Syntheses of phenylpyrazolodiazepin-7-ones as conformationally rigid analogs of aminopyrazole amide scaffold and their antiproliferative effects on cancer cells.

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Kim H, Kim M, Lee J, Yu H, Hah JM

Syntheses of phenylpyrazolodiazepin-7-ones as conformationally rigid analogs of aminopyrazole amide scaffold and their antiproliferative effects on cancer cells.

Bioorg Med Chem. 2011 Nov 15;19(22):6760-7. doi: 10.1016/j.bmc.2011.09.042. Epub 2011 Oct 1.

PubMed ID

22014755 [ View in PubMed

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Abstract

Recently, we have reported the syntheses and antiproliferative activities of N-(5-amino-1-(4-methoxybenzyl)-1H-pyrazol-4-yl amide derivatives on melanoma cells. As a continuous work for antiproliferative agents in melanoma, here we report the synthesis of conformationally rigid analogs, phenyl-6,8-dihydropyrazolo[3,4-b][1,4]diazepin-7(1H)-one derivatives 7a-g, 8a-o and their antiproliferative activities against A375P melanoma cell line and U937 hematopoietic cell line. Most compounds showed competitive antiproliferative activities to sorafenib, the reference standard. Among them, N-(3-(1-benzyl-7-oxo-1,6,7,8-tetrahydropyrazolo[3,4-b][1,4]diazepin-5-yl)phenyl)- 4-chloro-3-(trifluoro methyl)benzamide-amino-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-(3-(4-chloro-3-(tri fluoromethyl) phenyl) ureido)-2-methylbenzamide (7b) exhibited potent activities (GI(50)=0.43 muM and 0.06 muM) on both cell lines. It has been further confirmed to be a potent and selective Raf kinases inhibitor and also mild inhibitor of PI3Kalpha.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Staurosporine	Glycogen synthase kinase-3 beta	IC 50 (nM)	9.23	N/A	N/A	Details
Staurosporine	Tyrosine-protein kinase Lck	IC 50 (nM)	4.49	N/A	N/A	Details