Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases.

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Smaill JB, Baker EN, Booth RJ, Bridges AJ, Dickson JM, Dobrusin EM, Ivanovic I, Kraker AJ, Lee HH, Lunney EA, Ortwine DF, Palmer BD, Quin J 3rd, Squire CJ, Thompson AM, Denny WA

Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases.

Eur J Med Chem. 2008 Jun;43(6):1276-96. Epub 2007 Aug 6.

PubMed ID

17869387 [ View in PubMed

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Abstract

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) 0.057 microM) 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
3-(9-HYDROXY-1,3-DIOXO-4-PHENYL-2,3-DIHYDROPYRROLO[3,4-C]CARBAZOL-6(1H)-YL)PROPANOIC ACID	Wee1-like protein kinase	IC 50 (nM)	23	N/A	N/A	Details
9-HYDROXY-4-PHENYL-6H-PYRROLO[3,4-C]CARBAZOLE-1,3-DIONE	Wee1-like protein kinase	IC 50 (nM)	97	N/A	N/A	Details
9-HYDROXY-6-(3-HYDROXYPROPYL)-4-(2-METHOXYPHENYL)PYRROLO[3,4-C]CARBAZOLE-1,3(2H,6H)-DIONE	Wee1-like protein kinase	IC 50 (nM)	30	N/A	N/A	Details