Nakano Yusuke, Kato Yuko, Imai Keisuke, Ochiai Eiji, Namekawa Jun-Ichi, Ishizuka Seiichi, Takenouchi Kazuya, Tanatani Aya, Hashimoto Yuichi, Nagasawa Kazuo
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
J Med Chem. 2006 Apr 20;49(8):2398-406. doi: 10.1021/jm050738x.
A practical synthetic route to novel vitamin D antagonists of DLAM (1alpha,25-dihydroxyvitamin D(3)-26,23-lactam) was developed from vitamin D(2) via the 1,3-dipolar cycloaddition reaction as a key step. Six DLAM derivatives (24 compounds) with a variety of nitrogen substituents and stereochemistries at C23 and C25 were synthesized. Among these new derivatives, (23S,25S)-DLAM isomers bound effectively to VDRs and showed antagonistic activity in the HL-60 cell differentiation inhibition assay. The importance of the substituent on the nitrogen of DLAMs for antagonistic activity was also suggested by computational docking studies.
从维生素D₂出发，通过1,3 -偶极环加成反应作为关键步骤，开发了一种实用的合成新型DLAM（1α,25 -二羟基维生素D₃ - 26,23 -内酰胺）维生素D拮抗剂的路线。合成了六种具有各种氮取代基以及C23和C25处立体化学的DLAM衍生物（24种化合物）。在这些新衍生物中，(23S,25S)-DLAM异构体与维生素D受体（VDRs）有效结合，并在HL - 60细胞分化抑制试验中表现出拮抗活性。计算对接研究也表明了DLAMs氮原子上取代基对拮抗活性的重要性。
