Smith Jeffrey A, Maloney David J, Clark David E, Xu Yaming, Hecht Sidney M, Lannigan Deborah A
Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA.
Bioorg Med Chem. 2006 Sep 1;14(17):6034-42. doi: 10.1016/j.bmc.2006.05.009. Epub 2006 May 24.
We have previously reported the isolation of kaempferol 3-O-(3'',4''-di-O-acetyl-alpha-l-rhamnopyranoside) from Forsteronia refracta [Xu, Y.-M.; Smith, J. A.; Lannigan, D. A.; Hecht, S. M. Biorg. Med. Chem.2006, 14, 3974-3977.]. This flavonoid glycoside, termed SL0101, is a specific inhibitor of p90 ribosomal S6 kinase (RSK) with a dissociation constant of 1 microM. In intact cells, however, the EC50 for inhibition of RSK activity is 50 microM, which suggests that the efficacy of SL0101 could be limited by cellular uptake. Therefore, we investigated the possibility of developing a more potent RSK inhibitor by synthesizing SL0101 analogs with increased hydrophobic character. The total syntheses of kaempferol 3-O-(3'',4''-di-O-butyryl-alpha-L-rhamnopyranoside) (Bu-SL0101) and kaempferol 3-O-(2'',3'',4''-tri-O-acetyl-alpha-L-rhamnopyranoside) (3Ac-SL0101) were performed. The IC50 for inhibition of RSK activity in in vitro kinase assays for the analogs was similar to that obtained for SL0101. 3Ac-SL0101 demonstrated the same remarkable specificity for inhibiting RSK activity in intact cells as SL0101; however, Bu-SL0101 was not completely specific. 3Ac-SL0101 was approximately 2-fold more potent at inhibiting MCF-7 cell proliferation compared to SL0101 and preferentially decreased MCF-7 cell growth, as compared to the growth of the normal human breast line, MCF-10A. Thus the discovery of 3Ac-SL0101 as a more potent RSK-specific inhibitor than SL0101 should facilitate the development of RSK inhibitors as anti-cancer chemotherapeutic agents.
我们之前曾报道过从扭序花（Forsteronia refracta）中分离出山柰酚3 - O -（3''，4'' - 二 - O - 乙酰基 - α - L - 鼠李吡喃糖苷）[徐，Y.-M.；史密斯，J. A.；兰尼根，D. A.；赫克特，S. M.《生物有机与药物化学》2006年，第14卷，3974 - 3977页]。这种黄酮糖苷，称为SL0101，是p90核糖体S6激酶（RSK）的特异性抑制剂，解离常数为1微摩尔。然而，在完整细胞中，抑制RSK活性的半数有效浓度（EC50）为50微摩尔，这表明SL0101的功效可能受细胞摄取的限制。因此，我们研究了通过合成具有增加疏水特性的SL0101类似物来开发更有效的RSK抑制剂的可能性。进行了山柰酚3 - O -（3''，4'' - 二 - O - 丁酰基 - α - L - 鼠李吡喃糖苷）（Bu - SL0101）和山柰酚3 - O -（2''，3''，4'' - 三 - O - 乙酰基 - α - L - 鼠李吡喃糖苷）（3Ac - SL0101）的全合成。在体外激酶测定中，这些类似物抑制RSK活性的半数抑制浓度（IC50）与SL0101的相似。3Ac - SL0101在完整细胞中抑制RSK活性表现出与SL0101相同的显著特异性；然而，Bu - SL0101并非完全特异性。与SL0101相比，3Ac - SL0101在抑制MCF - 7细胞增殖方面效力约高2倍，并且与正常人乳腺细胞系MCF - 10A的生长相比，优先降低MCF - 7细胞的生长。因此，发现3Ac - SL0101作为一种比SL0101更有效的RSK特异性抑制剂，应该会促进RSK抑制剂作为抗癌化疗药物的开发。
