Ono Keiichiro, Yoshida Akihiro, Saito Nozomi, Fujishima Toshie, Honzawa Shinobu, Suhara Yoshitomo, Kishimoto Seishi, Sugiura Takayuki, Waku Keizo, Takayama Hiroaki, Kittaka Atsushi
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan.
J Org Chem. 2003 Sep 19;68(19):7407-15. doi: 10.1021/jo034787y.
Six novel 2-substituted analogues of 1alpha,25-dihydroxy-19-norvitamin D(3), 6a,b-8a,b, were efficiently synthesized utilizing (-)-quinic acid as the A-ring precursor. The C2-modified A-rings were prepared as 4-alkylated (3R,5R)-3,5-dihydroxycyclohexanones 12-15 from (-)-quinic acid based on radical allylation at the C4 position of methyl (-)-quinicate. The new type of the CD-ring coupling partner 23 was synthesized from 25-hydroxy Grundmann's ketone 19 to apply to the modified Julia olefination to construct a diene unit between the A-ring and the CD-ring. The coupling yields, including a deprotection step, were 47-62%. After the separation of the diastereomers based on C2 stereochemistry, the structure (2alpha or 2beta) was determined by (1)H NMR experiments and compared to DeLuca's 2-methyl- and 2-ethyl-1alpha,25-dihydroxy-19-norvitamin D(3). Thus, the synthesized 2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxy-19-norvitamin D(3) (8a) showed almost the same potency in binding to the bovine thymus vitamin D receptor (VDR) as the natural hormone 1, while its beta-isomer 8b had only a 3% affinity. Both 2alpha-allyl- and 2alpha-propyl-1alpha,25-dihydroxy-19-norvitamin D(3) (6a and 7a) and their 2beta-analogues (6b and 7b) possessed a weak affinity for the VDR. The strong VDR ligand 8a was ca. 36-fold more potent in induction of HL-60 cell differentiation than 1, and interestingly, even the weaker ligand 8b showed a 6.7-fold higher potency in the cell differentiation activity than that of 1.
以（-）-奎尼酸为A环前体，高效合成了6种新型的1α,25-二羟基-19-去甲维生素D（3）的2-取代类似物6a、b-8a、b。基于（-）-奎尼酸甲酯C4位的自由基烯丙基化反应，将C2修饰的A环制备为4-烷基化的（3R,5R）-3,5-二羟基环己酮12-15。新型CD环偶联伙伴23由25-羟基格伦德曼酮19合成，用于修饰的Julia烯化反应，以在A环和CD环之间构建二烯单元。包括脱保护步骤在内的偶联产率为47-62%。基于C2立体化学分离非对映异构体后，通过1H NMR实验确定结构（2α或2β），并与DeLuca的2-甲基-和2-乙基-1α,25-二羟基-19-去甲维生素D（3）进行比较。因此，合成的2α-（3-羟丙基）-1α,25-二羟基-19-去甲维生素D（3）（8a）与天然激素1结合牛胸腺维生素D受体（VDR）的活性几乎相同，而其β-异构体8b的亲和力仅为3%。2α-烯丙基-和2α-丙基-1α,25-二羟基-19-去甲维生素D（3）（6a和7a）及其2β-类似物（6b和7b）对VDR的亲和力较弱。强VDR配体8a诱导HL-60细胞分化的活性约为1的36倍，有趣的是，即使较弱的配体8b在细胞分化活性方面也比1高6.7倍。
