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 Publisher Pubmed



Iranshahi M¹ ; Chini MG² ; Masullo M² ; Sahebkar A¹ ; Javidnia A³ ; Chitsazian Yazdi M¹ ; Pergola C⁴ ; Koeberle A⁴ ; Werz O⁴ ; Pizza C² ; Terracciano S² ; Piacente S² ; Bifulco G²
Source: Journal of Natural Products Published:2015

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. © 2015 The American Chemical Society and American Society of Pharmacognosy.