Synthesis and biological evaluation of biotin conjugates of (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydro-phenanthrene-2,6-dicarbonitrile, an activator of the Keap1/Nrf2/ARE pathway, for the isolation of its protein targets.

Abstract

The tricycle 1 ((±)-(4bS,8aR,10aS))-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile), a potent activator of the Keap1/Nrf2/ARE pathway, has the potential to be a first in class drug for the treatment of diabetic nephropathy. To identify the protein targets for the development of 1, the (1:1)-diasteromeric mixture of biotinylated tricycles 3a and 3b were designed and synthesized. For the synthesis of 3a and 3b, a new important precursor, hydroxylated tricycle (±)-16 was synthesized from 4 by a C1 α-methyl group oxidation protocol, which involves cyclopalladation of the C1 α-methyl group from a C2-oxime. For the induction of the phase 2 cytoprotective enzyme NQO1 in Hepa1c1c7 murine hepatoma cells, the diasteromeric mixture 3a and 3b shows high potency (CD, 75 nM) although this potency is lower than that of 1 and 16. Thus, biotinylated tricycles 3a and 3b may be promising tools for the isolation of the protein targets of 1.

• Authors: Akira Saito, Maureen Higgins, Suqing Zheng, Wei Li, Iwao Ojima, Albena T Dinkova-Kostova, Tadashi Honda
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 20 Pg. 5540-3 (Oct 15 2013) ISSN: 1464-3405 [Electronic] England
• PMID: 24018193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• (3,7-dicyano-8a-ethynyl-1,4a-dimethyl-2,6-dioxo-1,2,4a,6,8a,9,10,10a-octahydro-phenanthren-1-yl)methyl 6-(5-(2-oxohexahydro-1H-thieno(3,4-d)imidazol-4-yl)pentanamido)hexanoate
• Adaptor Proteins, Signal Transducing
• Cytoskeletal Proteins
• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Phenanthrenes
• Protective Agents
• TBE 31
• Biotin
• NAD(P)H Dehydrogenase (Quinone)
• Nqo1 protein, mouse
• Carboxylic Ester Hydrolases
• arylesterase

Topics

• Adaptor Proteins, Signal Transducing (agonists, metabolism)
• Animals
• Biotin (analogs & derivatives, chemical synthesis, chemistry, isolation & purification, metabolism, pharmacology)
• Biotinylation
• Carboxylic Ester Hydrolases (chemistry, metabolism)
• Cell Line, Tumor
• Cytoskeletal Proteins (agonists, metabolism)
• Kelch-Like ECH-Associated Protein 1
• Liver (drug effects, metabolism)
• Mice
• NAD(P)H Dehydrogenase (Quinone) (metabolism)
• NF-E2-Related Factor 2 (agonists, metabolism)
• Phenanthrenes (chemical synthesis, isolation & purification, pharmacology)
• Protective Agents (chemical synthesis, isolation & purification, pharmacology)
• Signal Transduction (drug effects)
• Stereoisomerism