Sayed Khalid A El, Khanfar Mohammad A, Shallal Hassan M, Muralidharan A, Awate Bhushan, Youssef Diaa T A, Liu Yang, Zhou Yu-Dong, Nagle Dale G, Shah Girish
Department of Basic Pharmaceutical Sciences, University of Louisana, Monroe, Louisana 71209, USA.
J Nat Prod. 2008 Mar;71(3):396-402. doi: 10.1021/np070587w. Epub 2008 Feb 26.
The marine-derived macrolides latrunculins A ( 1) and B, from the Red Sea sponge Negombata magnifica, have been found to reversibly bind actin monomers, forming a 1:1 complex with G-actin and disrupting its polymerization. The microfilament protein actin is responsible for several essential functions within the cell such as cytokinesis and cell migration. One of the main binding pharmacophores of 1 to G-actin was identified as the C-17 lactol hydroxyl moiety that binds arginine 210 NH. Latrunculin A-17- O-carbamates 2- 6 were prepared by reaction with the corresponding isocyanates. Latrunculin A ( 1) and carbamates 4- 6 displayed potent anti-invasive activity against the human highly metastatic human prostate cancer PC-3M cells in a Matrigel assay at a concentration range of 50 nM to 1 microM. Latrunculin A ( 1, 500 nM) decreased the disaggregation and cell migration of PC-3M-CT+ spheroids by 3-fold. Carbamates 4 and 5 were 2.5- and 5-fold more active than 1, respectively, in this assay with less actin binding affinity. Latrunculin A ( 1, IC 50 6.7 microM) and its 17- O-[ N-(benzyl)carbamate ( 6, IC 50 29 microM) suppress hypoxia-induced HIF-1 activation in T47D breast tumor cells.
从红海海绵Negombata magnifica中提取的海洋来源大环内酯类化合物拉春库林A（1）和B，已被发现可与肌动蛋白单体可逆结合，与G-肌动蛋白形成1:1复合物并破坏其聚合。微丝蛋白肌动蛋白负责细胞内的多种重要功能，如胞质分裂和细胞迁移。1与G-肌动蛋白的主要结合药效基团之一被确定为与精氨酸210 NH结合的C-17内酯羟基部分。通过与相应的异氰酸酯反应制备了拉春库林A - 17 - O - 氨基甲酸酯2 - 6。在基质胶实验中，拉春库林A（1）和氨基甲酸酯4 - 6在50 nM至1 μM的浓度范围内对人高转移性前列腺癌PC - 3M细胞显示出强大的抗侵袭活性。拉春库林A（1，500 nM）使PC - 3M - CT + 球体的解体和细胞迁移减少了3倍。在该实验中，氨基甲酸酯4和5的活性分别比1高2.5倍和5倍，但其肌动蛋白结合亲和力较低。拉春库林A（1，IC50 6.7 μM）及其17 - O - [N - （苄基）氨基甲酸酯（6，IC50 29 μM）可抑制T47D乳腺肿瘤细胞中缺氧诱导的HIF - 1激活。
