Synthesis and identification of novel RSK-specific inhibitors
A composition comprising an SL0101 [kaempferol 3-O-(3″,4″-di-O-acetyl-α-L-rhamnopyranoside)] derivative compound that has enhanced ability to inhibit RSK activity, relative to the parent compound is provided. The compounds have utility for treating any disease or conditions characterized or associated with excess or undesirable RSK activity. For example the RSK inhibitors of the present invention can be used to reduce the proliferation of neoplastic cells or for inhibiting the establishment or maintenance of an intracellular pathogenic infection by pathogens whose pathogenicity derives in part from the pathogen's ability to impede endosomal/phagosomal maturation in the host cell.
1. A RSK inhibitor represented by the general structure of Formula III
wherein R 1 , R 3 and R 7 are each hydroxyl;
R 5 , R 6 , R 8 and R 9 are each hydrogen;
R 10 , R 11 and R 20 are independently selected from the group consisting of hydroxyl, —NHOCOR 14 , —OCOR 14 , —COR 14 and C 1 -C 4 alkoxy;
X is O or CH 2 ; and
R 14 is selected from the group consisting of hydrogen, and C 1 -C 4 alkyl.
2. The RSK inhibitor of claim 1 wherein
R 10 , R 11 and R 20 are independently selected from the group consisting of hydroxyl and —OCOR 14 , wherein at least one of R 10 , R 11 and R 20 is hydroxyl.
3. The RSK inhibitor of claim 2 wherein
one of R 10 and R 11 is —OCOCH 3 and the other is hydroxyl.
4. The RSK inhibitor of claim 1 wherein the inhibitor comprise the general structure of Formula IV:
wherein R 5 , R 6 , R 8 and R 9 are each hydrogen;
R 10 , R 11 and R 20 are independently selected from the group consisting of —OCOR 14 , —COR 14 and hydroxyl, and R 14 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl.
5. The RSK inhibitor of claim 4 wherein
at least one of R 10 , R 11 and R 20 is —OCOCH 3 , and at least one of R 10 , R 11 and R 20 is hydroxyl.
6. The RSK inhibitor of claim 5 wherein R 20 is OCOCH 3 , and one of R 10 and R 11 is OCOCH 2 , and the other is hydroxyl.
7. The RSK inhibitor of claim 4 wherein R 11 and R 20 are both OCOCH 3 , and R 10 is hydroxyl.
8. A pharmaceutical composition comprising a RSK specific inhibitor of claim 1 and a pharmaceutically acceptable carrier.
9. The composition of claim 8 , further comprising an anti-tumor agent.
10. A method of specifically inhibiting RSK activity, said method comprising the step of contacting a RSK enzyme with the RSK specific inhibitor of claim 1 .
11. A method for treating a disease or condition characterized by inappropriate RSK activation, said method comprising the step of administering to a human or other mammal in need thereof, a composition comprising the RSK specific inhibitor of claim 6 in an amount effective for specifically inhibiting RSK activity in the cells of said human or mammal.
12. The method of claim 11 wherein the disease is a neoplastic disease.
13. The method of claim 12 further comprising the step of administering to said patient in an anti-tumour therapy.