Mu Fanrong, Hamel Ernest, Lee Debbie J, Pryor Donald E, Cushman Mark
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 2003 Apr 24;46(9):1670-82. doi: 10.1021/jm020292+.
Compounds in the lavendustin A series have been shown to inhibit both protein-tyrosine kinases (PTKs) and tubulin polymerization. Since certain lavendustin A derivatives can exist in conformations that resemble both the trans-stilbene structure of the PTK inhibitor piceatannol and the cis-stilbene structure of the tubulin polymerization inhibitor combretastatin A-4, the possibility exists that the ratio of the two types of activities of the lavendustins could be influenced through the synthesis of conformationally restricted analogues. Accordingly, the benzylaniline structure of a series of pharmacologically active lavendustin A fragments was replaced by either their cis- or their trans-stilbene relatives, and effects on both inhibition of tubulin polymerization and cytotoxicity in cancer cell cultures were monitored. Both dihydrostilbene and 1,2-diphenylalkyne congeners were also prepared and evaluated biologically. Surprisingly, conformational restriction of the bridge between the two aromatic rings of the lavendustins had no significant effect on biological activity. On the other hand, conversion of the three phenolic hydroxyl groups of the lavendustin A derivatives to their corresponding methyl ethers consistently abolished their ability to inhibit tubulin polymerization and usually decreased cytotoxicity in cancer cell cultures as well, indicating the importance of at least one of the phenolic hydroxyl groups. Further investigation suggested that the phenolic hydroxyl group in the salicylamide ring was required for activity, while the two phenol moieties in the hydroquinone ring could be methylated with retention of activity. Two of the lavendustin A derivatives displayed IC(50) values of 1.4 microM for inhibition of tubulin polymerization, which ranks them among the most potent of the known tubulin polymerization inhibitors.
薰衣草色菌素A系列化合物已被证明能抑制蛋白酪氨酸激酶（PTK）和微管蛋白聚合。由于某些薰衣草色菌素A衍生物可能存在类似于PTK抑制剂白皮杉醇的反式芪结构和微管蛋白聚合抑制剂康普瑞汀A - 4的顺式芪结构的构象，因此有可能通过合成构象受限的类似物来影响薰衣草色菌素两种活性的比例。因此，一系列具有药理活性的薰衣草色菌素A片段的苄基苯胺结构被其顺式或反式芪类似物取代，并监测其对癌细胞培养中微管蛋白聚合抑制和细胞毒性的影响。还制备了二氢芪和1,2 - 二苯基炔同系物并进行了生物学评估。令人惊讶的是，薰衣草色菌素两个芳环之间桥的构象限制对生物活性没有显著影响。另一方面，将薰衣草色菌素A衍生物的三个酚羟基转化为相应的甲基醚，始终消除了它们抑制微管蛋白聚合的能力，并且通常也降低了癌细胞培养中的细胞毒性，这表明至少一个酚羟基很重要。进一步研究表明，水杨酰胺环中的酚羟基是活性所必需的，而对苯二酚环中的两个酚部分可以甲基化并保留活性。两种薰衣草色菌素A衍生物对微管蛋白聚合抑制的IC(50)值为1.4 microM，这使它们跻身已知最强效的微管蛋白聚合抑制剂之列。
