A‐Ring‐Modified 2‐Hydroxyethylidene Previtamin D₃ Analogues: Synthesis and Biological Evaluation

Abstract

Abstract:To investigate the biological profile of the previtamin form of vitamin D, we have synthesized new analogues of 19-nor-1α,25-dihydroxyprevitamin D3 bearing a 2-hydroxyethylidene moiety at the A-ring. The target compounds were prepared by convergent synthesis employing the Sonogashira coupling between an A-ring enyne synthon and a CD-ring/side chain vinyl triflate. We have demonstrated the versatility of shikimic acid as starting material for the synthesis of the A-ring precursors. The binding affinity to Vitamin D Receptor (VDR) and Vitamin D Binding Protein (DBP), and MCF-7 cell antiproliferative activity have been evaluated.

Production and Synthetic Modifications of Shikimic Acid

“…Use of shikimic acid or its epi isomers resulted in preparation of several 6- s - cis analogues of 1α,25-dihydroxyvitamin D 3 . , Recently, this was expanded to the preparation of 2-hydroxyethylidene previtamin D 3 analogues 745 and 746 (Scheme ). The oxidation of the free OH group at C-4 of the shikimic acid skeleton in 736 with Dess–Martin periodinane to the corresponding ketone 737 was followed by cyanomethylation to provide 738 as a mixture of isomers. Reduction of the nitrile to the allyl alcohol 739 and further protection led to formation of the synthon 740 .…”

Convergent Approaches and Biological Activity of C1 and/or C3 Mono or Diamino Derivatives of 1α,25‐Dihydroxy‐19‐nor‐vitamin D3. Key Enzymatic Desymmetrization of A‐Ring Synthon Precursor

“…Taking into account all these precedents and our research focused on the preparation of A-ring modified analogs, [15] we now describe several new derivatives (11)(12)(13)(14)(15) produced by replacing one or both hydroxyl groups of the A-ring of 1α,25-dihydroxy-19-norvitamin D 3 by amino groups and to change the configurations on C1 and C3 stereocenters (Figure 3). In addition to the synthesis, we also report the biological activities.…”

Stereodivergent Syntheses of All Stereoisomers of (−)‐Shikimic Acid: Development of a Chiral Pool for the Diverse Polyhydroxy‐cyclohexenoid (or ‐cyclohexanoid) Bioactive Molecules

“…(−)‐SA 1 is very useful material for syntheses of drugs and pharmaceutically valuable natural products. For examples, it has been extensively used in the syntheses of oseltamivir phosphate (Tamiflu), [7] valiolamine, [8] valienamine, [8a,9] NOV, [10] NOEV, [10] pericosines (A, B, D and E), [11] zeylenones, [12] (−)‐MK7607, [13] previtamin D 3 , [14] quercitols, [15] and (−)‐quinic acid [16] . (−)‐SA 1 and its derivatives might also be very important in drug discovery, since they have shown a wide range of physiological activities [17] such as antiviral, anti‐bacterial, anti‐fungi, anti‐osteoclastogenesis, anti‐platelet, anti‐thrombogenic, anti‐inflammatory, anti‐oxidant, and anti‐tumor activities.…”