2in6: Difference between revisions

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==Overview==

A series of N-6 substituted, 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared, from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds, were tested for their ability to inhibit the G2/M cell cycle checkpoint, kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains, were potent dual inhibitors. Acidic side chains provided potent (average, IC(50) 0.057muM) and selective (average ratio 223-fold) Wee1 inhibition., Co-crystal structures of inhibitors bound to Wee1 show that the, pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6, substituents involved in H-bonding to conserved water molecules. HT-29, cells treated with doxorubicin and then target compounds demonstrate an, active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced, phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2, checkpoint.

A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC(50) 0.057muM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.

==About this Structure==

Line 14:

[[Category: Single protein]]

[[Category: Transferase]]

[[Category: Baker, E.N.]]

[[Category: Baker, E N.]]

[[Category: Dickson, J.M.]]

[[Category: Dickson, J M.]]

[[Category: Ivanovic, I.]]

[[Category: Squire, C.J.]]

[[Category: Squire, C J.]]

[[Category: 839]]

[[Category: protein-inhibitor complex]]

[[Category: transferase]]

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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:54:23 2008''

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@@ Line 4: / Line 4: @@
 ==Overview==
-A series of N-6 substituted, 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared, from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds, were tested for their ability to inhibit the G2/M cell cycle checkpoint, kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains, were potent dual inhibitors. Acidic side chains provided potent (average, IC(50) 0.057muM) and selective (average ratio 223-fold) Wee1 inhibition., Co-crystal structures of inhibitors bound to Wee1 show that the, pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6, substituents involved in H-bonding to conserved water molecules. HT-29, cells treated with doxorubicin and then target compounds demonstrate an, active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced, phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2, checkpoint.
+A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC(50) 0.057muM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.
 ==About this Structure==
@@ Line 14: / Line 14: @@
 [[Category: Single protein]]
 [[Category: Transferase]]
-[[Category: Baker, E.N.]]
+[[Category: Baker, E N.]]
-[[Category: Dickson, J.M.]]
+[[Category: Dickson, J M.]]
 [[Category: Ivanovic, I.]]
-[[Category: Squire, C.J.]]
+[[Category: Squire, C J.]]
 [[Category: 839]]
 [[Category: protein-inhibitor complex]]
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 11:12:44 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:54:23 2008''