title: 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.affiliation: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States.
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.forename: Maureen
authors.initials: M
authors.lastname: Higgins
authors.forename: Suqing
authors.initials: S
authors.lastname: Zheng
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000819:agonists / Q000378:metabolism*; D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D019921:Biotinylation; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000819:agonists / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000378:metabolism*; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology; D020011:Protective Agents / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: C588144:(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; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D010616:Phenanthrenes; D020011:Protective Agents; C531972:TBE 31; D001710:Biotin; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase
keywords: Bioitin; Cyclopalladation; Diabetic nephropathy; Keap1/Nrf2/ARE pathway; Protein targets