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

• Published in: Journal of medicinal chemistry Vol. 49; no. 8; pp. 2398 - 2406
• Main Authors: Nakano, Yusuke, Kato, Yuko, Imai, Keisuke, Ochiai, Eiji, Namekawa, Jun-ichi, Ishizuka, Seiichi, Takenouchi, Kazuya, Tanatani, Aya, Hashimoto, Yuichi, Nagasawa, Kazuo
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 20.04.2006
• Subjects: Antineoplastic agents; Biological and medical sciences; General aspects; Medical sciences; Pharmacology. Drug treatments; Antineoplastic agent; Human; Promyelocytic leukemia; Steroid; Nuclear receptor; Cholecalciferol(1,25-dihydroxy); Lactam; Cell differentiation; In vitro; HL60 cell line; Cell line; Structure activity relation; Affinity; Antagonist; Chemical synthesis; Tumor cell; Diastereomer
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050738x

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.