Department of Pharmacology, ‡Cancer Therapy & Research Center, and §Department of Medicine, University of Texas Health Science Center at San Antonio , San Antonio, Texas 78229, United States.
J Med Chem. 2014 Jul 24;57(14):6141-9. doi: 10.1021/jm500619j. Epub 2014 Jul 2.
The taccalonolides are microtubule stabilizers isolated from plants of the genus Tacca. Taccalonolide AF is 231 times more potent than the major metabolite taccalonolide A and differs only by the oxidation of the C-22,23 double bond in A to an epoxy group in AF. In the current study, 10 other rare natural taccalonolides were epoxidized and in each case epoxidation improved potency. The epoxidation products of taccalonolide T and AI were the most potent, with IC50 values of 0.43 and 0.88 nM, respectively. These potent taccalonolides retained microtubule stabilizing effects, and T-epoxide demonstrated antitumor effects in a xenograft model of breast cancer. Additional reactions demonstrated that reduction of the C-6 ketone resulted in an inactive taccalonolide and that C-22,23 epoxidation restored its activity. These studies confirm the value of C-22,23 epoxidation as an effective strategy for increasing the potency of a wide range of structurally diverse taccalonolide microtubule stabilizers.
塔卡醇内酯是从塔卡属植物中分离得到的微管稳定剂。塔卡醇内酯 AF 的活性比主要代谢产物塔卡醇内酯 A 高 231 倍，仅在 A 中 C-22、23 双键的氧化为 AF 中的环氧基团上有所不同。在本研究中，其他 10 种罕见的天然塔卡醇内酯被环氧化，在每种情况下，环氧化都提高了活性。塔卡醇内酯 T 和 AI 的环氧化产物活性最强，IC50 值分别为 0.43 和 0.88 nM。这些强效的塔卡醇内酯保留了微管稳定作用，并且 T-环氧化物在乳腺癌异种移植模型中表现出抗肿瘤作用。其他反应表明，C-6 酮的还原导致塔卡醇内酯失活，而 C-22、23 环氧化恢复了其活性。这些研究证实了 C-22、23 环氧化作为提高广泛结构多样的塔卡醇内酯微管稳定剂活性的有效策略的价值。
