Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aobayama, Sendai, Japan.
Bioorg Med Chem. 2010 Feb;18(3):1083-92. doi: 10.1016/j.bmc.2009.12.045. Epub 2009 Dec 23.
A series of novel analogues of 1,5-bis(4-hydroxy-3-methoxyphenyl)-penta-(1E,4E)-1,4-dien-3-one (C(5)-curcumin), which is a natural analogue of curcumin isolated from the rhizomes of Curcuma domestica Val. (Zingiberacea), were synthesized and evaluated for their cytotoxicities against human colon cancer cell line HCT-116 to conclude the SAR of C(5)-curcuminoids for further development of their use in cancer chemotherapy: (1) Bis(arylmethylidene)acetone serves as a promising skeleton for eliciting cytotoxicity. (2) The 3-oxo-1,4-pentadiene structure is essential for eliciting cytotoxicity. (3) As for the extent of the aromatic substituents, hexasubstituted compounds exhibit strong activities, in which 3,4,5-hexasubstitution results in the highest potency. (5) The symmetry between two aryl rings is not an essential requirement for bis(arylmethylidene)acetones to elicit cytotoxicity. (6) para-Positions allows the installation of additional functional groups for use as molecular probes. By taking advantage of the SAR diagram, we have elaborated several advanced derivatives having GI(50) of single-digit micromolar potencies that will function as molecular probes to target and/or report key biomolecules interacting with curcumin and C(5)-curcumin.
一系列新型的 1,5-双(4-羟基-3-甲氧基苯基)-戊-(1E,4E)-1,4-二烯-3-酮（C(5)-姜黄素）类似物，这是从姜黄根茎中分离出的天然姜黄素类似物（姜科），被合成并评估了它们对人结肠癌细胞系 HCT-116 的细胞毒性，以总结 C(5)-姜黄素类化合物的 SAR，以进一步开发其在癌症化疗中的应用：（1）双（芳基亚甲基）丙酮作为一种有前途的骨架，具有细胞毒性。（2）3-氧代-1,4-戊二烯结构是产生细胞毒性所必需的。（3）对于芳香取代基的程度，六取代化合物表现出很强的活性，其中 3,4,5-六取代化合物具有最高的活性。（5）两个芳环之间的对称性不是双（芳基亚甲基）丙酮产生细胞毒性的必要条件。（6）对位允许安装额外的官能团，用作分子探针。利用 SAR 图，我们已经精心设计了几种具有单位数微摩尔效力的 GI(50)的高级衍生物，它们将作为分子探针，用于靶向和/或报告与姜黄素和 C(5)-姜黄素相互作用的关键生物分子。
