Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 13, Pages 5638-5648Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm500308c
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Funding
- MIUR [2009RMW3Z5]
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The anticarcinogenic and anti-inflammatory properties of curcumin have been extensively investigated, identifying prostaglandin E-2 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 (ie., mPGES-1, cyclooxygenases, 12/15-LOs, nuclear factor-kappa B, 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.
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