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Enzymatic Desymmetrization of 19‐ nor ‐Vitamin D 3 A‐Ring Synthon Precursor: Synthesis, Structure Elucidation, and Biological Activity of 1α,25‐Dihydroxy‐3‐ epi ‐19‐ nor ‐vitamin D 3 and 1β,25‐Dihydroxy‐19‐ nor ‐vitamin D 3
Author(s) -
GonzálezGarcía Tania,
Verstuyf Annemieke,
Verlinden Lieve,
Fernández Susana,
Ferrero Miguel
Publication year - 2018
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201800481
Subject(s) - chemistry , stereochemistry , calcitriol receptor , diastereomer , ketone , calcitriol , nuclear magnetic resonance spectroscopy , moiety , synthon , chemical synthesis , biochemistry , in vitro , organic chemistry , receptor , calcium
In a search for novel vitamin D derivatives of potential therapeutic value, structurally simple but synthetically challenging A‐ring epimers of the 19‐nor‐ Calcitriol [19‐ nor ‐1α,25‐(OH) 2 ‐D 3 ] at C1 and C3 were efficiently synthesized. Both analogues (1‐ epi‐ and 3‐ epi ‐19‐ nor ‐Calcitriol) were obtained through a convergent synthesis starting from cis,cis ‐1,3,5‐cyclohexanetriol and the protected 25‐hydroxy Grundmann′s ketone. After Julia‐Kocienski coupling of the corresponding C,D‐ring/side chain sulfone fragment with the A‐ring ketone moiety, both vitamin D analogues were isolated. The critical point was how to determine the structural configuration of both diastereoisomers since similar 1 H NMR spectra were observed. For that, a biocatalytic approach was crucial in the synthesis of orthogonally protected derivatives. NMR spectroscopy allows the unambiguous identification of these compounds and as a result the structural elucidation of the desired vitamin D diastereomeric analogues. Affinity studies demonstrated that these 1,25‐19‐ nor analogues have a very low affinity for the vitamin D receptor compared with 1α,25‐dihydroxyvitamin D 3 or 1α,25‐dihydroxy‐19‐ nor ‐vitamin D 3 . In addition, these analogues have a lower binding affinity for the human vitamin D binding protein than the natural hormone. In vitro cell culture studies revealed that synthesized analogues were less active than 1α,25‐dihydroxyvitamin D 3 in inhibiting cell proliferation.