Design and synthesis of novel 1,25-dihydroxyvitamin D-3 analogues having a spiro-oxetane fused at the C2 position in the A-ring

Four structurally novel stereoisomeric analogues of 1,25-dihydroxyvitamin D-3 (3a-d) bearing a spiro-oxetane fused at the C2 position of the A-ring have been designed and synthesised in a convergent manner. The requisite A-ring enyne precursors (13a,b) for the vitamin D analogues (3a,b) and (3c,d),...

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Bibliographic Details
Published inBioorganic & medicinal chemistry Vol. 21; no. 17; pp. 5209 - 5217
Main Authors Fujishima, Toshie, Nozaki, Takato, Suenaga, Tsutomu
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier 01.09.2013
Subjects
Biochemistry & Molecular Biology
Chemistry
Chemistry, Medicinal
Chemistry, Organic
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Physical Sciences
Science & Technology
Hormone
Steroid
Nuclear receptor
Vitamin
STEREOCHEMISTRY
VITAMIN-D-RECEPTOR
1-ALPHA,25-DIHYDROXYVITAMIN D-3
2-METHYL-1,25-DIHYDROXYVITAMIN D-3
Oxetane
BIOLOGICAL EVALUATION
DIASTEREOMERS
CONFORMATIONAL-ANALYSIS
EFFICIENT
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Summary:Four structurally novel stereoisomeric analogues of 1,25-dihydroxyvitamin D-3 (3a-d) bearing a spiro-oxetane fused at the C2 position of the A-ring have been designed and synthesised in a convergent manner. The requisite A-ring enyne precursors (13a,b) for the vitamin D analogues (3a,b) and (3c,d), respectively, were synthesised from pentaerythritol according to an eleven-step procedure. Preliminary biological evaluation of the analogues using the bovine thymus vitamin D receptor (VDR) suggested that the incorporation of the spiro-oxetane moiety instead of a gem-dimethyl group at the C2 position had a beneficial effect on the VDR affinity. (C) 2013 Elsevier Ltd. All rights reserved.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.06.032