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

Abstract

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.

• Authors: Jeffrey A Smith, David J Maloney, David E Clark, Yaming Xu, Sidney M Hecht, Deborah A Lannigan
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 14 Issue 17 Pg. 6034-42 (Sep 01 2006) ISSN: 0968-0896 [Print] England
• PMID: 16723233 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Benzopyrans
• Monosaccharides
• SL0101
• Ribosomal Protein S6 Kinases, 90-kDa
• Rhamnose

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Benzopyrans (chemistry, pharmacology)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Humans
• Molecular Structure
• Monosaccharides (chemistry, pharmacology)
• Rhamnose (chemistry)
• Ribosomal Protein S6 Kinases, 90-kDa (antagonists & inhibitors, metabolism)