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