Semi-synthetic mithramycin derivatives with anti-cancer activity
Mithramycin derivatives and their pharmaceutically acceptable salts are disclosed. The mithramycin derivatives can be used in the treatment of Ewing sarcoma or other cancer or neuro-disease associated with an aberrant erythroblast transformation-specific transcription factor.
1. An MTM SA derivative having the following formula:
or a pharmaceutically acceptable salt thereof; wherein Z represents O, S, N—R′; R and R′ represent, for each occurrence, H, alkyl, heterocyclic, aryl, heteroaryl, provided that R is not H when Z is O; ZR taken together represents an organic residue; and wherein MTM 1 represents the fused ring portion of the mithramycin structure and can include different sugars or sugar chains.
2. The MTM SA derivative according to claim 1 having the following formula:
wherein R 1 and R 2 can be the same or different and each of R 1 and R 2 can be an H, an amino acid conjugate or an ester derivative thereof, a lower straight chain or branched alkyl unsubstituted or substituted with one or more amino, alkyl amino, alkylcarboxyl, alkoxyl, alkylcarbonyl, hydroxyl, thio, alkyldisulfide, halo, provided that R 1 and R 2 are not both H simultaneously.
3. The MTM SA derivative of claim 2 , wherein NR 1 R 2 form a phenylalanine (Phe) conjugate or an ester derivative thereof.
4. The MTM SA derivative of claim 2 , wherein NR 1 R 2 form a tryptophan (Trp) conjugate or an ester derivative thereof.
5. The MTM SA derivative of claim 3 wherein the phenylalanine is substituted with an indole alkyl group.
6. The MTM SA derivative of claim 4 wherein the tryptophan is substituted with a phenyl alkyl group.
7. A method of preparing the MTM SA derivative of claim 2 , the method comprising coupling the terminal carboxylic acid group of MTM SA with an amine.
8. A method of treating cancer or neuro-disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the MTM SA derivative or a pharmaceutically acceptable salt thereof of claim 1 .
9. The method of claim 8 , wherein the method comprises treating Ewing sarcoma.
10. The method of claim 8 , wherein the method comprises treating lung cancer.
11. The method of claim 8 , wherein the method comprises treating colon cancer.
12. The method of claim 9 wherein the MTM SA derivative is a substituted or unsubstituted MTM SA-Trp or an ester derivative thereof or a pharmaceutically acceptable salt thereof.
13. The method of claim 9 wherein the MTM SA derivative is a substituted or unsubstituted MTM SA-Phe or an ester derivative thereof or a pharmaceutically acceptable salt thereof.
14. A method for selectively modulating the activity of a target ETS transcription factor in a patient in need thereof, including administering to the patient a therapeutically effective amount of an MTM SA derivative or a pharmaceutically acceptable salt thereof of claim 2 .
15. The method of claim 14 , wherein the MTM SA derivative is a substituted or unsubstituted MTM SA-Phe or an ester derivative thereof or a pharmaceutically acceptable salt thereof.
16. The method of claim 14 , wherein the MTM SA derivative is a substituted or unsubstituted MTM SA-Trp or an ester derivative thereof or a pharmaceutically acceptable salt thereof.