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

• Published in: Journal 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
• Language: English
• Published: United States American Chemical Society 25.10.2012
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Cadherins - metabolism; Calcitriol - analogs & derivatives; Calcitriol - chemical synthesis; Calcitriol - pharmacology; Calcium - blood; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cystatins - metabolism; Drug Screening Assays, Antitumor; Female; Humans; Mice; Molecular Docking Simulation; Receptors, Calcitriol - metabolism; Structure-Activity Relationship; Transcription, Genetic - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm3008272

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.