Design, synthesis and biological evaluation of bis(hydroxyphenyl) azoles as potent and selective non-steroidal inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) for the treatment of estrogen-dependent diseases

---

Atıf İçin Kopyala

Bey E., Marchais-Oberwinkler S., Kruchten P., Frotscher M., Werth R., Oster A., ...Daha Fazla

BIOORGANIC & MEDICINAL CHEMISTRY, cilt.16, sa.12, ss.6423-6435, 2008 (SCI-Expanded)

• Yayın Türü: Makale / Tam Makale
• Cilt numarası: 16 Sayı: 12
• Basım Tarihi: 2008
• Doi Numarası: 10.1016/j.bmc.2008.04.073
• Dergi Adı: BIOORGANIC & MEDICINAL CHEMISTRY
• Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
• Sayfa Sayıları: ss.6423-6435
• Anahtar Kelimeler: 17 beta-HSD1, 17 beta-HSD2, non-steroidal inhibitor, ER, estrogen-dependent diseases, bis(hydroxyphenyl) azoles, BREAST-CANCER, ESTRADIOL, DEHYDROGENASE, DERIVATIVES, STEROIDS, LIGANDS, COMPLEX, MAINTENANCE, TEMPLATES, CHEMISTRY
• Erzincan Binali Yıldırım Üniversitesi Adresli: Hayır

Özet

The 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) catalyses the reduction of the weakly active estrone (E1) into the most potent estrogen, 17 beta-estradiol (E2). E2 stimulates the growth of hormone-dependent diseases via activation of the estrogen receptors (ERs). 17 beta-HSD1 is often over-expressed in breast cancer cells. Thus, it is an attractive target for the treatment of mammary tumours. The combination of a ligand-and a structure-based drug design approach led to the identification of bis(hydroxyphenyl) azoles as potential inhibitors of 17 beta-HSD1. Different azoles and hydroxy substitution patterns were investigated. The compounds were evaluated for activity and selectivity with regard to 17 beta-HSD2, ER alpha and ER beta. The most potent compound is 3-[ 5-(4-hydroxyphenyl)-1,3-oxazol-2-yl] phenol (18, IC50 = 0.31 mu M), showing very good selectivity, high cell permeability and medium CaCo-2 permeability. (c) 2008 Elsevier Ltd. All rights reserved.