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Bisarylsulfonamide compounds and their use in cancer therapy

A compound and application technology, applied in the field of bisaryl sulfonamide compounds, can solve problems such as low affinity

Inactive Publication Date: 2005-09-07
CYCLACEL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although longer peptides containing this sequence are also potent inhibitors of p53 / HDM2 complex formation, the hexapeptide p53(18-23) itself has very low affinity [Böttger A, Böttger V , Garcia-Echeverria C, Chène P, Hochkeppel HK, Sampson W, Ang K, Howard SF, Picksley SM, Lane DP; J.Molec.Biol.1997;269:744-756]

Method used

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  • Bisarylsulfonamide compounds and their use in cancer therapy
  • Bisarylsulfonamide compounds and their use in cancer therapy
  • Bisarylsulfonamide compounds and their use in cancer therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0835] General method for the preparation of primary bisarylsulfonamides

[0836] The appropriate sulfonyl chloride (1.0 mol equiv) was suspended in dichloromethane. The suspension was cooled to 0 °C. While the reaction mixture is being stirred, a suitable amino component (suitably such as aniline, benzylamine, etc.) (1.1 molar equivalent) and pyridine (1.5 molar equivalent) are added. The reaction mixture was slowly warmed to room temperature. Stirring was continued until TLC [heptane:ethyl acetate (2:1)] indicated that the reaction was complete. The product was isolated and purified according to the following procedure: the reaction mixture was diluted with dichloromethane, then washed successively with dilute aqueous hydrochloric acid, saturated NaHCO 3 Aqueous, water and brine washes. MgSO for organic part 4 Drying and concentration under reduced pressure gave the crude sulfonamide. Column chromatography [column (Isolute SI; Jones Chromatography), heptane:ethyl ace...

Embodiment 2

[0952] General method for the preparation of N-alkylated primary bisarylsulfonamides

[0953] The primary bisarylsulfonamide (1.0 mol equivalent) of Example 1 was dissolved in anhydrous acetone, the solution was cooled to 0° C., and then triethylamine (5.0 mol equivalent) was slowly added. After 30 minutes, the alkylating agent (alkyl or aralkyl halide; 5.0 mol equiv.) was added slowly and the solution was stirred until TLC [heptane:ethyl acetate (2:1)] indicated complete reaction. The reaction mixture was then concentrated, diluted with water and extracted with ethyl acetate. After concentration of the extract, the residue was subjected to column chromatography [column (Isolute SI; Jones Chromatography), heptane:ethyl acetate (12:1→3:1)] to give the desired alkylated sulfonamide.

[0954] The N-alkylated bisarylsulfonamide compounds of the present invention are prepared as described above. The specific analysis results of representative compounds are as follows:

[0955]...

Embodiment 3

[0966] Fluorescence polarization competitive binding assay

[0967] The assay was done using a 96-well microtiter (Costar). TBS-BSA buffer solution (50 mM Tris pH7.4, 150 mM NaCl, and 0.1% BSA) of recombinant HDM2 (1.5 μg / well) was incubated at room temperature in the presence of serially diluted test compounds (at a final concentration of 5% DMSO in TBS-BSA buffer solution) for 5 minutes. Add a fluorescently labeled p53-derived peptide (Fluorescein-Met-Pro-Arg-Phe-Met-Asp-Tyr-Trp-Glu-Gly-Leu-Asn-NH 2 , 0.2 μM), and then the plate was incubated at room temperature for 45 minutes. The fluorescence polarization of the peptide was measured (excitation 485 nm, emission 520 nm). Calculate IC from dose-response curve 50 value.

[0968] ELISA-type competitive binding assay

[0969] Streptavidin-coated 96-well plates (Pierce Chemical Co., St. Louis, MO, USA) were washed with TBS / BSA (25 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.05% Tween 20, 0.1% BSA). Biotinylated p53-derived pep...

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Abstract

The present invention relates to the use of bisarylsulfonamide compounds of formula (I) wherein W is a CI-5 branched or unbranched alkyl group or a C2-5 alkenyl group; nis0or1; R<1> is H, a C, 1-8 branched or unbranched alkyl group, a C2-8 alkenyl group, or an aryl or aralkyl group; Ar<1> is a substituted thienyl, furyl, pyrrolyl, imidazothiazolyl, thiazolyl, pyridyl or phenyl group; and Ar<2> is a substituted phenyl, indolyl or benzoimidazolyl group; in the preparation of a medicament for treating proliferative disorders. Further aspects of the invention relate to compounds of formula (I), pharmaceutical compositions thereof, and an assay for determining binding to HDM2.

Description

field of invention [0001] The present invention relates to bisarylsulfonamide compounds. In particular, the present invention relates to bisarylsulfonamide compounds capable of binding the oncoprotein HDM2 while also modulating the HDM2-dependent regulation of the tumor suppressor p53 and / or the E2F transcription factor in living cells. A further aspect of the invention relates to pharmaceutical formulations containing such compounds, and their use, for example, in the treatment of humans or animals. Background technique [0002] The MDM2 oncogene was initially cloned as an amplification factor on the murine double-minute chromosome; the encoded main oncoprotein was defined as MDM2, and the known human equivalent protein is HDM2 [Zhang, Wang H; Curr.Pharmaceut.Design 2000; 6:393-416]. The relationship between HDM2 and human cancer is now well established. HDM2 is overexpressed in various tumors due to gene amplification or increased transcription or transcription [Momand ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/43A61K31/4439A61K31/454A61K31/5377A61P35/00C07C311/21C07C311/29C07C311/44C07D207/36C07D209/16C07D213/70C07D231/12C07D235/30C07D263/32C07D277/56C07D285/06C07D295/185C07D319/18C07D333/34C07D333/42C07D333/62C07D409/04C07D409/12C07D513/04
CPCC07D213/70C07D295/185C07D235/30C07C311/21C07D513/04C07D409/12C07D333/42C07C311/29C07D333/34C07C311/44C07D263/32C07D285/06C07D409/04C07D277/56C07D231/12C07D333/62C07D209/16C07D207/36C07D319/18A61K31/43A61K31/4439A61K31/454A61K31/5377C07D207/34C07D209/14C07D213/71C07D277/36C07D285/10C07D413/04A61P11/00A61P13/12A61P17/06A61P17/14A61P29/00A61P33/06A61P35/00A61P35/02A61P37/00A61P43/00A61P9/10
Inventor 王淑东达伦·吉布森肯尼思·邓肯凯文·贝利马克·托马斯戴维·麦卡勒姆丹尼拉·泽勒瓦尼古拉斯·J·特纳彼得·M·费希尔
Owner CYCLACEL
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