Synthesis and Biological
Evaluation of 1α,25-Dihydroxyvitamin
D<sub>3</sub> Analogues with a Long Side Chain at C12 and Short C17
Side Chains
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Abstract
Structure-guided optimization was used to design new
analogues
of 1α,25-dihydroxyvitamin D<sub>3</sub> bearing the main side
chain at C12 and a shorter second hydroxylated chain at C17. The new
compounds <b>5a</b>–<b>c</b> were efficiently synthesized
from ketone <b>9</b> (which is readily accessible from the Inhoffen–Lythgoe
diol) with overall yields of 15%, 6%, and 3% for <b>5a</b>, <b>5b</b>, and <b>5c</b>, respectively. The triene system was
introduced by the Pd-catalyzed tandem cyclization–Suzuki coupling
method. The new analogues were assayed against human colon and breast
cancer cell lines and in mice. All new vitamin D<sub>3</sub> analogues
bound less strongly to the VDR than 1α,25-dihydroxyvitamin D<sub>3</sub> but had similar antiproliferative, pro-differentiating, and
transcriptional activity as the native hormone. In vivo, the three
analogues had markedly low calcemic effects