Diaryl- and triaryl-pyrrole derivatives: inhibitors of the MDM2–p53 and MDMX–p53 protein–protein interactions† †Electronic supplementary information (ESI) available: Experimental details for compound synthesis, analytical data for all compounds and intermediates. Details for the biological evaluatio

Triarylpyrroles e.g. 4c and 4s inhibit the MDM2–p53 and MDMX–p53 protein–protein interactions.


General Synthetic Methods
Reagents were purchased from fine chemicals vendors, and used as received unless otherwise stated.
Solvents were purified and stored according to standard procedures. Petrol refers to that fraction in the boiling range 40-60 °C. THF refers to anhydrous tetrahydrofuran, obtained either by distillaton from sodium benzophenone, or from commercial sources. Melting points were obtained on a Stuart Scientific SMP3 apparatus and are uncorrected. Thin layer chromatography was performed using silica gel plates (Kieselgel 60F254; 0.2 mm), and visualized with UV light or potassium permanganate. Chromatography was conducted under medium pressure in glass columns or using a Biotage SP4 instrument in prepacked columns 60 Å). Proton (1H) and carbon (13C) nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Spectrospin AC 300E (1H at 300 MHz, 13C at 75 MHz), a Jeol JNM-LA500 spectrometer (1H at 500 MHz, 13C at 125 MHz), or a Bruker Avance II 500 (1H at 500 MHz, 13C at 125 MHz) employing the solvent as internal standard. IR spectra were recorded on a Bio-Rad FTS 3000MX diamond ATR. Liquid Chromatography-Mass Spectrometry (LCMS) was carried out on a Micromass Platform instrument operating in positive and negative ion electrospray mode, employing a 50 x 4.6 mm C18 column (Waters Symmetry or Waters Atlantis) with 5 or 12 min gradient elution with 0.05% formic acid in methanol (10-90%), final compounds were ≥ 95% purity. Elemental analyses were performed by The School of Pharmacy, Analytical Facility, University of London, WC1N 1AX. Accurate masses were measured using a Finnigan MAR 95 XP or a Finnigan MAR 900 XLT at the EPSRC National Mass Spectrometry Service Centre (Chemistry Department, University of Wales, Swansea, Wales, SA2 8PP).

General Procedure A
To a mixture of the appropriate aniline (1.1 eq unless otherwise stated) of 1,2-dibenzoylethane (1.0 eq) and 2,2,2,-trifluoroethanol in a sealed microwave vial of appropriate capacity, was added trifluoroacetic acid (2.0 eq), drop-wise, under N 2 and then heated by microwave for 20 min at 150 o C. The resulting suspension was basified by addition of aqueous sodium hydroxide (1M) with stirring, filtered, and the solid washed with ethanol. The crude product 5 was dried in vacuo.

General Procedure B
To an appropriate capacity microwave vial was added the appropriate pyrrole 5 (1.0 eq) and anhydrous DMF and the vial was sealed. The mixture was cooled to -5 o C in an ice-salt bath, phosphorus oxychloride (3.0 eq) was added dropwise, under N 2 and heated by microwave 10 min at 70 o C. The mixture was poured over ice, basified with sodium hydroxide (1M), and heated to reflux for 1 h, then cooled to 0 o C and ethyl acetate (50 A mixture of 1,4-dicarbonyl compound 12 (1 eq.), aniline (1.2 eq.), p-toluene sulfonic acid (PTSA, 0.05 eq.) and toluene (0.94 mL per mmol 12) was heated to reflux for 18 h. The mixture was cooled to rt, then filtered and washed with toluene through Celite™. The filtrate was concentrated in vacuo. Chromatography (silica; EtOAc, hexane) gave 13.

General Procedure H
To a solution of pyrrole ester 18 (1 eq.) in dry DCM (14 mL per mmol 18) at -78 o C under nitrogen was added di-isopropylaluminium hydride (DIBAL-H, 3 eq., 1 M solution in hexane) and the resulting solution allowed to stir for 2 hours. The mixture was quenched by the dropwise addition of methanol and allowed to warm to room temperature, diluted with aqueous Rochelle's salt and stirred vigorously for 30 min, then was extracted with EtOAc (x 4). The combined organic phases were washed with brine, dried (Na 2 SO 4 ), and concentrated in vacuo. Chromatography (silica; EtOAc, hexane) gave 19.
Tetrapropylammonium perruthenate (TPAP, 0.1 eq.) was added and the mixture stirred until TLC indicated the complete consumption of the starting material (ca. 30 min). The mixture was diluted with DCM and filtered and washed with ether thorough Celite™. The organic phase was washed with aq. sodium metabisulfite and brine. The aqueous layer was extracted with Et 2 O (x 3). The combined organic extracts were dried (MgSO 4 ) and concentrated in vacuo. Chromatography (silica; EtOAc, hexane) gave 17.