Synthesis of 1α,25-Dihydroxyvitamin D Analogues Featuring a S2-symmetric CD-ring Core

Garrett Minne,Lieve Verlinden,Annemieke Verstuyf,Pierre J De Clercq

doi:10.3390/molecules14020894

Garrett Minne, Lieve Verlinden + Show 2 more

Open Access

https://doi.org/10.3390/molecules14020894

Copy DOI

Journal: Molecules (Basel, Switzerland)	Publication Date: Feb 24, 2009
Citations: 22	License type: CC BY 4.0

Affiliation: Ghent University, KU Leuven

Abstract

Three analogues of 1α,25-dihydroxyvitamin D3 (calcitriol), featuring a trans-fused decalin C,D-core with local S2-symmetry, and possessing identical side-chain and seco-B,A-ring structures, have been synthesized starting from readily available (4aR,8aS)-octahydronaphthalene-1,5-dione (7). The very short sequences involve the simultaneous introduction of the side-chain and seco-B,A-ring fragments via Suzuki and Sonogashira coupling reactions. The analogues are devoid of relevant biological activity.

Highlights

Since the discovery that the biological action of vitamin D3 originates from the dihydroxylated metabolite 1α,25-dihydroxyvitamin D3 (1, calcitriol) and that, next to its classical role in the regulation of calcium homeostasis, these actions involve immunomodulation, cell differentiation and antiproliferation, there has been an intense search for structural analogues of calcitriol that might show a separation in calcemic and antiproliferative-prodifferentiating activities (Scheme 1) [1]
Whereas most efforts in the development of analogues have been directed towards modifications in the flexible parts, our laboratories have always focused on the central less accessible part of the molecule, and almost as a rule, such modifications have led to a reduction in calcemic activity [16]
In the present work advantage is taken of the S2-symmetry of the readily available bisenol triflate 8 to introduce simultaneously fragments that may be considered as structural variations of the classical side-chain and of the seco-B,A-ring of calcitriol

Summary

Introduction

Since the discovery that the biological action of vitamin D3 originates from the dihydroxylated metabolite 1α,25-dihydroxyvitamin D3 (1, calcitriol) and that, next to its classical role in the regulation of calcium homeostasis, these actions involve immunomodulation, cell differentiation and antiproliferation, there has been an intense search for structural analogues of calcitriol that might show a separation in calcemic and antiproliferative-prodifferentiating activities (Scheme 1) [1]. In principle the structural features of analogues 2 should allow for very direct and convergent syntheses in which the two identical fragments representing the side chain and the seco-B,A-ring are introduced simultaneously on a suitable functionalized trans-decalin core in a process were stereoisomers would not be formed.

Results

Conclusion