Synthesis and preliminary biological evaluation of new antiproliferative aromatic analogues of 1α,25-dihydroxyvitamin D3

• 5,7-diene in calcitriol can be rigidified in analogues without a total lost of the VDR affinity.
• The use of Negishi coupling is suitable for synthesis of aromatic vitamin D3 analogues.
• Particular reactivity of aryl bromide/triflate during the Negishi coupling.

In an effort to develop novel vitamin D3 analogues, a series of aromatic compounds was synthetized, using efficient Negishi cross coupling between alkenylzinc reagents of the C,D-ring moiety of vitamin D3, and various substituted aromatic halides as A-ring mimics. The study aimed at exploring the influence of the replacement of the original vitamin D3 diene by a styrene unit on the biological activities. Potency in the induction of the differentiation of HL-60 cells for the lead compound 36 was 12 fold less important than calcitriol correlating with a weaker binding affinity for VDR.

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