Mithramycin derivatives having increased selectivity and anti-cancer activity
Mithramycin side chain carboxylic acid (MTM-SA) derivative are provided, which include a substituted amino acid derivative, a substituted amino acid dipeptide derivative, or an unsubstituted dipeptide derivative. The MTM-SA derivatives are useful for treatment of cancer or neuro-diseases associated with an aberrant erythroblast transformation-specific transcription factor. Unique MTM-SA derivatives have increased selectively toward ETS transcription factor.
1. A mithramycin side chain carboxylic acid (MTM SA) derivative having the following formula:
MTM-SA-R′
or a pharmaceutically acceptable salt thereof, wherein R′ is
(a) a substituted tryptophan (Trp) or phenylalanine (Phe) derivative having a substitution on a phenyl or indole ring of the amino acid derivative, wherein the substitution is selected from the group consisting of lower alkyl, prenyl, aryl, alkylaryl, alkoxyl, nitro, halogen, and halocarbon;
(b) a substituted Trp, Phe, Trp-Phe, or Phe-Trp dipeptide derivative having a substitution on a phenyl or indole ring of the amino acid dipeptide derivative, wherein the substitution is selected from the group consisting of lower alkyl, prenyl, aryl, alkylaryl, alkoxyl, nitro, halogen, and halocarbon; or
(c) an unsubstituted Trp, Phe, Trp-Phe, or Phe-Trp dipeptide derivative.
2. The MTM-SA derivative of claim 1 , wherein R′ is a substituted tryptophan (Trp) derivative.
3. The MTM-SA derivative of claim 2 , having the following formula:
wherein X is selected from lower alkyl, prenyl, aryl, alkylaryl, alkoxyl, nitro, halogen, and halocarbon.
4. The MTM-SA derivative of claim 3 , wherein X is selected from methyl, allyl, O-allyl, prenyl, 5,6-benzo, benzyl, phenyl, phenyl-triazole, F, and CF 3 .
5. The MTM-SA derivative of claim 1 , selected from the formulae consisting of:
wherein R is selected from the group consisting of methyl, allyl, O-allyl, prenyl, benzyl, phenyl, phenyl-triazole, F, and CF 3 .
6. The MTM-SA derivative of claim 1 , having the following formula:
wherein R is selected from the group consisting of methyl, benzyl, allyl, and prenyl.
7. The MTM-SA derivative of claim 1 , having the following formula:
wherein R is selected from the group consisting of OMe, NO 2 , and O-allyl.
8. The MTM-SA derivative of claim 1 , having the following formula:
wherein R is selected from the group consisting of phenyl and allyl.
9. The MTM-SA derivative of claim 1 , having the following formula:
wherein R is selected from the group consisting of F and CF 3 .
10. The MTM-SA derivative of claim 1 , wherein R′ is a substituted phenylalanine (Phe) derivative.
11. The MTM-SA derivative of claim 10 , having the following formula:
12. The MTM-SA derivative of claim 1 , wherein R′ is a substituted Trp, Phe, Trp-Phe, or Phe-Trp dipeptide derivative or an unsubstituted Trp, Phe, Trp-Phe, or Phe-Trp dipeptide derivative.
13. The MTM-SA derivative of claim 1 , selected from the formulae consisting of:
wherein one of R 1 and R 2 is MTM-SA, and the other of R 1 and R 2 is CO 2 CH 3 ; R 3 is H or Me; X is selected from the group consisting of methyl, allyl, O-allyl, prenyl, 5,6-benzo, benzyl, phenyl, phenyl-triazole, F, and CF 3 ; and Y is selected from the group consisting of H and 3, 4-benzo.
14. The MTM-SA derivative of claim 1 , wherein R′ is a substituted Trp, Phe, Trp-Phe, or Phe-Trp dipeptide derivative having a substitution on a phenyl or indole ring of the Trp, Phe, Trp-Phe, or Phe-Trp dipeptide derivative, wherein the substitution is selected from the group consisting of lower alkyl, prenyl, aryl, alkylaryl, alkoxyl, nitro, halogen, and halocarbon; or an unsubstituted Trp, Phe, Trp-Phe, or Phe-Trp dipeptide derivative.
15. 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 .
16. The method of claim 15 , wherein the method comprises treating Ewing sarcoma.
17. The method of claim 15 , wherein the method comprises treating lung cancer.
18. The method of claim 15 , wherein the method comprises treating leukemia or lymphoma.
19. The method of claim 15 , wherein the method comprises treating colon cancer.
20. 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 1 .