Abstract
Novel vitamin D receptor antagonists, 24,24-ethanovitamin D3 -26,23-lactones 6 and 7 and their 2α-functionalized analogues 6a -c and 7a -c were synthesized and their biological activities were evaluated. The triene structure of vitamin D3 was constructed using Pd-catalyzed alkenylative cyclization of A-ring precursor enynes 12 and 12a -c with the CD-ring bromo-olefin counterpart having 24,24-ethano-α-methylene-γ-lactone on the side chain (21 or 22 ). The CD-ring precursors 21 and 22 were efficiently synthesized via Ru-catalyzed intermolecular enyne metathesis of 15 with ethylene to give dienone 17 followed by cyclopropanation. The VDR antagonistic activity of the newly designed vitamin D3 lactones 6 and 7 increased to 2.8 times that of TEI-9647 (2 ) in a HL-60 cell differentiation evaluating system. Moreover, introduction of three substituents, that is, a methyl (6a and 7a ), a 3-hydroxypropyl (6b and 7b ), or a 3-hydroxypropoxyl group (6c and 7c ) into the C2α position of 6 and 7 , resulted in marked enhancement, up to 19 times, of the antagonistic activity toward VDR.
Key words
vitamins - antagonist - lactones - ruthenium - metathesis - enynes
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