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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Abstract 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.
AbstractList 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.
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.
Author Pérez-Fernández, Román
Seoane, Samuel
Pérez, Xenxo
Maestro, Miguel
Mouriño, Antonio
Muñoz, Alberto
Carballa, Diego M
Zacconi, Flavia
Larriba, María Jesús
Alvarez-Díaz, Silvia
Rumbo, Antonio
Torneiro, Mercedes
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Snippet 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...
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...
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SubjectTerms 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
Title Synthesis and Biological Evaluation of 1α,25-Dihydroxyvitamin D3 Analogues with a Long Side Chain at C12 and Short C17 Side Chains
URI http://dx.doi.org/10.1021/jm3008272
https://www.ncbi.nlm.nih.gov/pubmed/22989379
https://search.proquest.com/docview/1115528506
Volume 55
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