Synthesis and biological properties of 2-methylene-19-nor-25-dehydro-1α-hydroxyvitamin D3-26,23-lactones—weak agonists

In a continuing effort to explore the 2-methylene-1α-hydroxy-19-norvitamin D3 class of pharmacologically important vitamin D compounds, two novel 2-methylene-19-nor-25-dehydro-1α-hydroxyvitamin D3-26,23-lactones, GC-3 and HLV, were synthesized and biologically tested. Based on reports of similarly structured molecules, it was hypothesized that these compounds might act as antagonists, at least in vitro. The pathway designed to synthesize these compounds was based on two key steps: first, the Lythgoe-type Wittig–Horner coupling of Windaus–Grundmann-type ketone 18, with phosphine oxide 15, followed, later in the synthesis, by the Zn-mediated Reformasky-type allylation of aldehyde 20 with methylbromomethylacrylate 8. Our biological data show that neither compound has antagonistic activity but acts as weak agonists in vitro and in vivo.

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