Proteasome inhibitors having chymotrypsin-like activity
Disclosed herein is the use of HLM-008182, as well as its analogues formed via in-house synthesis, as a potent proteasome inhibitors. A new method was developed for HLM-008182 through a four-step protocol and the method was further optimized to a two step protocol. The synthesis in both protocols was regioselective with TiCl 4 . The reaction was highly efficient with microwave assisted heating and THF as solvent. The modification around the molecule HLM-008182 established primary SAR, indicating that the proteasome inhibition activity was a function of the 2-side chain.
1. A compound having the structure shown in formula I:
a. wherein R 1 is;
b. wherein R 2 is selected from the group consisting of alkylcarbonyl; and;
d. wherein R 3 is an aryl or heteroaryl then R 3 is selected from the group consisting of
2. The compound of claim 1 , wherein R 2 is selected from the group consisting of CH 2 COOH, CH 2 COOC 2 H 5 , (CH 2 ) 2 COOCH 3 , (CH 2 ) 2 COOH, (CH 2 ) 2 CONHCH(CH 2 ) 2 , CH(CH 3 )COOH, CH 2 COOH, CH 2 COOC 2 H 5 , (CH 2 ) 2 COOCH 3 , (CH 2 ) 2 COOH, (CH 2 ) 2 CONHCH(CH 2 ) 2 .
3. The compound of claim 1 , wherein when R 2 is CH 2 COOH then R 3 is selected from the group consisting of
4. The compound of claim 1 , wherein R 2 is CH 2 COOC 2 H 5 and R 3 is selected from the group consisting of
5. The compound of claim 1 , wherein R 2 is (CH 2 ) 2 COOCH 3 and R 3 is selected from the group consisting of
6. The compound of claim 1 , wherein R 2 is (CH 2 ) 2 COOH and R 3 is
7. The compound of claim 1 , wherein R 2 is (CH 2 ) 2 CONHCH(CH 2 ) 2 and R 3 is
8. The compound of claim 1 , wherein R 2 is CH(CH 3 )COOH and R 3 is selected from the group consisting of
9. The compound of claim 1 , wherein the compound is selected from the group consisting of Ethyl 2-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)acetate, Ethyl 2-(1-hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)acetate, 2-(1-hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)acetic acid, 2 (1 hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)acetic acid, Methyl 3-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)propanoate, Ethyl 2-(1-oxo-4-(phenylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)acetate, Ethyl 2-(1-oxo-4-(tosylimino)-1,4-dihydronaphthalen-2-ylthio)acetate, Ethyl 2-(4-(4-chlorobenzylsulfonylimino)-1-oxo-1,4-dihydronaphthalen-2-ylthio)-acetate, Methyl 3-(1-hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)propanoate, Ethyl 2-(1-hydroxy-4-(phenylsulfonamido)naphthalen-2-ylthio)acetate, Ethyl 2-(1-hydroxy-4-(4-nitrophenylsulfonamido)naphthalen-2-ylthio)acetate, 3-(1-hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)propanoic acid, 2-(1-hydroxy-4-(phenylsulfonamido)naphthalen-2-ylthio)acetic acid, N,N-dimethyl-3-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)propanamide, (N-methyl-3-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)propanamide, N-cyclopropyl-3-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)propanamide, (Z)-2-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)acetic acid, Methyl-3-(4-(4,5-dichlorothiophene-2-sulfonamido)-1-hydroxynaphthalen-2-ylthio)propanoate, 2-(4-(4,5-dichlorothiophene-2-sulfonamido)-1-hydroxynaphthalen-2-ylthio)acetic acid, 2-(4-(5-chlorothiophene-2-sulfonamido)-1-hydroxynaphthalen-2-ylthio)acetic acid, 2-(4-(4-chlorophenylsulfonamido)-1-hydroxynaphthalen-2-ylthio)acetic acid, 2-(1-hydroxy-4-(naphthalene-2-sulfonamido)naphthalen-2-ylthio)acetic acid, Ethyl 2-(4-(biphenyl-4-ylsulfonamido)-1-hydroxynaphthalen-2-ylthio)acetate, 2-(4-(biphenyl-4-ylsulfonamido)-1-hydroxynaphthalen-2-ylthio)acetic acid, 2-(4-(biphenyl-4-ylsulfonamido)-1-hydroxynaphthalen-2-ylthio)benzoic acid, 2-(4-(4-chlorophenylsulfonamido)-1-hydroxynaphthalen-2-ylthio)propanoic acid, 2-(1-hydroxy-4-(naphthalene-2-sulfonamido)naphthalen-2-ylthio)propanoic acid.
10. A compound having the structure shown in formula II:
a. wherein R 1 is S, P, B, Cl, Br, I, heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocycloalkoxy and heterocycloalkoxycarbonyl;
b. wherein R 2 is selected from the group consisting of alkylcarbonyl; and
d. wherein R 3 is an aryl or heteroaryl then R 3 is selected from the group consisting of
11. The compound of claim 10 , wherein R 2 is selected from the group consisting of CH 2 COOH, CH 2 COOC 2 H 5 , (CH 2 ) 2 COOCH 3 , (CH 2 ) 2 COOH, (CH 2 ) 2 CONHCH(CH 2 ) 2 , CH(CH 3 )COOH, CH 2 COOH, CH 2 COOC 2 H 5 , (CH 2 ) 2 COOCH 3 , (CH 2 ) 2 COOH, (CH 2 ) 2 CONHCH(CH 2 ) 2 .
12. The compound of claim 10 , wherein R 3 is selected from the group consisting of
13. The compound of claim 10 , wherein R 2 is CH 2 COOH and R 3 is selected from the group consisting of:
14. The compound of claim 10 , wherein and R 2 is CH 2 COOC 2 H 5 and R 3 is selected from the group consisting of
15. The compound of claim 10 , wherein R 2 is (CH 2 ) 2 COOCH 3 and R 3 is selected from the group consisting of
16. The compound of claim 10 , wherein R 2 is (CH 2 ) 2 COOH and R 3 is
17. The compound of claim 10 , wherein R 2 is (CH 2 ) 2 CONHCH(CH 2 ) 2 and R 3 is
18. The compound of claim 10 , wherein R 2 is CH(CH 3 )COOH and R 3 is selected from the group consisting of