Belactosin derivatives as therapeutic agents/biological probes and their synthesis
Derivatives of belactosin and their synthesis are disclosed. In certain embodiments, compounds of the present invention exhibit anti-cancer, antiviral, antibiotic, and/or auto-immune therapeutic abilities. In general, methods of synthesis disclosed herein allow for introduction of a variety of substituents at numerous positions as well as the facile introduction of a beta-lactone ring moiety. The synthetic steps comprise, in preferred embodiments, a tandem Mukaiyama aldol lactonization reaction. Data demonstrating the utility of some of the derivatives as proteasome inhibitors is also disclosed.
1. A compound of the following formula:
wherein W is H, alkyl, aryl or a carboxylic acid protecting group;
R 1 and R 3 are each independently selected from the group consisting of H, alkyl, aryl and an amine protecting group;
R 5 is H, alkyl, aryl, an amine protecting group or
wherein m equals 1-5 and X is a fluorophore;
R 7 is selected from the group consisting of H, alkyl and aryl;
R 8 is alkyl
R 9 is alkyl or OR 10 , wherein R 10 is alkyl; and
n equals 1-7;
and diastereomers and optical isomers thereof.
2. The compound of claim 1 , wherein R 1 is an amine protecting group, and diastereomers and optical isomers thereof.
3. The compound of claim 1 , wherein R 5 is an amine protecting group, and diastereomers and optical isomers thereof.
4. The compound of claim 1 , wherein R 7 is alkyl further defined as —CH 3 , and diastereomers and optical isomers thereof.
5. The compound of claim 1 , wherein R 5 is
and diastereomers and optical isomers thereof.
6. The compound of claim 5 , wherein m is 1, and diastereomers and optical isomers thereof.
7. The compound of claim 5 , wherein X is selected from the group consisting of:
and diastereomers and optical isomers thereof.
8. The compound of claim 1 , wherein R 1 is H, and diastereomers and optical isomers thereof.
9. The compound of claim 1 , wherein R 3 of the compound is H, and diastereomers and optical isomers thereof.
10. The compound of claim 1 , wherein n equals 1-5, and diastereomers and optical isomers thereof.
11. A compound having the formula:
wherein R is alkyl or aryl, and diastereomers and optical isomers thereof.
12. A compound having the formula:
wherein R is alkyl or aryl, and diastereomers and optical isomers thereof.
13. The compound of claim 1 , wherein the compound is comprised in a composition, wherein the composition comprises a pharmaceutically acceptable excipient or diluent.
14. A method of synthesizing a compound of the following formula:
comprising:
reacting a first compound of formula (1a)
and diastereomers and optical isomers thereof,
wherein
W is H, alkyl, aryl or a carboxylic acid protecting group;
R 1 and R 3 are each independently selected from the group consisting of H, alkyl, aryl and an amine protecting group;
R 5 is H, alkyl, aryl, an amine protecting group or
wherein m equals 1-5 and X is a fluorophore;
R 7 is selected from the group consisting of H, alkyl and aryl;
R 16 is selected from the group consisting of H, —C(O)C(O)H and —C(O)C(O)R 17 ,
wherein R 17 is selected from the group consisting of alkyl and aryl; and
n equals 1-7, and
with a second compound of formula (1b)
and diastereomers and optical isomers thereof,
wherein R 8 is alkyl,
in the presence of a coupling agent.
15. The method of claim 14 , wherein R 5 is an amine protecting group.
16. The method of claim 14 , wherein R 7 is alkyl further defined as —CH 3 .
17. The method of claim 14 , wherein R 5 is an amine protecting group and R 7 is alkyl further defined as —CH 3 .
18. The method of claim 14 , wherein R 5 is
19. The method of claim 18 , wherein m is 1.
20. The method of claim 18 , wherein X is selected from the group consisting of:
21. The method of claim 14 , wherein R 1 is H.
22. The method of claim 14 , wherein R 3 is H.
23. The method of claim 14 , wherein R 8 is lower alkyl.
24. The method of claim 1 , wherein n equals 1-5.
25. The compound of claim 1 , further defined as:
wherein:
W is benzyl,
R 5 is an amine protecting group,
R 7 is methyl,
R 8 is lower alkyl,
n is 1-7,
and diastereomers and optical isomers thereof.
26. The compound of claim 25 , further defined as:
27. The compound of claim 1 , wherein R 9 is alkyl.
28. The compound of claim 27 , wherein R 9 is methyl.
29. The compound of claim 27 , wherein alkyl is further defined as heteroatom-substituted alkyl.
30. The compound of claim 28 , wherein heteroatom-substituted alkyl is further defined as —CH 2 F, —CHF 2 , —CF 3 , —CH 2 SMe, or —CH 2 OMe.
31. The compound of claim 1 , wherein R 9 is OR 10 .
32. The compound of claim 31 , wherein R 9 is —OCH 3 .