Format

Send to

Choose Destination
Bioorg Med Chem. 2014 Oct 1;22(19):5220-33. doi: 10.1016/j.bmc.2014.08.007. Epub 2014 Aug 14.

Synthesis of non-prenyl analogues of baccharin as selective and potent inhibitors for aldo-keto reductase 1C3.

Author information

1
Gifu Pharmaceutical University, Gifu 501-1196, Japan. Electronic address: sendo@gifu-pu.ac.jp.
2
Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan.
3
Gifu Pharmaceutical University, Gifu 501-1196, Japan.
4
Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia.
5
Department of Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
6
Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan; Graduate School of Science and Technology for Research, University of Toyama, Toyama 930-8555, Japan.

Abstract

Inhibitors of a human member (AKR1C3) of the aldo-keto reductase superfamily are regarded as promising therapeutics for the treatment of prostatic and breast cancers. Baccharin [3-prenyl-4-(dihydrocinnamoyloxy)cinnamic acid], a component of propolis, was shown to be both potent (Ki 56 nM) and highly isoform-selective inhibitor of AKR1C3. In this study, a series of derivatives of baccharin were synthesized by replacing the 3-prenyl moiety with aryl and alkyl ether moieties, and their inhibitory activities for the enzyme were evaluated. Among them, two benzyl ether derivatives, 6m and 6n, showed an equivalent inhibitory potency to baccharin. The molecular docking of 6m in AKR1C3 has allowed the design and synthesis of (E)-3-{3-[(3-hydroxybenzyl)oxy]-4-[(3-phenylpropanoyl)oxy]phenyl}acrylic acid (14) with improved potency (Ki 6.4 nM) and selectivity comparable to baccharin. Additionally, 14 significantly decreased the cellular metabolism of androsterone and cytotoxic 4-oxo-2-nonenal by AKR1C3 at much lower concentrations than baccharin.

KEYWORDS:

AKR1C3; Aldo-keto reductase; Baccharin; Cancer; Inhibitor; Selectivity

PMID:
25182963
DOI:
10.1016/j.bmc.2014.08.007
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center