Fujishima Toshie, Kittaka Atsushi, Kurihara Masaaki, Saito Nozomi, Honzawa Shinobu, Kishimoto Seishi, Sugiura Takayuki, Waku Keizo, Takayama Hiroaki
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa 199-0195, Japan.
J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):89-92. doi: 10.1016/j.jsbmb.2004.03.053.
All four possible A-ring stereoisomers of 2,2-dimethyl-1,25-dihydroxyvitamin D(3) (4) were designed and convergently synthesized. Nine-step conversion of methyl hydroxypivalate 6 provided the desired A-ring enyne synthon (13a,b) in good overall yield. Cross-coupling reaction of the A-ring synthon 13a,b with the CD-ring portion in the presence of palladium catalyst, followed by deprotection, gave the vitamin analogues (4a-d). We also synthesized four stereoisomers of 2,2-ethano-1,25-dihydroxyvitamin D(3) (5), as novel spiro-ring analogues having cyclopropane fused at the C2 position. Biological potencies of the synthesized compounds were assessed in terms of the vitamin D receptor (VDR) binding affinity, as well as the HL-60 cell differentiation-inducing activity. The 2,2-ethano analogue 5a showed a comparable activity to the natural hormone 1, while the 2,2-dimethyl analogue 4a exhibited one-third of the activity of 1 in cell differentiation, with the reduced VDR binding affinity.
设计并汇聚合成了2,2-二甲基-1,25-二羟基维生素D(3)（4）的所有四种可能的A环立体异构体。甲基羟基新戊酸酯6经过九步转化，以良好的总收率得到了所需的A环烯炔合成子（13a,b）。A环合成子13a,b与CD环部分在钯催化剂存在下进行交叉偶联反应，然后脱保护，得到维生素类似物（4a-d）。我们还合成了2,2-亚乙基-1,25-二羟基维生素D(3)（5）的四种立体异构体，它们是在C2位置稠合有环丙烷的新型螺环类似物。根据维生素D受体（VDR）结合亲和力以及HL-60细胞分化诱导活性对合成化合物的生物活性进行了评估。2,2-亚乙基类似物5a表现出与天然激素1相当的活性，而2,2-二甲基类似物4a在细胞分化中的活性仅为1的三分之一，且VDR结合亲和力降低。
