4- and 6-( p-Sulphamoylphenyl)androstenediones: Studies of aromatase inhibitor-based oestrone sulphatase inhibition

• Published in: Steroids Vol. 75; no. 12; pp. 891 - 896
• Main Authors: Watari, Yoko, Yamaguchi, Satoshi, Takahashi, Madoka, Nagaoka, Masao, Numazawa, Mitsuteru
• Format: Journal Article
• Language: English
• Published: NEW YORK Elsevier Inc 01.12.2010; Elsevier
• Subjects: Androstenedione - chemical synthesis; Androstenedione - chemistry; Androstenedione - pharmacology; Aromatase - metabolism; Aromatase inhibitor; Aromatase Inhibitors - chemical synthesis; Aromatase Inhibitors - chemistry; Aromatase Inhibitors - pharmacology; Biochemistry & Molecular Biology; Biological and medical sciences; Endocrinology & Metabolism; Fundamental and applied biological sciences. Psychology; Human placental microsomes; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Oestrone sulphatase inhibitor; p-Sulphamoylphenyl-substituted androstenedione; Science & Technology; Sulfatases - antagonists & inhibitors; Vertebrates: endocrinology; p-Sulphamoylphenyl-substituted androstenedione; Aromatase inhibitor; Oestrone sulphatase inhibitor; Human placental microsomes; INACTIVATION; ESTROGENS; p-Sulphamoylphenyl-substituted; ANALOGS; BREAST-TUMOR TISSUES; androstenedione; SITE-DIRECTED INHIBITOR; POTENT INHIBITORS; STEROID SULFATASE; Human; Placenta; Fetal membrane; Inhibition; Androstenedione; Microsome
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2010.05.011

4-( p-Sulphamoylphenyl)androstenedione ( 3) and 6α- p-sulphamoylphenyl analogues 12– 14 were synthesised and tested as aromatase inhibitors as well as oestrone sulphatase inhibitors in human placental microsomes. All of the p-sulphamoylphenyl compounds synthesised were powerful inhibitors of aromatase with apparent K i values ranging between 30 and 97 nM. In addition, the aromatase inhibitory activities of 6α- p-hydroxyphenyl compounds 9– 11, which may be produced from their respective sulphamoylphenyl compounds by action of oestrone sulphatase, were also high in a range of 23 and 75 nM of the K i values. On the other hand, all of the sulphamoylphenyl compounds were poor inhibitors of oestrone sulphatase with more than about 200 μM of IC 25 values. Although the present findings of the oestrone sulphatase inhibition are disappointing, such attempts may be valuable to develop a new class of drugs having a dual function, aromatase inhibitor and oestrone sulphatase inhibitor, for the treatment of oestrogen-dependent breast cancer.