Boronic and borinic acid compound as inhibitors of sulfenic acid-containing proteins

Patent metadata

Field	Value
Publication number	US-9309508-B2
Application number	US-201414576613-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	Nov 27, 2012
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

A boronic or borinic acid compound is used to inhibit the activity of a sulfenic acid-containing protein. Thus, a biologically-active sulfenic acid-containing protein is contacted with an activity-inhibiting effective amount of a boronic or borinic acid compound of Formula I or a salt, hydrate or solvate thereof, whose components are disclosed within, and that contact is maintained for a time sufficient to inhibit the biological activity of the protein.

First claim

The invention claimed is:

1. A method of inhibiting the biologic activity of a biologically-active sulfenic acid-containing enzyme that comprises the step of contacting said enzyme with an activity-inhibiting effective amount of a boronic acid or borinic acid compound of Formula V or a salt, hydrate, or solvate thereof, and maintaining that contact for a time sufficient to inhibit the activity of that enzyme

wherein
A is OR 7 ,
E is N, or CR 2 ;
G is N, or CR 3 ;
W is N, or CR 4 ;
X is N or CR 5 ;
Y is N or CR 6 ;
R* is R 1 or OR 1 ;
R 1 and R 7 are selected independently from the group consisting of hydrido, optionally substituted C 1 -C 8 hydrocarbyl, optionally substituted aryl, arC 1 -C 8 hydrocarbyl, and optionally substituted heteroaryl, wherein said optional substituents are selected from the group consisting of C 1 -C 8 hydrocarbyl, aryl, arC 1 -C 8 hydrocarbyl, heteroaryl, heteroarC 1 -C 8 hydrocarbyl, heterocyclyl, cyclohydrocarbyloxy, heterocyclyloxy, —C(O)-aryl, hydrocarbyloxy, aryloxy, heteroaryloxy, —OC(O)—(C 1 -C 8 hydrocarbyl), —OCH 2 CH 2 OH, —O(CH 2 ) 3 CO 2 H, 2-(morpholino)ethoxy, —(CH 2 ) k OH (where k=1, 2 or 3), —CH 2 NH 2 , —CH 2 NH(C 1 -C 8 -hydrocarbyl), —CH 2 N(C 1 -C 8 hydrocarbyl) 2 , halogen, formyl, thioformyl, —CH═NOH, —CO 2 H, thiocarboxyl, sulfonyl, C 1 -C 8 hydrocarbyl-sulfonyl, arylsulfonyl, heteroarylsulfonyl, C 1 -C 8 -hydrocarbylsulfinyl, arylsulfinyl, heteroaryl-sulfinyl, —CO 2 (C 1 -C 8 -hydrocarbyl, —C(O)NH 2 , —C(O)NH(C 1 -C 8 -hydrocarbyl), —CON(C 1 -C 8 hydrocarbyl) 2 , —OH, —SH, —S—(C 1 -C 8 -hydrocarbyl), —S-aryl, —SO 2 (C 1 -C 8 -hydrocarbyl), —SO 2 N(C 1 -C 8 -hydrocarbyl) 2 , C 1 -C 8 -hydrocarbyl-sulfonylamino, aryl-sulfonylamino, —SO 2 NH 2 , —SO 3 H, —SCF 3 , —CN, CHF 2 , —CF 3 , —NO 2 , amino, —NH(C 1 -C 8 -hydrocarbyl, —N(C 1 -C 8 -hydrocarbyl) 2 , arylamino, diarylamino, —NHSO 2 (C 1 -C 8 -hydrocarbyl), —C(O)NH(C 1 -C 8 -hydrocarbyl), and —C(O)N(C 1 -C 8 -hydrocarbyl) 2 ;
R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen (hydrido), C 1 -C 8 hydrocarbyl, aryl, arC 1 -C 8 -hydrocarbyl, heteroaryl, heteroarC 1 -C 8 -hydrocarbyl, heterocyclyl, cyclohydrocarbyloxy, heterocyclyloxy, —C(O)-aryl, hydrocarbyloxy, aryloxy, heteroaryloxy, —OC(O)—(C 1 -C 8 -hydrocarbyl), —OCH 2 CH 2 OH, —O(CH 2 ) 3 CO 2 H, 2-(morpholino)ethoxy, —(CH 2 ) k OH (where k=1, 2 or 3), —CH 2 NH 2 , —CH 2 NH(C 1 -C 8 -hydrocarbyl), —CH 2 N(C 1 -C 8 hydrocarbyl) 2 , halogen, formyl, thioformyl, —CH═NOH, —CO 2 H, thiocarboxyl, sulfonyl, C 1 -C 8 -hydrocarbyl-sulfonyl, arylsulfonyl, heteroarylsulfonyl, C 1 -C 8 -hydrocarbylsulfinyl, arylsulfinyl, heteroarylsulfinyl, —CO 2 (C 1 -C 8 -hydrocarbyl), —C(O)NH 2 , —C(O)NH(C 1 -C 8 -hydrocarbyl), —CON(C 1 -C 8 -hydrocarbyl) 2 , —OH, —SH, —S—(C 1 -C 8 -hydrocarbyl), —S-aryl, —SO 2 (C 1 -C 8 -hydrocarbyl), —SO 2 N(C 1 -C 8 -hydrocarbyl) 2 , C 1 -C 8 -hydrocarbyl-sulfonylamino, aryl-sulfonylamino, —SO 2 NH 2 , —SO 3 H, —SCF 3 , —CN, —CHF 2 , —CF 3 , —NO 2 , amino, —NH(C 1 -C 8 -hydrocarbyl), —N(C 1 -C 8 -hydrocarbyl) 2 , arylamino, diarylamino, —NHSO 2 (C 1 -C 8 -hydrocarbyl), —CONH(C 1 -C 8 -hydrocarbyl), and —C(O)N(C 1 -C 8 -hydrocarbyl) 2 , wherein said C 1 -C 8 -hydrocarbyl, aryl, arC 1 -C 8 hydrocarbyl, heteroaryl, heteroarC 1 -C 8 -hydrocarbyl, cyclohydrocarbyl and heterocyclic groups in each of the R 2 , R 3 , R 4 , R 5 and R 6 (R 2-6 ) substituents are themselves optionally substituted and wherein said optional substituents are selected from the group consisting of C 1 -C 8 -hydrocarbyl, aryl, arC 1 -C 8 -hydrocarbyl, heteroaryl, heteroarC 1 -C 8 -hydrocarbyl, heterocyclyl, cyclohydrocarbyloxy, heterocyclyloxy, —C(O)-aryl, hydrocarbyloxy, aryloxy, heteroaryloxy, —OC(O)—(C 1 -C 8 -hydrocarbyl), —OCH 2 CH 2 OH, —O(CH 2 ) 3 CO 2 H, 2-(morpholino)ethoxy, —(CH 2 ) k OH (where k=1, 2 or 3), —CH 2 NH 2 , —CH 2 NH(C 1 -C 8 -hydrocarbyl), —CH 2 N(C 1 -C 8 -hydrocarbyl) 2 , halogen, formyl, thioformyl, —CH═NOH, —CO 2 H, thiocarboxyl, sulfonyl, C 1 -C 8 -hydrocarbyl-sulfonyl, arylsulfonyl, heteroarylsulfonyl, C 1 -C 8 -hydrocarbylsulfinyl, arylsulfinyl, heteroaryl-sulfinyl, —CO 2 (C 1 -C 8 hydrocarbyl, —C(O)NH 2 , —C(O)NH(C 1 -C 8 -hydrocarbyl), —CON(C 1 -C 8 -hydrocarbyl) 2 , —OH, —SH, —S—(C 1 -C 8 -hydrocarbyl), —S-aryl, —SO 2 (C 1 -C 8 -hydrocarbyl), —SO 2 N(C 1 -C 8 -hydrocarbyl) 2 , C 1 -C 8 -hydrocarbylsulfonylamino, aryl sulfonylamino, —SO 2 NH 2 , —SO 3 H, —SCF 3 , —CN, —CHF 2 , —CF 3 , —NO 2 , amino, —NH(C 1 -C 8 -hydrocarbyl, —N(C 1 -C 8 -hydrocarbyl) 2 , arylamino, diarylamino, —NHSO 2 (C 1 -C 8 hydrocarbyl), —C(O)NH(C 1 -C 8 -hydrocarbyl), and —C(O)N(C 1 -C 8 -hydrocarbyl) 2 .

2. The method according to claim 1 , wherein, one or more adjacent pairs of R 2 , R 3 , R 4 , R 5 and R 6 together with the atoms to which they are bonded form an optionally substituted mono- or bicyclic aromatic ring or heteroaromatic ring Ar2 that is fused to depicted ring Ar1.

3. The method according to claim 1 , wherein R* is OR 1 , A is OR 7 , and said boronic acid or borinic acid compound is a boronic acid compound.

4. The method according to claim 3 , wherein the sulfenic acid of said biologically-active sulfenic acid-containing enzyme is present in an active site of the enzyme.

5. The method according to claim 3 , wherein none of E, G, W, X or Y is N.

6. The method according to claim 5 , wherein R* is OR 1 , A is OR 7 , each of R 2 and R 4 is hydrogen to provide a boronic acid compound of Formula V-1, below

7. The method according to claim 6 , wherein
R 7 and R 1 are both H;
each of R 3 , R 5 , and R 6 is independently selected from the group consisting of nitro, halogen, C 1 -C 8 hydrocarbyl, —CHF 2 , —CF 3 , C 1 -C 8 -hydrocarbyloxy, aryloxy and di-C 1 -C 8 -hydrocarbylamino.

8. The method according to claim 7 , only one or none of R 3 , R 5 , and R 6 is other than hydrogen.

9. The method according to claim 1 , wherein R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, 4-nitro, 3-nitro, 3-bromo, 4-bromo, 4-fluoro and 4-methoxy.

10. The method according to claim 1 , wherein said biologically-active sulfenic acid-containing enzyme is selected from the group consisting of peroxiredoxin, protein tyrosine phosphatase, aldose reductase, Orp1, GAPDH, and nitrile hydratase.

Assignees

• Benkovic Stephen
• Liu Chunyu
• Tomsho John W
• Penn State Res Found

Inventors

• Benkovic Stephen
• Liu Chunyu
• Tomsho John W

Classifications

• C12N9/88

  Lyases (4.) · CPC title

• C12N9/99 Primary

  Enzyme inactivation by chemical treatment · CPC title

• C12Y402/01084 Primary

  Nitrile hydratase (4.2.1.84) · CPC title