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SAR studies on curcumin's pro-inflammatory targets: discovery of prenylated pyrazolocurcuminoids as potent and selective novel inhibitors of 5-lipoxygenase.

Journal of medicinal chemistry (2014-06-13)
Andreas Koeberle, Eduardo Muñoz, Giovanni B Appendino, Alberto Minassi, Simona Pace, Antonietta Rossi, Christina Weinigel, Dagmar Barz, Lidia Sautebin, Diego Caprioglio, Juan A Collado, Oliver Werz
ABSTRACT

The anticarcinogenic and anti-inflammatory properties of curcumin have been extensively investigated, identifying prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), key enzymes linking inflammation with cancer, as high affinity targets. A comparative structure-activity study revealed three modifications dissecting mPGES-1/5-LO inhibition, namely (i) truncation of the acidic, enolized dicarbonyl moiety and/or replacement by pyrazole, (ii) hydrogenation of the interaryl linker, and (iii) (dihydro)prenylation. The prenylated pyrazole analogue 11 selectively inhibited 5-LO, outperforming curcumin by a factor of up to 50, and impaired zymosan-induced mouse peritonitis along with reduced 5-LO product levels. Other pro-inflammatory targets of curcumin (i.e., mPGES-1, cyclooxygenases, 12/15-LOs, nuclear factor-κB, nuclear factor-erythroid 2-related factor-2, and signal transducer and activator of transcription 3) were hardly affected by 11. The strict structural requirements for mPGES-1 and 5-LO inhibition strongly suggest that specific interactions rather than redox or membrane effects underlie the inhibition of mPGES-1 and 5-LO by curcumin.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Curcumin, from Curcuma longa (Turmeric), powder
Sigma-Aldrich
Curcumin, ≥94% (curcuminoid content), ≥80% (Curcumin)
USP
Curcumin, United States Pharmacopeia (USP) Reference Standard
Curcumin, primary reference standard
Supelco
Curcumin, analytical standard
Supelco
Curcumin, matrix substance for MALDI-MS, ≥99.5% (HPLC)