title: Efficient synthesis of 2-modified 1alpha,25-dihydroxy-19-norvitamin D3 with Julia olefination: high potency in induction of differentiation on HL-60 cells.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Ono
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yoshida
authors.forename: Nozomi
authors.initials: N
authors.lastname: Saito
authors.forename: Toshie
authors.initials: T
authors.lastname: Fujishima
authors.forename: Shinobu
authors.initials: S
authors.lastname: Honzawa
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Suhara
authors.forename: Seishi
authors.initials: S
authors.lastname: Kishimoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sugiura
authors.forename: Keizo
authors.initials: K
authors.lastname: Waku
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism; D013329:Structure-Activity Relationship; D013950:Thymus Gland
chemical_list: D018167:Receptors, Calcitriol; C083610:1,25-dihydroxy-19-norvitamin D3; D002117:Calcitriol