Heteroatom-substituted analogues of orphan nuclear receptor small heterodimer partner ligand and apoptosis inducer (E)-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid.
Heteroatom-substituted analogues of orphan nuclear receptor small heterodimer partner ligand and apoptosis inducer (E)-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid.
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孤儿核受体小异二聚体伴侣配体和凋亡诱导剂 (E)-4-[3-(1-金刚烷基)-4-羟基苯基]-3-氯肉桂酸的杂原子取代类似物。
DOI：
10.1021/jm200051z
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发表时间：
2011
影响因子：
7.3
通讯作者：
Dawson,MarciaI
中科院分区：
文献类型：
--
作者：
Xia,Zebin;Farhana,Lulu;Correa,RicardoG;Das,JayantaK;Castro,DavidJ;Yu,Jinghua;Oshima,RobertG;Reed,JohnC;Fontana,JosephA;Dawson,MarciaI
3-氯-(E)-4-[3′-(1-Adamantyl)-4′-hydroxyphenyl]-3-chlorocinnamic酸(3-Cl-AHPC)诱导癌细胞周期停滞和凋亡。由于其药理性质、溶解性、生物利用度和毒性需要改进翻译，因此对其进行了结构修饰，在肉桂环上引入氮原子，并将其E-双键替换为(X=O、N和S)，目的是在不影响诱导细胞凋亡的情况下增强这些性质。具有与肉桂基苯环相对应的杂环中氮原子的类似物具有相同或更高的生物活性。嘧啶和吡啶类似物在磷酸盐缓冲盐水和水中都更易溶解。2，5-二取代吡啶类似物是诱导KG-1急性髓系白血病细胞凋亡的最强诱导剂，而根据KG-1细胞的凋亡活性和溶解性，2，5-二取代嘧啶被证明是治疗急性髓系白血病更有前途的候选药物。
(E)-4-[3′-(1-Adamantyl)-4′-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell cycle arrest and apoptosis of cancer cells. Because its pharmacologic propertiessolubility, bioavailability, and toxicityrequired improvement for translation, structural modifications were made by introducing nitrogen atoms into the cinnamyl ring and replacing itsE-double bond with XCH2(X = O, N, and S) with the objective of enhancing these properties without impacting apoptosis-inducing activity. Analogues having nitrogen atoms in heterocyclic rings corresponding to the cinnamyl phenyl ring displayed equal or higher biological activities. The pyrimidine and pyridine analogues were more soluble in both phosphate-buffered saline and water. While the 2,5-disubstituted pyridine analogue was the most potent inducer of KG-1 acute myeloid leukemia cell apoptosis, on the basis of apoptotic activity in KG-1 cells and solubility, the 2,5-disubstituted pyrimidine proved to be the more promising candidate for treatment of acute myeloid leukemia.