Wu Yue, Hu Mingyang, Yang Li, Li Xiang, Bian Jinlei, Jiang Fen, Sun Haopeng, You Qidong, Zhang Xiaojin
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Med Chem Lett. 2015 Jun 15;25(12):2584-8. doi: 10.1016/j.bmcl.2015.04.031. Epub 2015 Apr 18.
DDO-6101, a natural-product-like caged xanthone discovered previously in our laboratory based on the pharmacophoric scaffold of Garcinia natural product gambogic acid (GA), shows potent cytotoxicity in vitro but poor efficacy in vivo due to its poor druglike properties. In order to improve the druglike properties and in vivo cytotoxic potency, a novel series of 19 prenyl group-modified derivatives of DDO-6101 was synthesized and evaluated for their in vitro antitumor activity and druglike properties. The SAR and SPR information of these compounds was also obtained. In the light of the in vitro antitumor activity and druglike properties such as aqueous solubility and permeability, compound 6f (named as DDO-6306) was advanced into in vivo efficacy experiment. The results showed that DDO-6306 is more potent than DDO-6101 in vivo and is a promising antitumor candidate for further evaluation.
DDO-6101是一种天然产物样的笼状呫吨酮，此前我们实验室基于藤黄属天然产物藤黄酸（GA）的药效基团支架发现了它。它在体外显示出强大的细胞毒性，但由于其较差的类药性质，在体内的疗效不佳。为了改善类药性质和体内细胞毒性效力，合成了一系列19种新型的DDO-6101异戊烯基修饰衍生物，并对其体外抗肿瘤活性和类药性质进行了评估。还获得了这些化合物的构效关系（SAR）和表面等离子体共振（SPR）信息。根据体外抗肿瘤活性和诸如水溶性和渗透性等类药性质，化合物6f（命名为DDO-6306）进入体内疗效实验。结果表明，DDO-6306在体内比DDO-6101更有效，是一个有前景的有待进一步评估的抗肿瘤候选物。
