de Medina Philippe, Paillasse Michael R, Payré Bruno, Silvente-Poirot Sandrine, Poirot Marc
Equipe Métabolisme, Oncogenèse et Différenciation Cellulaire, Inserm U563, Toulouse, France.
J Med Chem. 2009 Dec 10;52(23):7765-77. doi: 10.1021/jm901063e.
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.
我们在此描述新型烷基氨基氧甾醇的合成及其生物学特性。通过5,6-α-环氧甾醇与包括组胺、腐胺、亚精胺或精胺在内的各种天然胺进行反式双轴氨解反应来合成化合物。本文介绍了这16种新型5α-羟基-6β-氨基烷基甾醇的区域选择性合成。首先对化合物进行体外树突生长和细胞毒性筛选，选择了两个先导化合物并进一步进行表征。5α-羟基-6β-[2-(1H-咪唑-4-基)乙氨基]胆甾烷-3β-醇，称为树突生成素A，可诱导多种癌症（包括转移性黑色素瘤和乳腺癌）代表性肿瘤细胞系的生长控制、分化和死亡。5α-羟基-6β-[3-(4-氨基丁基氨基)丙氨基]胆甾-7-烯-3β-醇，称为树突生成素B，可在纳摩尔浓度下诱导多种细胞系的神经突生长、多能细胞中的神经元分化以及正常神经元的存活。总之，我们报道了两种新型烷基氨基氧甾醇，树突生成素A和树突生成素B，它们是一类在纳摩尔浓度下诱导细胞分化的化合物中的首批成员，是治疗癌症或神经退行性疾病的有前景的新先导化合物。
