Vitamin D analogue: potent antiproliferative effects on cancer cell lines and lack of hypercalcemic activity.

The active form of vitamin D3, 1α,25(OH)2D3, plays a major role in maintaining calcium/phosphate homeostasis. In addition, it is a potent antiproliferative and pro-differentiating agent. Unfortunately, it usually causes hypercalcemia in vivo when effective antitumour doses are used. It has therefore been found necessary to synthesise new analogues that retain or even increase the antitumour effects but preclude hypercalcemia. This report presents the synthesis of a novel Gemini vitamin D analogue (UVB1) and its biological evaluation. We demonstrate that this compound has potent antitumoural effects over a wide panel of tumour cell lines while showing lack of hypercalcemic activity and toxicity effects in in vivo assays.

Gemini analogs of vitamin D.

The Gemini analogs are the last significant contribution to the family of vitamin D derivatives in medicine, for the treatment of cancer. The first Gemini analog was characterized by two symmetric side chains at C-20. Following numerous modifications, the most active analog bears a C-23-triple bond, C-26, 27- hexafluoro substituents on one side chain and a terminal trideuteromethylhydroxy group on the other side chain. This progression was possible due to improvements in the synthetic methods for the preparation of these derivatives, which allowed for increasing molecular complexity and complete diastereoselective control at C-20 and the substituted sidechains.

Stereoselective synthesis of C24-hydroxylated vitamin D3 analogs: a practical and expeditius route to calcipotriol.

The synthesis of the clinically important drug calcipotriol (2, MC903) is described as an example of a new and efficient approach to C24-hydroxylated analogs and metabolites of vitamin D3 (1). The key step of the process is the generation of the C24 stereocenter by DAIB [(-)-3-exo-(dimethylamino)isoborneol]-catalyzed addition of the alkenylzinc derivative of alkyne 3 to cyclopropylcarboxaldehyde.

Crystal structure of the vitamin D nuclear receptor ligand binding domain in complex with a locked side chain analog of calcitriol.

The crystal structures of vitamin D nuclear receptor (VDR) have revealed that all compounds are anchored by the same residues to the ligand binding pocket (LBP). Based on this observation, a synthetic analog with a locked side chain (21-nor-calcitriol-20(22),23-diyne) has been synthesized in order to gain in entropy energy with a predefined active side chain conformation. The crystal structure of VDR LBD bound to this locked side chain analogue while confirming the docking provides a structural basis for the activity of this compound.

The first locked side-chain analogues of calcitriol (1alpha,25-dihydroxyvitamin D3) induce vitamin D receptor transcriptional activity.

[structure: see text]. We describe the synthesis of the first locked side-chain analogues of the natural hormone 1alpha,25-(OH)2-D3 and their effects on gene transcription in human colon cancer cells. Analogue 2 was more potent than 1alpha,25-(OH)2-D3 at inducing vitamin D receptor (VDR) transcriptional activity. Analogues 3a and 3b show potency similar to that of 1alpha,25-(OH)2-D3, whereas 3c was less active. The novel analogues efficiently bind VDR in vivo to induce transcription from a consensus vitamin D responsive element (VDRE).