Further Synthetic and Biological Studies on Vitamin D Hormone Antagonists Based on C24-Alkylation and C2-Functionalization of 25-Deh
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- 作者：Nozomi Saito ; Toshihiro Matsunaga ; Hiroshi Saito ; Miyuki Anzai ; Kazuya Takenouchi ; Daishiro Miura ; Jun-ichi Namekawa ; Seiichi Ishizuka ; Atsushi Kittaka
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：November 30, 2006
- 年：2006
- 卷：49
- 期：24
- 页码：7063 - 7075
- 全文大小：284K
- 年卷期：v.49,no.24(November 30, 2006)
- ISSN：1520-4804
文摘
An efficient synthesis and the biological evaluation of 80 novel analogs of 25-dehydro-1
-hydroxyvitaminD3-26,23S-lactone 2 (TEI-9647) and its 23R epimer (3) in which the lactone ring was systematicallyfunctionalized by introduction of a C1 to C4 primary alkyl group at the C24 position (5 sets of 4 diastereomers),together with their C2-methyl, 3-hydroxypropyl, and 3-hydroxypropoxy-substituted derivatives weredescribed. The triene structure of the vitamin D3 was constructed using palladium-catalyzed alkenylativecyclization of the A-ring precursor enyne with the CD-ring counterpart bromoolefin having the C24-alkylatedlactone moiety on the side chain. The CD-ring precursors having 23,24-cis lactones were prepared by usinga chromium-mediated syn-selective allylation-lactonization process, and the 23,24-trans lactone derivativeswere derived from these via inversion of the C23 stereochemistry. The biological evaluation revealedthat both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition ofvitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length ofthe primary alkyl group on the lactone ring. Furthermore, the C2-functionalization of the C24-alkylatedvitamin D3 lactones dramatically enhanced their biological activities. The most potent compound to emerge,(23S,24S)-2-(3-hydroxypropoxy)-24-propyl exhibited almost 1000-fold stronger antagonistic activity (IC50= 7.4 pM) than 2 (IC50 = 6.3 nM).
-hydroxyvitaminD3-26,23S-lactone 2 (TEI-9647) and its 23R epimer (3) in which the lactone ring was systematicallyfunctionalized by introduction of a C1 to C4 primary alkyl group at the C24 position (5 sets of 4 diastereomers),together with their C2-methyl, 3-hydroxypropyl, and 3-hydroxypropoxy-substituted derivatives weredescribed. The triene structure of the vitamin D3 was constructed using palladium-catalyzed alkenylativecyclization of the A-ring precursor enyne with the CD-ring counterpart bromoolefin having the C24-alkylatedlactone moiety on the side chain. The CD-ring precursors having 23,24-cis lactones were prepared by usinga chromium-mediated syn-selective allylation-lactonization process, and the 23,24-trans lactone derivativeswere derived from these via inversion of the C23 stereochemistry. The biological evaluation revealedthat both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition ofvitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length ofthe primary alkyl group on the lactone ring. Furthermore, the C2-functionalization of the C24-alkylatedvitamin D3 lactones dramatically enhanced their biological activities. The most potent compound to emerge,(23S,24S)-2-(3-hydroxypropoxy)-24-propyl exhibited almost 1000-fold stronger antagonistic activity (IC50= 7.4 pM) than 2 (IC50 = 6.3 nM).