Prev. Article Next Article Table of Contents

Article

Practical Synthesis and Evaluation of the Biological Activities of 1α,25-dihydroxyvitamin D₃ Antagonists, 1α,25-dihydroxyvitamin D₃-26,23-lactams. Designed on the Basis of the Helix 12-Folding Inhibition Hypothesis

Supporting Info

Yusuke Nakano,^† Yuko Kato,^†^‡ Keisuke Imai,^§ Eiji Ochiai,^‡ Jun-ichi Namekawa,^‡ Seiichi Ishizuka,^‡ Kazuya Takenouchi,^‡ Aya Tanatani,^† Yuichi Hashimoto,^† and Kazuo Nagasawa*

Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan, Teijin Institute for Bio-medical Research, 4-3-2, Asahigaoka, Hino, Tokyo 191-8512, Japan, Drug Discovery Research, Astellas Pharma Inc., Miyukigaoka 21, Tsukuba, Ibaraki 305-8585, Japan, and Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo 184-8588, Japan

J. Med. Chem., 2006, 49 (8), pp 2398–2406

DOI: 10.1021/jm050738x

Publication Date (Web): March 30, 2006

†

University of Tokyo.

‡

Teijin Institute for Bio-medical Research.

Astellas Pharma Inc..

To whom correspondence should be addressed. Tel: +81-42-388-7295. Fax: +81-42-388-7295. E-mail: knaga@cc.tuat.ac.jp.

Tokyo University of Agriculture and Technology.

Abstract

A practical synthetic route to novel vitamin D antagonists of DLAM (1α,25-dihydroxyvitamin D₃-26,23-lactam) was developed from vitamin D₂ 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.

View: Full Text HTML | Hi-Res PDF

Tools

SciFinder Links

Accession Codes

PDB: 1DB1

History

Published In Issue April 20, 2006
Received July 29, 2005

Recommend & Share

Related Content

A New and Efficient Synthesis of Pyrrolo[2,3-d]pyrimidine Anticancer Agents: Alimta (LY231514, MTA), Homo-Alimta, TNP-351, and Some Aryl 5-Substituted Pyrrolo[2,3-d]pyrimidinesThe Journal of Organic Chemistry
- A New and Efficient Synthesis of Pyrrolo[2,3-d]pyrimidine Anticancer Agents: Alimta (LY231514, MTA), Homo-Alimta, TNP-351, and Some Aryl 5-Substituted Pyrrolo[2,3-d]pyrimidines
  Edward C. Taylor and Bin Liu
  The Journal of Organic Chemistry 2003 68 (26), pp 9938–9947
  Abstract: Alimta, as well as homo-Alimta, a nonbridged analogue of Alimta, and TNP-351 have been prepared by a new method that involves Michael addition of the appropriate 1-nitroalkene with 2,6-diamino-3H-pyrimidin-4-one or 2,4,6-triaminopyrimidine, followed by a ...
  Abstract | Full Text HTML | Hi-Res PDF
Total Synthesis of (−)-Penifulvin A, an Insecticide with a Dioxafenestrane SkeletonJournal of the American Chemical Society
- Total Synthesis of (−)-Penifulvin A, an Insecticide with a Dioxafenestrane Skeleton
  Tanja Gaich and Johann Mulzer
  Journal of the American Chemical Society 2009 131 (2), pp 452–453
  Abstract: Herein we report the first total synthesis of Penifulvin A, a sesquiterpenoid with a novel dioxa-fenestrane structure. Penifulvin A is a potent insecticide against the fall armyworm Spodoptera frugiperda which causes enormous damage in the US by consuming ...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF
Evolution of the Total Synthesis of (−)-Okilactomycin Exploiting a Tandem Oxy-Cope Rearrangement/Oxidation, a Petasis−Ferrier Union/Rearrangement, and Ring-Closing MetathesisJournal of the American Chemical Society
- Evolution of the Total Synthesis of (−)-Okilactomycin Exploiting a Tandem Oxy-Cope Rearrangement/Oxidation, a Petasis−Ferrier Union/Rearrangement, and Ring-Closing Metathesis
  Amos B. Smith III, Todd Bosanac and Kallol Basu
  Journal of the American Chemical Society 2009 131 (6), pp 2348–2358
  Abstract: An effective, asymmetric total synthesis of the antitumor antibiotic (−)-okilactomycin (1), as well as assignment of the absolute configuration, has been achieved exploiting a convergent strategy. Highlights of the synthesis include a diastereoselective ...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF

Article

Practical Synthesis and Evaluation of the Biological Activities of 1α,25-dihydroxyvitamin D₃ Antagonists, 1α,25-dihydroxyvitamin D₃-26,23-lactams. Designed on the Basis of the Helix 12-Folding Inhibition Hypothesis