Yukiko Iwasaki

Novel synthesis of 2-Substituted 19-norvitamin D A-ring phosphine oxide from d-glucose as a building block

19-norvitamin D A-ring phosphine oxide 5 was synthesized by a new sequence mode starting from D-glucose as a chiral template. Transformation of the pyranoside ring into the A-ring carbocycle was achieved by the Pd-catalyzed Ferrier rearrangement. The phosphine oxide 5 was obtained in an 18% overall yield by this novel cost-effective method.

Two-dimensional alanine scanning mutational analysis of the interaction between the vitamin D receptor and its ligands: studies of A-ring modified 19-norvitamin D analogs☆☆☆

To clarify the structure-function relationship (SFR) of vitamin D analogs in terms of their interaction with the vitamin D receptor (VDR), we have proposed a new approach, two-dimensional alanine scanning mutational analysis (2D-ASMA). In this paper, attention was focused on the interactions around the A-ring of vitamin D. For this purpose, we synthesized four new 2-substituted 19-norvitamin D derivatives (3-6). The VDR affinity (3-6: 1, 5, 2 and 1/140, respectively) and transcriptional activity (3-6: 10, 30, 2 and 0.3, respectively) of the four compounds were evaluated relative to 1,25-(OH)(2)D(3) (5) (normalized to 1). Then, the transcriptional activities of wild-type and 18 mutant VDRs induced by the four compounds (3-6) were investigated. The results of this 18 x 4 2D-ASMA were presented as a patch table, and the effects of the mutations were analyzed in comparison with the natural hormone (1) and 2-methylene-19-nor-20-epi-1,25-(OH)(2)D(3) (2MD, 2). Of the four A-ring analogs, the 2alpha-hydroxyethoxy derivative (3) showed striking differences in the pattern on the patch table. From the results, we suggest a docking mode of this compound (3) in which the A-ring adopts the alpha conformation.

4,4-Difluoro-1α,25-dihydroxyvitamin D3: Analog to probe A-ring conformation in vitamin D-receptor complex

Abstract 4,4-Difluoro-1α,25-dihydroxyvitamin D 3 was synthesized from ergosterol and analysis of its 19 F NMR showed it to be a useful probe to analyze the receptor-bound A-ring conformation of vitamin D.

Regioselective synthesis of 19-fluorovitamin D via fluorination of vitamin D-sulfur dioxide adducts

Abstract 19-Fluorovitamin D derivatives are conveniently synthesized by the regioselective electrophilic fluorination of vitamin D-SO 2 adducts followed by desulfonylation and photochemical isomerization.

Determination of 25-hydroxyvitamin D3 in human plasma using a non-radioactive tetranorvitamin D analogue as an internal standard

A convenient non-radioactive method for assaying plasma 25-hydroxyvitamin D3 is described. The method uses 22-hydroxytetranorvitamin D3 as an internal standard and includes two-step liquid- and solid-phase extractions and quantification by normal-phase HPLC. The intra- and inter-assay coefficients of variation were 2.2% and 2.4%, respectively, and the analytical recovery of 25-hydroxyvitamin D3 added to plasma was quantitative. Assay linearity was obtained in the range 0.5-4.0 ml of plasma. When compared with the method employing a radioactive 25-hydroxyvitamin D3 tracer, the correlation coefficient was 0.990 (slope 0.999 and intercept 1.19 ng/ml).

Isolation and identification of 2α,25-dihydroxyvitamin D3, a new metabolite from Pseudonocardia autotrophica 100U-19 cells incubated with Vitamin D3

Pseudonocardia autotrophica converted Vitamin D(3) to 25-hydroxyvitamin D(3) and 1alpha,25-dihydroxyvitamin D(3). The hydroxylation of Vitamin D(3) with P. autotrophica was enhanced by the addition of cyclodextrin. In this microbial hydroxylation, a new Vitamin D(3) metabolite was observed in the reaction mixture of P. autotrophica and Vitamin D(3), and was isolated in a pure form by several steps of chromatography. The structure of the new metabolite was determined to be 2alpha,25-dihydroxyvitamin D(3) by UV, NMR and mass spectroscopic analyses. Biological evaluation of the new metabolite was conducted by means of several experiments.

Reaction of geometrical isomers of retinoic acid with 1,2,4-triazoline-3,5-dione having fluorescent chromophore

Abstract Reactions of 1,2,4-triazoline-3,5-dione having fluorescent chromophore (DMEQ-TAD) with 9 Z -, 11 Z -, 13 Z -, and 11 Z , 13 Z -isomers of retinoic acid were studied. Except for the 9 Z -isomer, the reactions gave the 7,10-adducts in high selectivity while 9 Z -isomer gave only th 5,8,11,14-bis adducts. Interesting self-sensitized photochemical isomerizations of these adducts and the mechanism of the addition reactions are discussed.