| Abstrakt: |
3- And 4-imidazol-1-yl-methyl substituted biphenyl compounds (named as meta- and para-substituted compounds) were synthesized bearing additional substituents in 3′-/4′-position as inhibitors of P450 17 (17α-hydroxylase-C17,20-lyase). P450 17 is the key enzyme of androgen biosynthesis. Its inhibition is a novel therapeutic strategy for treatment of prostate cancer (PC). Twenty-nine compounds were synthesized by Ar-Mg-Br, Negishi or Suzuki aryl–aryl cross coupling and tested toward human and rat enzyme. Most of the compounds showed moderate to excellent activity against one of the enzymes (0.087μM≤IC50≤7.7 μM (ketoconazole: 0.74μM) for the human enzyme, 0.63μM≤ IC50≤32μM (ketoconazole: 67μM) for the rat enzyme). Interestingly, strong species differences were observed. In addition compounds were tested for inhibition toward P450 arom. The 3-imidazol-1-yl-methyl substituted compounds showed good inhibitory activity of P450 arom, while for the 4-substituted compounds negligible inhibition was found. For the most active group of P450 17 inhibitors, (i.e. the 4-imidazol-1-yl-methyl substituted compounds) a QSAR study was performed for inhibition of the human enzyme leading to the result that a hydrophilic substituent in 3′-/4′-position is very important. The most promising compounds (with respect to activity toward both enzymes) were tested in vivo using SD-rats for reduction of plasma testosterone concentrations 2 and 6h after single ip application. The fluorine substituted compound 8cScheme 1Preparation of compounds. Reagents: Method A: Pd(PPh3)4, Na2CO3, toluene; Method B: Mg, Pd(PPh3)4, THF; Method C: BBr3, CH2Cl2MeOH; Method D: Pd/C, H2, p; Method E: H2SO4, rflx; Method F: HCl, resorcin; Method G: BuLi, ZnCl2, Pd(PPh3)4; Method H: NBS, CCl4; Method I: imidazole, 18-K-6, K2CO3, acetone; Method K: H2SO4, HOAc.decreased the testosterone plasma concentration to castration level (after 2h; 5 mg/kg) showing a biological half live of about 6h. |
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