawa, Yu; Yanagita, Ryo C.; Hamada, Naoko, Journal of the American Chemical Society, 2009, vol. 131, p. 7573 - 7579

  摘要：

  DOI：

文献信息

• Synthesis and biological activities of simplified aplysiatoxin analogs focused on the CH/π interaction
  作者：Takumi Kobayashi、Ryo C. Yanagita、Kazuhiro Irie

  DOI：10.1016/j.bmcl.2020.127657

  日期：2020.12

  Debromoaplysiatoxin (DAT) is a potent protein kinase C (PKC) activator with tumor-promoting and pro-inflammatory activities. Irie and colleagues have found that 10-methyl-aplog-1 (1), a simplified analog of DAT, has strong anti-proliferative activity against several cancer cell lines with few adverse effects. Therefore, 1 is a potential lead compound for cancer therapy. We synthesized a new derivative

  Debromoaplysiatoxin（DAT）是一种有效的蛋白激酶C（PKC）激活剂，具有促肿瘤和促炎作用。Irie和同事发现10-methyl-aplog-1（1）是DAT的简化类似物，对几种癌细胞系具有很强的抗增殖活性，几乎没有不良反应。因此，1是用于癌症治疗的潜在先导化合物。我们合成了一种新的衍生物2，该衍生物在侧链末端位置具有一个萘环而不是苯环，以增加CH /π与PKCδ-C1B结构域的Pro-241的相互作用。基于的合成路线上1，2由6-羟基-1-萘甲酸以26个线性步骤聚合合成总收率为0.18％。虽然抗增殖活性2比的更有效1，结合效力2到PKCδ-C1B域没有超过的1。分子动力学模拟表明2具有同时形成氢键和与PKCδ-C1B结构域的CH /π相互作用的能力。着眼于氢键，它们在涉及CH /π相互作用的结合模式中的几何形状似乎不是最理想的，这可以解释2的亲和力比1略低。这项研究可能
• Synthesis and Biological Evaluation of the 12,12-Dimethyl Derivative of Aplog-1, an Anti-Proliferative Analog of Tumor-Promoting Aplysiatoxin
  作者：Yu NAKAGAWA、Masayuki KIKUMORI、Ryo C. YANAGITA、Akira MURAKAMI、Harukuni TOKUDA、Hiroshi NAGAI、Kazuhiro IRIE

  DOI：10.1271/bbb.110130

  日期：2011.6.23

  Aplog-1 is a unique analog of tumor-promoting aplysiatoxin that inhibits tumor-promotion by phorbol diesters and proliferation of tumor cells. While the structural features relevant to the biological activities of Aplog-1 remain to be identified, recent studies by us have suggested that local hydrophobicity around the spiroketal moiety of Aplog-1 is a crucial determinant of its anti-proliferative activity. This hypothesis led us to design 12,12-dimethyl-Aplog-1 (3), in which a hydrophobic geminal dimethyl group is installed proximal to the spiroketal moiety to improve biological potency. As expected, 3 was more effective than Aplog-1 in inhibiting cancer cell growth and binding to protein kinase Cδ, a putative receptor responsible for the biological response of Aplog-1. Moreover, an induction test on Epstein-Barr virus early antigen demonstrated 3 to be a better anti-tumor promoter than Aplog-1. These results indicate that 3 is a superior derivative of Aplog-1, and thus a more promising lead for anti-cancer drugs.

  Aplog-1是一种独特的促肿瘤阿普唑啉类似物，它能抑制磷酸二酯对肿瘤的促进作用和肿瘤细胞的增殖。虽然与 Aplog-1 生物活性相关的结构特征仍有待确定，但我们最近的研究表明，Aplog-1 的螺酮分子周围的局部疏水性是决定其抗增殖活性的关键因素。根据这一假设，我们设计出了 12,12-二甲基-Aplog-1（3），其中在螺旋酮基的近端安装了一个疏水性二甲基基团，以提高生物效力。不出所料，3 在抑制癌细胞生长和与蛋白激酶 Cδ 结合方面比 Aplog-1 更有效，蛋白激酶 Cδ 是 Aplog-1 生物反应的受体。此外，对 Epstein-Barr 病毒早期抗原的诱导测试表明，3 比 Aplog-1 具有更好的抗肿瘤促进作用。这些结果表明，3 是 Aplog-1 的高级衍生物，因此更有希望成为抗癌药物的先导。
• JP6170908
  申请人：——

  公开号：——

  公开（公告）日：——
• Synthesis and Biological Activities of Acetal Analogs at Position 3 of 10-Methyl-Aplog-1, a Potential Anti-Cancer Lead Derived from Debromoaplysiatoxin
  作者：Kazuhiro Irie、Koutaro Hayakawa、Yusuke Hanaki、Harukuni Tokuda、Ryo C. Yanagita、Yu Nakagawa、Mutsumi Okamura、Shingo Dan

  DOI：10.3987/com-18-s(t)37

  日期：——

  10-Methyl-Aplog-1 (1), a simplified analog of tumor-promoting debromoaplysiatoxin (DAT), is a potential anti-cancer lead because, unlike DAT, 1 is not tumor-promoting or proinflammatory. However, its synthesis required 23 linear steps with an overall yield of 1.1%. To develop a more synthetically accessible compound, we designed a new analog (2) whose carbon atom at position 4 was replaced with an oxygen atom. Simultaneous construction of the spiroketal at position 7, the acetal at position 3, and the macrolactone ring enabled us to reduce the synthetic steps to produce 2 and its 3-epimer (16) in 18 linear steps with overall yields of 0.30 and 0.67% respectively. Although both analogs retained anti-proliferative activity, it was weaker than that of 1.