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Synthesis of novel brassinosteroid biosynthesis inhibitors based on the ketoconazole scaffold.

Abstract
Brassinosteroids (BRs) are steroidal plant hormones that control several important agronomic traits such as plant architecture, seed yield, and stress tolerance. Inhibitors that target BR biosynthesis are candidate plant growth regulators. We synthesized novel triazole derivatives, based on the ketoconazole scaffold, that function as inhibitors of BR biosynthesis. The biological activity of the test compounds was evaluated by determining their ability to induce dwarfism in Arabidopsis seedlings grown in the dark. The chemically induced dwarfism of Arabidopsis seedlings was further evaluated by a rescue experiment using the co-application of brassinolide and/or gibberellins (GA). The structure-activity relationship studies revealed a potent BR biosynthesis inhibitor, 2RS, 4RS-1-{2-(4-chlorophenyl)-4-[2-(2-ethoxyphenyl)-ethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole (7m), with an IC(50) value of 0.10±0.03 μM for retardation of Arabidopsis seedling stem elongation. The compound-induced hypocotyl dwarfism was counteracted by the co-application of 10nM brassinolide, but not 1 μM GA(3), which produced seedlings that resembled BR-deficient mutants. This result suggests that 7m is a potent and specific inhibitor of BR biosynthesis.
AuthorsKeimei Oh, Kazuhiro Yamada, Tadao Asami, Yuko Yoshizawa
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 4 Pg. 1625-8 (Feb 15 2012) ISSN: 1464-3405 [Electronic] England
PMID22264483 (Publication Type: Journal Article)
CopyrightCopyright © 2011 Elsevier Ltd. All rights reserved.
Chemical References
  • 2RS, 4RS-1-(2-(4-chlorophenyl)-4-(2-(2-ethoxyphenyl)-ethyl)-1,3-dioxolan-2-ylmethyl)-1H-1,2,4-triazole
  • Brassinosteroids
  • Dioxolanes
  • Triazoles
  • Ketoconazole
Topics
  • Arabidopsis (drug effects, growth & development)
  • Brassinosteroids (antagonists & inhibitors)
  • Dioxolanes (chemistry, pharmacology)
  • Inhibitory Concentration 50
  • Ketoconazole (chemical synthesis, chemistry, pharmacology)
  • Molecular Structure
  • Structure-Activity Relationship
  • Triazoles (chemical synthesis, chemistry, pharmacology)

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