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  • Title: Further synthetic and biological studies on vitamin D hormone antagonists based on C24-alkylation and C2alpha-functionalization of 25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactones.
    Author: Saito N, Matsunaga T, Saito H, Anzai M, Takenouchi K, Miura D, Namekawa J, Ishizuka S, Kittaka A.
    Journal: J Med Chem; 2006 Nov 30; 49(24):7063-75. PubMed ID: 17125259.
    Abstract:
    An efficient synthesis and the biological evaluation of 80 novel analogs of 25-dehydro-1alpha-hydroxyvitamin D3-26,23S-lactone 2 (TEI-9647) and its 23R epimer (3) in which the lactone ring was systematically functionalized by introduction of a C1 to C4 primary alkyl group at the C24 position (5 sets of 4 diastereomers), together with their C2alpha-methyl, 3-hydroxypropyl, and 3-hydroxypropoxy-substituted derivatives were described. The triene structure of the vitamin D3 was constructed using palladium-catalyzed alkenylative cyclization of the A-ring precursor enyne with the CD-ring counterpart bromoolefin having the C24-alkylated lactone moiety on the side chain. The CD-ring precursors having 23,24-cis lactones were prepared by using a chromium-mediated syn-selective allylation-lactonization process, and the 23,24-trans lactone derivatives were derived from these via inversion of the C23 stereochemistry. The biological evaluation revealed that both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition of vitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length of the primary alkyl group on the lactone ring. Furthermore, the C2alpha-functionalization of the C24-alkylated vitamin D3 lactones dramatically enhanced their biological activities. The most potent compound to emerge, (23S,24S)-2alpha-(3-hydroxypropoxy)-24-propyl exhibited almost 1000-fold stronger antagonistic activity (IC50=7.4 pM) than 2 (IC50=6.3 nM).
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