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 5a–c were efficiently synthesized from ketone 9 (which is readily accessible from the Inhoffen–Lythgoe diol...

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Published inJournal of medicinal chemistry Vol. 55; no. 20; pp. 8642 - 8656
Main Authors Carballa, Diego M, Seoane, Samuel, Zacconi, Flavia, Pérez, Xenxo, Rumbo, Antonio, Alvarez-Díaz, Silvia, Larriba, María Jesús, Pérez-Fernández, Román, Muñoz, Alberto, Maestro, Miguel, Mouriño, Antonio, Torneiro, Mercedes
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 25.10.2012
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Summary: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 5a–c were efficiently synthesized from ketone 9 (which is readily accessible from the Inhoffen–Lythgoe diol) with overall yields of 15%, 6%, and 3% for 5a, 5b, and 5c, 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.
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/jm3008272