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J Nat Prod. 2015 Dec 24;78(12):2867-79. doi: 10.1021/acs.jnatprod.5b00700. Epub 2015 Nov 20.

Can Small Chemical Modifications of Natural Pan-inhibitors Modulate the Biological Selectivity? The Case of Curcumin Prenylated Derivatives Acting as HDAC or mPGES-1 Inhibitors.

Author information

1
Biotechnology Research Center and School of Pharmacy, Mashhad University of Medical Sciences , Vakil Abad Boulevard, Opposite Mellat Park, 91775-1365 Mashhad, Iran.
2
Department of Pharmacy, University of Salerno , Via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.
3
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences , Enghlab Street, 14155-6559 Tehran, Iran.
4
Institute of Pharmacy, Friedrich Schiller University Jena , Philosophenweg 14, 07743 Jena, Germany.

Abstract

Curcumin, or diferuloylmethane, a polyphenolic molecule isolated from the rhizome of Curcuma longa, is reported to modulate multiple molecular targets involved in cancer and inflammatory processes. On the basis of its pan-inhibitory characteristics, here we show that simple chemical modifications of the curcumin scaffold can regulate its biological selectivity. In particular, the curcumin scaffold was modified with three types of substituents at positions C-1, C-8, and/or C-8' [C5 (isopentenyl, 5-8), C10 (geranyl, 9-12), and C15 (farnesyl, 13, 14)] in order to make these molecules more selective than the parent compound toward two specific targets: histone deacetylase (HDAC) and microsomal prostaglandin E2 synthase-1 (mPGES-1). From combined in silico and in vitro analyses, three selective inhibitors by proper substitution at position 8 were revealed. Compound 13 has improved HDAC inhibitory activity and selectivity with respect to the parent compound, while 5 and 9 block the mPGES-1 enzyme. We hypothesize about the covalent interaction of curcumin, 5, and 9 with the mPGES-1 binding site.

PMID:
26588603
DOI:
10.1021/acs.jnatprod.5b00700
[Indexed for MEDLINE]

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