Development of Analogues of 1α,25-Dihydroxyvitamin D3 with Biased Side Chain Orientation: Methylated Des-C,D-Homo Analogues

Abstract

The discovery that 1alpha,25-dihydroxyvitamin D3 is effective in the inhibition of cellular proliferation and in the induction of cellular differentiation has led to a search for analogues in which these activities and the classical calcemic activity of this hormone are separated. In this context, the synthesis and biological evaluation are reported of the three stereoisomeric CD-ring modified structural analogues in order to enforce a particular and different orientation of the 25-hydroxylated side chain. Comparison of the results of the biological evaluation and conformational analysis of the side chain suggests one defined and "active" geometry.

Development of Analogues of 1α,25‐Dihydroxyvitamin D3 with Biased Side‐Chain Orientation: C20 Methylated Des‐C,D‐homo Analogues

“…Further synthesis of key intermediates 12a , 13a , and 13b from 10a , 11a , and 11b , respectively, proceeds by dissolving metal reduction of the corresponding unsaturated estersobtained by Peterson or Horner–Wadsworth–Emmons (HWE) olefination. The choice of this methodology was dictated by prior work in which it was observed that the reduction of 18 (mixture of E , Z isomers) with lithium in liquid ammonia led to saturated ester 19 in high yield with the ethoxycarbonylmethyl side chain in the preferred equatorial orientation (Scheme ) 10…”

Analogs of Calcitriol

“…In particular, the relative orientation of the methyl substituents at C-13, C-16, or C-20 determines the distinct conformation of the side chain at C-17. The most biologically active compounds of this series of D6-ring analogs were the ones with the side chain associated with the active region (based on calculated occupancies of the side chain) [35,38].…”

Structure–function relationships of vitamin D including ligand recognition by the vitamin D receptor

“…Semi-nonsteroidal vitamin D analogs have also been reported in which a part of the natural hormone was significantly modified: such as aromatic A-ring analogs 98,99 and des-C,D-homo analogs. 100 We look forward to the development of non-steroidal vitamin D analogs having novel and selective action spectra, and their use in treating diseases such as cancer, immune disorders, and Alzheimer's disease.…”