Selective hdac8 inhibitors and their uses
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example 1
Materials and Methods
[0234]1.1 All of the starting materials were obtained commercially and were used without further purification. All of the reported yields are for isolated products and are not optimized. Nuclear magnetic resonance (1H and 13C NMR) spectra were recorded with a Bruker DRX-500 spectrometer (operating at 500 MHz), with chemical shifts in parts per million (8) downfield from TMS, the internal standard. Mass spectral (MS) data were obtained using an Agilent 6110 Quadrupole LC / MS system with a 0.3 mL / min flow rate using a gradient mobile phase consisting of 0.1% trifluoroacetic acid (TFA) in water and 0.1% TFA in acetonitrile. UV detection was monitored at 227 nm. Mass spectra were acquired either in positive or in negative mode scanning over the mass range of 105-1500. The purities of the final compounds were determined using an Agilent 1200 series HPLC system using a C-18 column (Waters Sunfire C18 3.5 μm, 2.1 mm×100 mm) and were found to be >95%. Flash column chroma...
example 2 chemical synthesis
and Structures
[0249]
2.1 General Synthesis of the 2-aryl-4,5-dihydro-1H-imidazole (11, n=2) and 2-aryl-1,4,5,6-tetrahydropyrimidine (11, n=3)
[0250]To a solution of the aldehyde 10 (1 eq.) in tert-butanol (9.0 ml / mmol) the diamine (1.1 eq.) was added and the solution was stirred at 70° C. for 30 min. K2CO3 (4 eq.) and I2 (1.25 eq.) was added at 70° C. and the mixture was stirred at this temperature for further 3 h. The mixture was cooled down to rt and Na2S2O3 was added until the iodine color almost disappear. The organic layer was separated and the solvent was removed in vacuo. The received solid was dissolved in water (7.5 ml / mmol) and 2 N NaOHaq was added until pH=12-14. The aqueous layer was separated with CHCl3 (3×3.75 ml / mmol), the combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The product can be used without further purification.
2-(2-Bromophenyl)-1,4,5,6-tetrahydropyrimidine (11a)
[0251]2-Bromobenzaldehyde (10a) (1 ml, 8.56 mmol) and 1,3 diamin...
example 3
Inhibition of Histonedeacetylase Activity
[0298]For HDAC1, 2, 3 and 6:
[0299]The activity of HDAC1 was determined by a colorimetric assay as described by Wegener et al (2003). 1 nM of HDAC1 was incubated with increasing concentrations of the respective compound for 30 minutes at 30° C. The reaction was initiated by addition of 50 μM of the substrate Boc-Lys(Ac)-AMC. After an incubation of 60 minutes the reaction was stopped by addition of 20 μM SAHA and the deacetylated substrate was converted into a fluorescent product by the addition of trypsin.
[0300]For HDAC4, 5, 7 and 8:
[0301]The activity of HDAC4 was determined by a colorimetric assay as described by Wegener et al. (2003). 1 nM of HDAC4 was incubated with increasing concentrations of the respective compound for 30 minutes at 30° C. The reaction was initiated by addition of 20 μM of the substrate Boc-Lys(trifluoracetyl)-AMC. After an incubation of 60 minutes the reaction was stopped by addition of 20 μM SAHA and the deacetylated s...
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