Zhang Han-Zhong, Kasibhatla Shailaja, Wang Yan, Herich John, Guastella John, Tseng Ben, Drewe John, Cai Sui Xiong
Maxim Pharmaceuticals, Inc., 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
Bioorg Med Chem. 2004 Jan 15;12(2):309-17. doi: 10.1016/j.bmc.2003.11.013.
Gambogic acid (2), a natural product isolated from the resin of Garcinia hurburyi tree, was discovered to be a potent apoptosis inducer using our cell- and caspase-based high-throughput screening assays. Gambogic acid was found to have an EC(50) of 0.78 microM in the caspase activation assay in T47D breast cancer cells. The apoptosis-inducing activity of gambogic acid was further characterized by a nuclear fragmentation assay and flow cytometry analysis in human breast tumor cells T47D. Gambogic acid was found to induce apoptosis independent of cell cycle, which is different from paclitaxel that arrests cells in the G2/M phase. To understand the structure-activity relationship (SAR) of gambogic acid, derivatives of 2 with modifications to different function groups were prepared. SAR studies of gambogic acid, as measured by the caspase activation assay, showed that the 9,10 carbon-carbon double bond of the alpha,beta-unsaturated ketone is important for biological activity, while the 6-hydroxy and 30-carboxy group can tolerate a variety of modifications. The importance of the 9,10 carbon-carbon double bond was confirmed by the traditional growth inhibition assay. The high potency of 2 as an inducer of apoptosis, its novel mechanism of action, easy isolation and abundant supply, as well as the fact that it is amenable to chemical modification, makes gambogic acid an attractive molecule for the development of anticancer agents.
藤黄酸（2）是从藤黄树树脂中分离得到的一种天然产物，通过我们基于细胞和半胱天冬酶的高通量筛选试验，发现它是一种有效的凋亡诱导剂。在T47D乳腺癌细胞的半胱天冬酶激活试验中，藤黄酸的EC(50)为0.78微摩尔。通过核碎裂试验和流式细胞术分析，在人乳腺肿瘤细胞T47D中进一步表征了藤黄酸的凋亡诱导活性。发现藤黄酸诱导凋亡与细胞周期无关，这与使细胞停滞在G2/M期的紫杉醇不同。为了了解藤黄酸的构效关系（SAR），制备了对不同官能团进行修饰的2的衍生物。通过半胱天冬酶激活试验测定的藤黄酸的SAR研究表明，α,β-不饱和酮的9,10碳-碳双键对生物活性很重要，而6-羟基和30-羧基可以耐受多种修饰。传统的生长抑制试验证实了9,10碳-碳双键的重要性。2作为凋亡诱导剂的高效性、其新颖的作用机制、易于分离和丰富的供应，以及它适合化学修饰这一事实，使得藤黄酸成为开发抗癌药物的一个有吸引力的分子。
