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

TY - JOUR

T1 - 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

AU - Saito, Akira

AU - Higgins, Maureen

AU - Zheng, Suqing

AU - Li, Wei

AU - Ojima, Iwao

AU - Dinkova-Kostova, Albena T.

AU - Honda, Tadashi

N1 - Copyright © 2013 Elsevier Ltd. All rights reserved.

PY - 2013/10/15

Y1 - 2013/10/15

N2 - 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 a-methyl group oxidation protocol, which involves cyclopalladation of the C1 a-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.

AB - 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 a-methyl group oxidation protocol, which involves cyclopalladation of the C1 a-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.

KW - Adaptor Proteins, Signal Transducing

KW - Animals

KW - Biotin

KW - Biotinylation

KW - Carboxylic Ester Hydrolases

KW - Cell Line, Tumor

KW - Cytoskeletal Proteins

KW - Liver

KW - Mice

KW - NAD(P)H Dehydrogenase (Quinone)

KW - NF-E2-Related Factor 2

KW - Phenanthrenes

KW - Protective Agents

KW - Signal Transduction

KW - Stereoisomerism

UR - https://www.scopus.com/pages/publications/84884279351

U2 - 10.1016/j.bmcl.2013.08.058

DO - 10.1016/j.bmcl.2013.08.058

M3 - Article

C2 - 24018193

AN - SCOPUS:84884279351

SN - 0960-894X

VL - 23

SP - 5540

EP - 5543

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 20

ER -