SAR Studies on Curcumin’s Pro-inflammatory Targets: Discovery of Prenylated Pyrazolocurcuminoids as Potent and Selective Novel Inhibitors of 5-Lipoxygenase

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.

Curcumin reverses neurochemical, histological and immuno-histochemical alterations in the model of global brain ischemia

“…Considering the involvement of inflammation in brain ischemic episodes and the anti-inflammatory property of curcumin, as well as its antioxidant activity observed even at lower doses, as shown by us 14 and others,42, 52, 53, 54 our data emphasize the potential benefit of curcumin in the prevention or treatment of stroke.…”

Biodegradable micelles enhance the antiglioma activity of curcumin in vitro and in vivo

“…[8][9][10][11][24][25][26][27] It has received extensive attention with its unique effectiveness in glioma therapy. Previous studies demonstrated that Cur can significantly inhibit the proliferation of glioma cells by downregulating multidrug resistance proteins that cause the efflux of many chemotherapeutic agents.…”

α‐Tocopherol long‐chain metabolite α‐13’‐COOH affects the inflammatory response of lipopolysaccharide‐activated murine RAW264.7 macrophages

“…Eicosanoids were analyzed by multiple reaction monitoring. The parameters were adjusted as described . Automatic peak integration was performed with Analyst software version 1.6 (AB Sciex, Darmstadt, Germany) using IntelliQuan default settings.…”