Radiation countermeasure agents
Methods and compositions for reducing radiation damage in a subject with analog or derivative of benzo[c]chromen-6-one.
1. A method for reducing radiation damage, reducing potential damage by exposure to radiation, treating damage caused by exposure to radiation, and/or inhibiting formation of damage caused by radiation in a subject comprising administering to the subject an effective amount of an agent which is an analog or derivative of benzo[c]chromen-6-one.
2. The method of claim 1 wherein the agent is administered to the subject after the subject has been exposed to radiation.
3. The method of claim 1 wherein the agent is administered to the subject before the subject has been exposed to radiation.
4. The method of claim 1 wherein the agent has the structure of formula I
where,
R1=H or alkyl;
R2=H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is halo, aryl, or heteroaryl, O-Ac, O—PO3, O—SO3, or OSO2NH2;
R3=H, OH, O-alkyl, O—CH2Aryl, O—CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4=H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OPO3, OSO3, or OSO2NH2;
R5=H, Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6=H;
R7=H, Acyl, substituted alkyl, where substitution is hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is O—PO3 or OSO3;
R8=H; and
X=O, N, or S;
in free or pharmaceutically acceptable salt form.
5. The method of claim 1 wherein the agent has the structure of formula II
where,
R1=H or alkyl;
R2=H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is halo, aryl, or heteroaryl, O-Ac, O—PO3, O—SO3, or OSO2NH2;
R3=H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O-acyl, or nitro;
R4=H, Alkyl, CH2Aryl, substituted alkyl, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OPO3, OSO3, or OSO2NH2;
R5=H, Aryl, heteroaryl or substituted alkyl; and
R6=H, Alkyl, or Aryl;
in free or pharmaceutically acceptable salt form.
6. The method of claim 1 wherein the agent has the structure of formula III
where,
R1=alkyl or H;
R3=Acetyl; and
R4=H or Alkyl;
in free or pharmaceutically acceptable salt form.
7. The method of claim 1 wherein the agent has the structure of formula IV
where,
R1=H or F;
R2=H or nitro;
R3=H;
R4=H; and
R5=alkyl, substituted alkyl or aryl;
in free or pharmaceutically acceptable salt form.
8. The method of claim 1 wherein the agent is selected from the group consisting of compounds presented in Table I.
9. The method of claim 8 wherein the agent is SG00529
in free or pharmaceutically acceptable salt form.
10. The method of claim 8 wherein the agent is SG00529.
11. The method of claim 8 wherein the agent is SG00574
12. The method of claim 1 wherein the radiation is ionizing radiation.
13. The method of claim 1 wherein the subject is a mammal.
14. The method of claim 1 wherein the subject is human.
15. The method of claim 1 wherein the subject is suffering from or will likely suffer from acute radiation syndrome or radiation sickness.
16. The method of claim 1 wherein the subject is suffering from cancer.
17. The method of claim 16 wherein the subject is being treated with radiation therapy and/or chemotherapy.
18. The method of claim 1 wherein the subject is suffering from leucopenia, neutropenia, purpura, hemorrhage, diarrhea, vomiting, and/or hypotension.
19. The method of claim 1 further comprising administering a cytoprotective agent.
20. A method for reducing radiation damage, reducing potential damage by exposure to radiation, treating damage caused by exposure to radiation, and/or inhibiting formation of damage caused by radiation in a subject comprising administering to the subject an effective amount of an agent which is an analog or derivative of benzo[c]chromen-6-one;
further comprising administering a compound which inhibits the PI3K/Akt/mTOR pathway.
21. The method of claim 1 wherein the agent is administered every hour, 2 hours, 3 hours, 6 hours, or daily following exposure to radiation.
22. The method of claim 1 wherein the agent is administered to achieve a blood plasma level of about 0.1 to about 1000 μM.
23. The method of claim 1 wherein the agent is administered in a dose of about 0.1-1000 mg/kg.
24. The method of claim 1 wherein the agent is administered to the subject within 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 1 day, or 2 days after the subject has been exposed to radiation.
25. The method of claim 1 wherein the agent is administered to the subject 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 1 day, or 2 days before the subject has been exposed to radiation.
26. A pharmaceutical composition comprising a compound of formula I
where,
R1=H or alkyl;
R2=H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-substituted alkyl, where substitution is halo, aryl, or heteroaryl, O-Ac, O—PO3, O—SO3, or OSO2NH2;
R3=H, OH, O-alkyl, O—CH2Aryl, O—CH2heteroaryl, O-alkylaryl, O-acyl, or nitro;
R4=H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OPO3, OSO3, or OSO2NH2;
R5=H, Oxo, aryl, hydroxyl, alkyl, or O-alkyl;
R6=H;
R7=H, Acyl, substituted alkyl, where substitution is hydroxyl or sulfamoyl, alkyl, O-alkyl, or O-substituted alkyl where substitution is O—PO3 or OSO3;
R8=H; and
X=O, N, or S;
in free or pharmaceutically acceptable salt form, in combination with a cytoprotective agent in a pharmaceutically acceptable carrier.
27. A pharmaceutical composition comprising a compound of formula II:
where,
R1=H or alkyl;
R2=H, O-alkyl, OH, amino, O-heterocyc, O-aryl, O-substituted alkyl where substitution is halo, aryl, or heteroaryl, O-Ac, O—PO3, O—SO3, or OSO2NH2;
R3=H, O-alkyl, O-substituted alkyl where substitution is aryl or heteroaryl, OH, O-acyl, or nitro;
R4=H, Alkyl, CH2Aryl, substituted alkyl, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OPO3, OSO3, or OSO2NH2;
R5=H, Aryl, heteroaryl or substituted alkyl; and
R6=H, Alkyl, or Aryl;
in free or pharmaceutically acceptable salt form, in combination with a cytoprotective agent in a pharmaceutically acceptable carrier.
28. A pharmaceutical composition comprising a compound of formula III
where,
R1=alkyl or H;
R3=Acetyl; and
R4=H or Alkyl;
in free or pharmaceutically acceptable salt form, in combination with a cytoprotective agent in a pharmaceutically acceptable carrier.
29. A pharmaceutical composition comprising a compound of formula IV
where,
R1=H or F;
R2=H or nitro;
R3=H;
R4=H; and
R5=alkyl, substituted alkyl or aryl;
in free or pharmaceutically acceptable salt form, in combination with a cytoprotective agent in a pharmaceutically acceptable carrier.