Studies on Chemical Structure Modification and Structure?Activity Relationship of Derivatives of Gambogic Acid at C(39)
Studies on Chemical Structure Modification and Structure?Activity Relationship of Derivatives of Gambogic Acid at C(39)
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DOI：
10.1002/cbdv.201100415
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发表时间：
2012-08-01
影响因子：
2.9
通讯作者：
You, Qi-Dong
中科院分区：
文献类型：
--
作者：
Sun, Hao-Peng;Liu, Zong-Liang;You, Qi-Dong
天然产物藤黄酸在抑制癌细胞系方面表现出高效力。对藤黄酸进行合理的药物修饰，可改善其理化性质和类药性。去调查结构？为了研究藤黄酸的活性关系，寻找其化学骨架上合理的修饰位置，我们设计、合成并表征了16个在C（39）位进行修饰的藤黄酸衍生物。结构？活性关系（SAR）。通过A549、BGC 823、U251、HepG 2和MDA-MB-231癌细胞系的MTT（=3-（4，5-二甲基噻唑-2-基）-2，5-二苯基-2H-溴化四唑）测定获得抗增殖数据。所合成的化合物大多表现出较强的抑制作用。SAR研究表明，在C（39）的脂肪族氨基部分的衍生物比那些与其他取代基更有效。C（39）位置可以进行不同种类的化学修饰而不会导致活性丧失。化合物4和6可作为潜在的先导化合物用于进一步开发新的抗癌药物。
The natural product gambogic acid exhibits high potency in inhibiting cancer cell lines. Rational medicinal modifications on gambogic acid will improve its physicochemical properties and drug-like characters. To investigate the structure?activity relationship of gambogic acid and also to find rational modification position on its chemical skeleton, we designed, synthesized, and characterized 16 derivatives of gambogic acid that were modified at C(39). The structure?activity relationships (SARs) were discussed. The anti-proliferation data were accquired through MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assays of A549, BGC823, U251, HepG2, and MDA-MB-231 cancer cell lines. Most of the synthesized compounds showed strong inhibitory effects. The SAR study revealed that derivatives with aliphatic amino moieties at C(39) were more potent than those with other substituents. The C(39) position can undergo different kinds of chemical modifications without leading to loss of activity. Compounds 4 and 6 can serve as potential lead compounds for further development of new anticancer drugs.