Compounds that interact with kinases
A method of inhibiting or effecting the activity of protein kinase activity which comprises contacting a protein kinase with a compound of formula (I) being a derivative of a furanose or pyranose form of a monosaccharide, or a pharmaceutically acceptable salt thereof.
1. A method of identifying a compound that inhibits or enhances the activity of a protein kinase comprising:
a) contacting said protein kinase with a compound of formula I, being a derivative of a furanose or pyranose form of a monosaccharide, or a pharmaceutically acceptable salt thereof
Wherein;
n is 1 or 2,
X is selected from the group consisting of: OR1, an unsubstituted 5 or 6 membered heterocyclic moiety, a substituted 5 or 6 membered heterocyclic moiety, an unsubstituted 9 or 10 membered heterobicyclic moiety and a substituted 9 or 10 membered heterobicyclic moiety,
R1 is selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl,
Y is selected from the group consisting of an unsubstituted 5 or 6 membered heterocyclic moiety; a substituted 5 or 6 membered heterocyclic moiety, an unsubstituted 9 or 10 membered heterobicyclic moiety and a substituted 9 or 10 membered heterobicyclic moiety; an amino acid, a dipeptide, and
R6 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl,
with the proviso that R6, R7 and R8 are not all H,
R9 is selected from H, or —(CO)—R6,
R7, R8, R11, R12, R14, are independently selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl and C6 to C14 heteroarylalkyl,
R13 is selected from the group consisting of: unsubstituted phenyl unsubstituted benzyl, substituted phenyl, substituted benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl, —S—R6 and —O—R6,
R15 is absent or is at least one substituent on the aromatic ring which are independently selected from the group consisting of: OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and thioheteroaryl,
wherein at least one of R1-R14 is substituted and these substituents and the substituents on the substituted 5 or 6 membered heterocyclic moiety and the substituted 9 or 10 membered heterobicyclic moiety are selected from the group consisting of: OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroary, and
b) assaying the activity of said protein kinase in the presence of said compound of formula I and in the absence of said compound of formula I,
wherein, when the activity of said protein kinase in the presence of said compound of formula I is higher than the activity of said protein kinase in the absence of said compound of formula I, said compound of formula I is an enhancer of the activity of said protein kinase, and when the activity of said protein kinase in the presence of said compound of formula I is lower than the activity of said protein kinase in the absence of said compound of formula I, said compound of formula I is an inhibitor of the activity of said protein kinase.
2. The method of claim 1 , wherein R1 is substituted, cyclic or acyclic, branched and/or linear.
3. The method of claim 1 , wherein R7 and R8 combine to form a cyclic structure.
4. The method of claim 1 , wherein R6 and one of R7 or R8 combine to form a cyclic structure.
5. The method of claim 1 , wherein R11 and R12 combine to form cyclic structure.
6. The method of claim 1 , wherein
X is selected from: OR1,
R1 and R3 are independently selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl,
R4 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 aryalkyl and C3 to C14 heteroarylalkyl,
R5 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl,
R2 is selected from the group consisting of: —(C═O)—R3, —(C═O)—OR4, and —(C═O)—NH—R4,
Y is selected from:
7. The method of claim 6 , wherein at least one of R1 to R5 is substituted, cyclic or acyclic, branched and/or linear.
8. The method of claim 6 , wherein R7 and R8 combine to form a cyclic structure.
9. The method of claim 6 , wherein R6 and one of R7 or R8 combine to form a cyclic structure.
10. The method of claim 6 , wherein R11 and R12 combine to form a cyclic structure.
11. The method of claim 1 when the group X is
12. The method of claim 1 , wherein the group X is
13. The method of claim 1 , wherein X is —OR1.
14. The method of claim 6 wherein the group Y is
15. The method of claim 6 wherein Y is
16. The method of claim 6 , wherein Y is
17. The method of claim 6 , wherein Y is
18. The method of claim 6 , wherein Y is
19. The method of claim 6 , wherein Y is
20. The method of claim 6 , wherein Y is
21. The method of claim 1 wherein the protein kinase is a serine or threonine kinase.
22. The method of claim 1 wherein the protein kinase is a tyrosine kinase.
23. The method of claim 1 wherein the protein kinase is selected from the group consisting of one or more of the isoforms of:
A protein kinase C;
B Tie-2, also known as TEK, HPK-6, TIE-2, VMCM, VMCM1;
C c-Kit, also known as SCFR, CD117, PBT;
D VEGF-R2/KDR; also known as VEGFR2, VEGFR-2, VEGFR, Hs.KDR, Hs.12337, FLK1, FLK-1;
E EGF-R, also known as ERBB1, ERBB, EGFRvIII;
F Abl, also known as c-ab1, c-ABL, JTK7, p150, ABL1;
G MET, also known as HGFR, C-MET, RCCP2;
H CDK2, also known as p34CDK2, p33CDK2, p33CDK2;
I PDGF, also known as PDGFR1, PDGFR, PDGF-R-beta JTK12, CD140B, PDGFRB;
J FGFR-1, also known as N-SAM, LOC51033, FLT2, FLJ14326, CEK, C-FGR, BFGFR, H5, H4, H3, H2, FLG; and
K P38 MAP Kinase, also known as p38alpha, p38ALPHA, SAPK2a, SAPK2A, PRKM15, PRKM14, Mxi2, MXI2, Exip, EXIP, CSPB1, CSBP2, CSBP1, p38, RK, P38, MAPK14.