Enzymatic Desymmetrization of 19‐nor‐Vitamin D3 A‐Ring Synthon Precursor: Synthesis, Structure Elucidation, and Biological Activity of 1α,25‐Dihydroxy‐3‐epi‐19‐nor‐vitamin D3 and 1β,25‐Dihydroxy‐19‐nor‐vitamin D3

Abstract

AbstractIn 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‐D3] 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 1H 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 D3 or 1α,25‐dihydroxy‐19‐nor‐vitamin D3. 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 D3 in inhibiting cell proliferation.magnified image