期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 19, 页码 13112-13124出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00900
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资金
- Xunta de Galicia [GRC/ED431B/2021/004]
- FEDER/Ministerio de Ciencia, Innovacion y Universidades-Agencia Estatal de Investigacion [PGC2018-100776-B-I00]
- ANR [ANR-21-CE17-0009-01]
- Instruct-ERIC
- German Academic Exchange Service (DAAD)
- Agence Nationale de la Recherche (ANR) [ANR-21-CE17-0009] Funding Source: Agence Nationale de la Recherche (ANR)
This article reports the development of two highly active and noncalcemic analogues of 1,25D3 that lack the C-ring and possess an m-phenylene ring that replaces the natural D-ring. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D3. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.
The toxic calcemic effects of the natural hormone 1 alpha ,25-dihydroxyvita m i n D3 (1,25D3 , 1,25-dihydroxycholecalcifer-ol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D3 that lack the C-ring and possess an m-phenylene ring that replaces the natural D-ring. The new analogues (3a, 3b) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system. Both compounds were synthesized by the Pd-catalyzed tandem cyclization/cross coupling approach starting from alkyne 6 and diphenol 8. Key steps include a stereoselective Cu-assisted addition of a Grignard reagent to an aromatic alkyne and a Takai olefination of an aromatic aldehyde. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D3. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.
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