Synthesis and Biological Evaluation of 1α,25-Dihydroxyvitamin D₃ Analogues with a Long Side Chain at C12 and Short C17 Side Chains

Structure-guided optimization was used to design new analogues of 1α,25-dihydroxyvitamin D₃ 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 D₃ analogues bound less strongly to the VDR than 1α,25-dihydroxyvitamin D₃ but had similar antiproliferative, pro-differentiating, and transcriptional activity as the native hormone. In vivo, the three analogues had markedly low calcemic effects