The inhibition of Aurora kinases in order to arrest mitosis and subsequently inhibit tumor growth via apoptosis of proliferating cells has generated significant discussion within the literature. We report a novel class of Aurora kinase inhibitors based upon a phthalazinone pyrazole scaffold. The development of the phthalazinone template resulted in a potent Aurora-A selective series of compounds (typically >1000-fold selectivity over Aurora-B) that display good pharmacological profiles with significantly improved oral bioavailability compared to the well studied Aurora inhibitor VX-680.
Materials and MethodsGeneral. Reagents were obtained from commercial suppliers and used as received. Solvents were purchased from commercial suppliers in the anhydrous form or dried via distillation. Solvents were removed with a rotary evaporator at low vacuum pressure, followed by drying on high vacuum. Flash chromatography was performed according to the method of Still 1 using 60-mesh silica gel from E. Merck & Co. Thin-layer chromatography was performed using Merck silica gel 60 F 254 plates. Analytical S2 HPLC traces were obtained using a Varian DYNAMAX-100 Å (4.6 mm x 250 mm) reverse-phase C18 column. Solvent mixtures for all chromatographic analyses included 0.1% TFA. The HPLC gradient was as follows: equilibration in 9:1 H 2 O-MeCN at 1 mL•min -1 flow rate, followed by ramping to 1:19 H 2 O-MeCN over 15 min. This solvent mixture was then run for an additional 10 min for a total elution time of 25 min. Retention times were recorded for this gradient. Preparative HPLC purification was accomplished using a Varian DYNAMAX-100 Å (21.4 mm x 50 mm) reverse-phase C18 column. The gradient for preparative purification was as follows: equilibration in 9:1 H 2 O-MeCN at 20 mL•min -1 flow rate for 10 min, followed by ramping to 1:19 H 2 O-MeCN over 15 min. This solvent mixture was then run for an additional 5 min for a total elution time of 20 min. A liquid chromatography-mass spectrometry (LCMS) equipped with a Zorbax SB-C18 reverse-phase column (2.1 mm ID x 5 cm) was used for identification of compounds. The LCMS gradient was as follows: equilibration in 9:1 H 2 O-MeCN at 0.4 mL•min -1 flow rate, followed by ramping to 1:19 H 2 O-MeCN over 8 min. This solvent mixture was then run for an additional 3 min for a total elution time of 11 min.
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