Design and synthesis of tetraol derivatives of 1,12-dicarba- closo -dodecaborane as non-secosteroidal vitamin D analogs
2014; Elsevier BV; Volume: 24; Issue: 18 Linguagem: Inglês
10.1016/j.bmcl.2014.07.075
ISSN1464-3405
AutoresShinya Fujii, Atsushi Kano, Hiroyuki Masuno, Chalermkiat Songkram, Emiko Kawachi, Tomoya Hirano, Aya Tanatani, Hiroyuki Kagechika,
Tópico(s)Radiopharmaceutical Chemistry and Applications
ResumoVitamin D receptor (VDR), a nuclear receptor for 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3, 1), is a promising target for multiple clinical applications. We recently developed non-secosteroidal VDR ligands based on a carbon-containing boron cluster, 1,12-dicarba-closo-dodecaborane (p-carborane), and examined the binding of one of them to VDR by means of crystallographic analysis. Here, we utilized that X-ray structure to design novel p-carborane-based tetraol-type vitamin D analogs, and we examined the biological activities of the synthesized compounds. Structure-activity relationship study revealed that introduction of an ω-hydroxyalkoxy functionality enhanced the biological activity, and the configuration of the substituent significantly influenced the potency. Among the synthesized compounds, 4-hydroxybutoxy derivative 9a exhibited the most potent activity, which was equal to that of the secosteroidal vitamin D analog, 19-nor-1α,25-dihydroxyvitamin D3 (2).
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