Design, Synthesis, and Biological Evaluation of a 1α,25-Dihydroxy-19-norvitamin D₃ Analogue with a Frozen A-Ring Conformation

Abstract

To establish the conformation of vitamin D compounds responsible for biological activity, a 1alpha,25-dihydroxy-19-norvitamin D analogue 4 possessing a 1alpha-hydroxy group fixed in the axial orientation (beta-chair form) was synthesized. The starting compounds were bicyclic lactones 6, 7a, and 7b, derived from the quinic acid lactone, which were converted to the bicyclic ketone 13. Julia coupling of this compound with sulfone 15 produced the 19-norvitamin D analogue 4, possessing an additional ring connecting the 3beta-oxygen and C-2, and the isomeric 3beta-hydroxy compound 5. In vitro, both analogues 4 and 5 exhibit reduced activity compared to the natural hormone 1, but the binding, differentiation, and transcriptional activities of analogue 5 are markedly higher than that of 4 constrained in the alpha-chair conformation. Surprisingly, in vivo tests in mice showed that the analogue 4 significantly increases serum calcium at dose levels similar to 1alpha,25-(OH)2D3. These seemingly discordant results are discussed.

New 1α,25-Dihydroxy-19-norvitamin D3 Compounds Constrained in a Single A-Ring Conformation: Synthesis of the Analogues by Ring-Closing Metathesis Route and Their Biological Evaluation

“…The latter proved to be identical in all respects with the previously synthesized compound; its silyl derivative 6 was used by us as a building block in the synthesis of the vitamin D analogue 3. 15 The Julia olefination reaction, carried out with the ketone 5 and the anion of the sulfone 25, was followed by the acidic deprotection of the hydroxyls. The resulting 19-norvitamin D compounds 2 and 26 were separated and purified by repeated HPLC.…”

“…We have recently described the preparation of such 19-norvitamin D compound 3 possessing the propylidene substituent at C-2 connected to a 3 -oxygen atom. 15 The synthesized analogue 3 was characterized, in comparison to the natural hormone, by very low binding and transciptional activity. To our surprise, the in vivo tests showed remarkable potency of this compound.…”

Application of aluminum triiodide in organic synthesis

“…[38][39] (IV) In a similar manner (±)-plumbazeylanone (54), a trimer of naphthoquinone, was achieved by exhaustive demethylation of ether 53 followed by air oxidation in 65% yield (Scheme 3D). 40 (V) Resveratrol (56b) and its derivatives such as oxyresveratrol (56c) and piceatannol (56d) were obtained by exhaustive deprotection of related phenolic methyl ethers (55). The transformations were complete after 3 hours of refluxing in acetonitrile, and afforded polyphenols (56a~56d) in 68~83% yields.…”

“…51 The method could not be extended to aldehydes due to the formation of hemithioacetals. [55][56][57] (III) MOE was attached to a diarylmethane scaffold (74) for additional coordinations to reactive lithium species and hence for improved enantiomeric excess (75) in asymmetric alkylation (Scheme 5C). The protecting group was removed by AlI 3 to afford (R)-2-(1-phenylethyl)phenol (76) in 75% yield.…”

New 1α,25-dihydroxy-19-norvitamin D3 analogs with a frozen A-ring conformation

“…Almost four decades later, the X-ray crystallographic studies of a complex of the natural hormone 1 and hVDR mutant supported this assumption [8]. To exclude the possibility of chair inversion occurring in the physiological milieu, we have synthesized the 19-norvitamin D analogs 2 and 3 in which the ring A could exist only in the ␣-chair form [9,10]. Although these compounds had very poor binding affinities to VDR, they both showed surprisingly high calcemic activity in vivo, suggesting a possible cleavage of their dihydropyran (dihydrofuran) ring.…”