Synthesis and evaluation of raloxifene derivatives as a selective estrogen receptor down-regulator |
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| Affiliation: | 1. National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan;2. School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan;3. Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama, Kanagawa 226-8501, Japan;1. Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland;2. The Emmanuel Institute of Biochemical Physics, Russian Academy of Sciences, Kosygina 4, Moscow 119991, Russia;1. Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland;2. Department of Pharmacological Screening, Jagiellonian University Medical College, Kraków, Poland;3. Department of Pharmacobiology, Jagiellonian University Medical College, Kraków, Poland;4. Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland;1. Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan;2. Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan;3. Division of Organic Chemistry, National Institute of Health Sciences, Tokyo 158-8501, Japan;4. Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan;1. Department of Dermatology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France;2. Department of Plastic Surgery, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France;3. Department of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France;4. INSERM U976 and Univ Paris Diderot, Sorbonne Paris Cité, Paris, France;5. Department of Pathology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France;1. Department of Chemistry, Government College (Affiliated to Veer Narmad South Gujarat University, Surat), Daman, UT DNH & DD, India;2. Post Graduate Department of Chemistry, S. P. Mandali’s Sir Parashurambhau College (Affiliated to Savitribai Phule Pune University), Tilak Road, Pune 411 030, India;3. Combi Chem Bio Resource Centre, National Chemical Laboratory, Pune 411 008, India |
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| Abstract: | Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. A selective estrogen receptor down-regulator (SERD) that acts as not only an inhibitor of ligand binding, but also induces the down-regulation of ER, would be useful for the treatment for ER-positive breast cancer. We previously reported that tamoxifen derivatives, which have a long alkyl chain, had the ability to down-regulate ERα. With the aim of expanding range of the currently available SERDs, we designed and synthesized raloxifene derivatives, which had various lengths of the long alkyl chains, and evaluated their SERD activities. All compounds were able to bind ERα, and RC10, which has a decyl group on the amine moiety of raloxifene, was shown to be the most potent compound. Our findings suggest that the ligand core was replaceable, and that the alkyl length was important for controlling SERD activity. Moreover, RC10 showed antagonistic activity and its potency was superior to that of 4,4′-(heptane-4,4-diyl)bis(2-methylphenol) (18), a competitive antagonist of ER without SERD activity. These results provide information that will be useful for the development of promising SERDs candidates. |
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| Keywords: | Selective estrogen receptor down-regulator ER-positive breast cancer Raloxifene |
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