Influence of rhamnose substituents on the potency of SL0101, an inhibitor of the Ser/Thr kinase, RSK

We have previously reported the isolation of kaempferol 3-O-(3″,4″-di-O-acetyl-α-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 μM. In intact cells, however, the EC₅₀ for inhibition of RSK activity is 50 μM, 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-α-l-rhamnopyranoside) (Bu-SL0101) and kaempferol 3-O-(2″,3″,4″-tri-O-acetyl-α-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 ∼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.