Synthesis of new alkylaminooxysterols with potent cell differentiating activities: identification of leads for the treatment of cancer and neurodegenerative diseases. - Archive ouverte HAL Access content directly
Journal Articles Journal of Medicinal Chemistry Year : 2009

Synthesis of new alkylaminooxysterols with potent cell differentiating activities: identification of leads for the treatment of cancer and neurodegenerative diseases.

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Abstract

We describe here the syntheses and the biological properties of new alkylaminooxysterols. Compounds were synthesized through the trans-diaxial aminolysis of 5,6-alpha-epoxysterols with various natural amines including histamine, putrescine, spermidine, or spermine. The regioselective synthesis of these 16 new 5alpha-hydroxyl-6beta-aminoalkylsterols is presented. Compounds were first screened for dendrite outgrowth and cytotoxicity in vitro, and two leads were selected and further characterized. 5alpha-Hydroxy-6beta-[2-(1H-imidazol-4-yl)ethylamino]cholestan-3beta-ol, called dendrogenin A, induced growth control, differentiation, and the death of tumor cell lines representative of various cancers including metastatic melanoma and breast cancer. 5alpha-Hydroxy-6beta-[3-(4-aminobutylamino)propylamino]cholest-7-en-3beta-ol, called dendrogenin B, induced neurite outgrowth on various cell lines, neuronal differentiation in pluripotent cells, and survival of normal neurones at nanomolar concentrations. In summary, we report that two new alkylaminooxysterols, dendrogenin A and dendrogenin B, are the first members of a class of compounds that induce cell differentiation at nanomolar concentrations and represent promising new leads for the treatment of cancer or neurodegenerative diseases.
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Dates and versions

inserm-00519151 , version 1 (18-09-2010)

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Philippe de Médina, Michael R. Paillasse, Bruno Payré, Sandrine Silvente-Poirot, Marc E. Poirot. Synthesis of new alkylaminooxysterols with potent cell differentiating activities: identification of leads for the treatment of cancer and neurodegenerative diseases.. Journal of Medicinal Chemistry, 2009, 52 (23), pp.7765-77. ⟨10.1021/jm901063e⟩. ⟨inserm-00519151⟩
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