Salinosporamides and methods for use thereof
View Patent ↗The present invention is based on the discovery that certain fermentation products of the marine actinomycete strains CNB392 and CNB476 are effective inhibitors of hyperproliferative mammalian cells. The CNB392 and CNB476 strains lie within the family Micromonosporaceae, and the generic epithet Salinospora has been proposed for this obligate marine group. The reaction products produced by this strain are classified as salinosporamides, and are particularly advantageous in treating neoplastic disorders due to their low molecular weight, low IC 50 values, high pharmaceutical potency, and selectivity for cancer cells over fungi.
1. An isolated compound having the structure (I):
wherein:
R 1 to R 3 are each independently —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, hydroxy, halogen, amino, amido, carboxyl, —C(O)H, acyl, oxyacyl, carbamate, sulfonamide, or sulfuryl,
Each R 4 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl;
E 1 to E 4 are each independently —O, —NR 5 , or —S, wherein R 5 is —H or C 1 –C 6 alkyl; and
X is 0 to 8.
2. The compound of claim 1 , wherein E 1 , E 3 , and E 4 are —O, and E 2 is —NH.
3. The compound of claim 1 , wherein R 1 and R 2 are —H, alkyl, or substituted alkyl, and R 3 is hydroxy or alkoxy.
4. The compound of claim 1 , wherein R 1 is a substituted alkyl.
5. The compound of claim 4 , wherein the substituted alkyl is a halogenated alkyl.
6. The compound of claim 5 , wherein the halogenated alkyl is a chlorinated alkyl.
7. The compound of claim 6 , wherein the compound has the structure (IV):
8. The compound of claim 7 , wherein the compound has the structure:
9. A pharmaceutical composition comprising at least one compound of claim 1 in a pharmaceutically acceptable carrier therefor.
10. A pharmaceutical composition, comprising an effective amount of a pharmaceutically acceptable carrier and a compound of claim 1 .
11. The pharmaceutical composition of claim 10 , further comprising at least one additional anti-neoplastic agent.
12. A pharmaceutical composition, comprising an effective amount of a pharmaceutically acceptable carrier and a compound having the structure:
13. A pharmaceutical composition useful for inhibiting proliferation of mammalian colon cancer cells, comprising an effective amount of a pharmaceutically acceptable carrier and a compound of claim 1 .
14. The pharmaceutical composition of claim 13 , further comprising at least one additional anti-neoplastic agent.
15. A pharmaceutical composition useful for inhibiting proliferation of mammalian colon cancer cells, comprising an effective amount of a pharmaceutically acceptable carrier and a compound having the structure: