82966-35-6Relevant academic research and scientific papers
Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition
Li, Yingjun,Pasunooti, Kalyan Kumar,Li, Ruo-Jing,Liu, Wukun,Head, Sarah A.,Shi, Wei Q.,Liu, Jun O.
, p. 11158 - 11168 (2019/01/08)
Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC50 of 73 nM without a significant effect on CYP3A4 (EC50 > 20 μM). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.
Stereoisomers of ketoconazole: Preparation and biological activity
Rotstein,Kertesz,Walker,Swinney
, p. 2818 - 2825 (2007/10/02)
The four stereoisomers of the antifungal agent ketoconazole (1) were prepared and evaluated for their selectivity in inhibiting a number of cytochrome P-450 enzymes. Large differences in selectivity among the isomers were observed for inhibition of the cytochromes P-450 involved in steroid biosynthesis, whereas little differences was observed for inhibition of those associated with hepatic drug metabolism. The cis-(2S,4R) isomer 2 was the most effective against rat lanosterol 14α-demethylase, (2S,4R)-2 > (2R,4S)-4 >> (2R,4R)-3 = (2S,4S)-5, and progesterone 17α,20-lyase, (2S,4R)-2 >> (2S,4S)-5 > (2R,4R)-3 = (2R,4S)-4, whereas the cis-(2R,4S) isomer 4 was more effective against cholesterol 7α-hydroxylase, (2R,4S)-4 > (2S,4S)-5 > (2R,4R)-3 > (2S,4R)-2, and the trans-(2S,4S) isomer 5 was the most effective against aromatase, (2S,4R)-5 >> (2R,4R)-3 = (2R,4S)-4 > (2S,4R)-2. The cis- (2S,4R) and trans-(2R,4R) isomers 2 and 3 are equipotent in inhibiting corticoid 11β-hydroxylase and much more effective than their antipodes. Little selectivity was observed for inhibition of cholesterol side chain cleavage or xenobiotic hydroxylases. These data indicate that the affinity of azoles for cytochrome P-450 enzymes involved in steroid synthesis is highly dependent on the stereochemistry of the entire molecule, whereas binding to drug metabolizing enzymes is a less selective process.
