Oves Daniel, Fernández Susana, Ferrero Miguel, Bouillon Roger, Verstuyf Annemieke, Gotor Vicente
Departamento de Química Orgánica e Inorgánica, Facultad de Química, Universidad de Oviedo, Spain.
Bioorg Med Chem. 2006 Feb 15;14(4):928-37. doi: 10.1016/j.bmc.2005.09.009. Epub 2005 Oct 4.
A concise route to 1alpha,3beta-diamino-25-hydroxy-3-deoxyvitamin D(3) (5) and 1beta,3alpha-diamino-25-hydroxy-3-deoxyvitamin D(3) (6) has been developed starting from (R)- or (S)-carvone for the construction of the modified A-ring fragments. The conversion of the hydroxyl group to amine function with complete inversion of the configuration was efficiently accomplished by Mitsunobu reaction using phthalimide as nucleophile or activation of the hydroxyl group as mesylate followed by reaction with NaN(3). Diamino 5 and 6 as well as monoamino 3, 4, 30, and 31 vitamin D(3) derivatives have shown poor binding to VDR compared with 1alpha,25-dihydroxyvitamin D(3). The most active compound in the inhibition of MCF-7 cell proliferation and HL 60 cell differentiation was 1alpha-amino analogue 3. Also, very low in vivo calcemic effects of derivatives 3 and 4 were found.
从（R）-或（S）-香芹酮出发，已开发出一条简洁的路线来合成1α,3β-二氨基-25-羟基-3-脱氧维生素D₃（5）和1β,3α-二氨基-25-羟基-3-脱氧维生素D₃（6），用于构建修饰的A环片段。通过使用邻苯二甲酰亚胺作为亲核试剂的Mitsunobu反应，或者将羟基活化为甲磺酸酯然后与NaN₃反应，可有效地实现羟基向胺官能团的转化，且构型完全翻转。与1α,25-二羟基维生素D₃相比，二氨基5和6以及单氨基3、4、30和31维生素D₃衍生物对维生素D受体（VDR）的结合能力较差。在抑制MCF-7细胞增殖和HL 60细胞分化方面，活性最高的化合物是1α-氨基类似物3。此外，还发现衍生物3和4的体内血钙升高作用非常低。
