Design and synthesis of silicon-containing steroid sulfatase inhibitors possessing pro-estrogen antagonistic character |
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| Institution: | 1. Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan;2. Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan;3. Department of Biochemistry, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan;1. Laboratory of Theoretical Chemistry, Department of Chemistry, University of Maragheh, P.O. Box 5513864596, Maragheh, Iran;2. Quantum Chemistry Group, Department of Chemistry, Faculty of Sciences, Arak University, Arak 38156-8-8349, Iran;1. Wonkwang University, Iksan 570-749, Jeonbuk, Republic of Korea;2. CF Technology Division, AUK Corporation, Iksan 570-210, Jeonbuk, Republic of Korea;1. Laboratoire de Physico-Chimie Informatique (PCI), Unité de Chimie Physique Théorique et Structurale, University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium;2. Laboratoire CEISAM – UMR CNRS 6230, Université de Nantes, 2 rue de la Houssinière, BP92208, 44322 Nantes Cedex 3, France;3. Institut Universitaire de France 103, Boulevard St Michel, 75005 Paris Cedex 5, France |
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| Abstract: | Steroid sulfatase (STS) is a potential target for treatment of postmenopausal hormone-dependent breast cancer. Several steroidal STS inhibitors have been reported, but steroidal compounds are difficult to optimize and may interact with other targets. On the other hand, we have shown that diphenylmethane (DPM) derivatives act as estrogen receptor (ER) agonists and antagonists. Here, we aimed to design and synthesize non-steroidal DPM-type STS inhibitors that would also serve as pro-estrogen antagonists, releasing a metabolite with ERα-antagonistic activity upon hydrolysis by STS. We synthesized a series of compounds and evaluated their biological activities by means of STS-inhibitory activity assay and ER reporter gene assay. Among them, silicon-containing compound 16a showed strong STS-inhibitory activity (IC50 = 0.17 μM). Further, its putative metabolite (12a) exhibited potent ERα-antagonistic activity (IC50 = 29.7 nM). |
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| Keywords: | Steroid sulfatase inhibitor Estrogen antagonist Silicon Diphenylmethane Breast cancer |
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