Design, synthesis, and biological evaluation of biotin conjugates of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid for the isolation of the protein targets.
2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO, 1) and related compounds [for example, CDDO-Me (2) and CDDO-Im (3)] are potential anti-inflammatory, cancer chemopreventive, and chemotherapeutic agents. However, the mechanisms responsible for the multiple effects of CDDO are still unclear. Clarification of these mechanisms and particularly isolation of the protein targets are essential for the development of CDDO and its analogues as clinically useful drugs. Such knowledge would provide superior opportunities for designing new compounds with improved potency and selectivity. Therefore, to isolate protein targets using affinity chromatography with immobilized streptavidin as a carrier, we have designed and synthesized C-17 and C-23 biotin conjugates of CDDO (4, 5, and 6) on the basis of our established structure-activity relationships. For the synthesis of 6, a new important precursor, 23-hydroxy-CDDO-Me (29) was synthesized from 20 by a C-23 oxidation protocol, which involves cyclopalladation of the C-4 methyl group from a 3-one oxime. The inhibitory activity of C-23 conjugate 6 is only about 3 times less potent than the mother compound, CDDO, against the proliferation of MCF-7 breast cancer cells. Consequently, 6 may be a very promising tool for the isolation of the protein targets of CDDO.
Honda
Tadashi
T
Department of Chemistry, Dartmouth College, 6128 Burke Laboratory, Hanover, New Hampshire 03755, USA.
Janosik
Tomasz
T
Honda
Yukiko
Y
Han
Jie
J
Liby
Karen T
KT
Williams
Charlotte R
CR
Couch
Robin D
RD
Anderson
Amy C
AC
Sporn
Michael B
MB
Gribble
Gordon W
GW
D001671:Biochemistry / Q000379:methods*; D001710:Biotin / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002846:Chromatography, Affinity; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D011506:Proteins / Q000187:drug effects / Q000302:isolation & purification*; D019809:Streptavidin / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D011506:Proteins; D009828:Oleanolic Acid; D001710:Biotin; D019809:Streptavidin