The recent progress of isoxazole in medicinal chemistry.

Recent advances (2015-2016) in anticancer hybrids.

Curcumin is the active component of dried rhizome of Curcuma longa, a perennial herb belonging to ginger family, cultivated extensively in south and southeastern tropical Asia. It is widely consumed in the Indian subcontinent, south Asia and Japan in traditional food recipes. Extensive research over last few decades has shown that curcumin is a potent anti-inflammatory agent with powerful therapeutic potential against a variety of cancers. It suppresses proliferation and metastasis of human tumors through regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases and other enzymes. It induces apoptotic cell death and also inhibits proliferation of cancer cells by cell cycle arrest. Pharmacokinetic data has shown that curcumin undergoes rapid metabolism leading to glucuronidation and sulfation in the liver and excretion in the feces, which accounts for its poor systemic bioavailability. The compound has, therefore, been formulated and administered using different drug delivery systems such as liposomes, micelles, polysaccharides, phospholipid complexes and nanoparticles that can overcome the limitation of bioavailability to some extent. Attempts to avoid rapid metabolism of curcumin until now have been met with limited success. This has prompted researchers to look for new synthetic curcumin analogs in order to overcome the drawbacks of limited bioavailability and rapid metabolism, and gain efficacy with reduced toxicity. In this review we provide a summarized account of novel synthetic curcumin formulations and analogs, and the recent progress in the field of cancer prevention and treatment.

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Perspectives on new synthetic curcumin analogs and their potential anticancer properties

Turmeric is traditionally used as a spice and coloring in foods. Curcumin is the primary active ingredient in the turmeric, and compelling evidence has shown that it has the ability to inhibit inflammation. However, the mechanism mediating its anti-inflammatory effects are not fully understood. We report that curcumin inhibited caspase-1 activation and IL-1β secretion through suppressing LPS priming and the inflammasome activation pathway in mouse bone marrow-derived macrophages. The inhibitory effect of curcumin on inflammasome activation was specific to the NLRP3, not to the NLRC4 or the AIM2 inflammasomes. Curcumin inhibited the NLRP3 inflammasome by preventing K+ efflux and disturbing the downstream events, including the efficient spatial arrangement of mitochondria, ASC oligomerization, and speckle formation. Reactive oxygen species, autophagy, sirtuin-2, or acetylated α-tubulin was ruled out as the mechanism by which curcumin inhibits the inflammasome. Importantly, in vivo data show that curcumin attenuated IL-1β secretion and prevented high-fat diet-induced insulin resistance in wide-type C57BL/6 mice but not in Nlrp3-deficient mice. Curcumin also repressed monosodium urate crystal-induced peritoneal inflammation in vivo. Taken together, we identified curcumin as a common NLRP3 inflammasome activation inhibitor. Our findings reveal a mechanism through which curcumin represses inflammation and suggest the potential clinical use of curcumin in NLRP3-driven diseases.

Curcumin Suppresses IL-1β Secretion and Prevents Inflammation through Inhibition of the NLRP3 Inflammasome

http://www.rsc.org/suppdata/cc/c2/c2cc33576j/c2cc33576j.pdf

Remarkable photocytotoxicity of curcumin in HeLa cells in visible light and arresting its degradation on oxovanadium(IV) complex formation.

Although curcumin is known for its anticarcinogenic properties, the exact mechanism of its action or the identity of the target receptor is not completely understood. Studies on a series of curcumin analogues, synthesized to investigate their tubulin binding affinities and tubulin self-assembly inhibition, showed that: (i) curcumin acts as a bifunctional ligand, (ii) analogues with substitution at the diketone and acetylation of the terminal phenolic groups of curcumin are less effective, (iii) a benzylidiene derivative, compound 7, is more effective than curcumin in inhibiting tubulin self-assembly. Cell-based studies also showed compound 7 to be more effective than curcumin. Using fluorescence spectroscopy we show that curcumin binds tubulin 32 A away from the colchicine-binding site. Docking studies also suggests that the curcumin-binding site to be close to the vinblastine-binding site. Structure–activity studies suggest that the tridented nature of compound 7 is responsible for its higher affinity fo...

Curcumin recognizes a unique binding site of tubulin.

Curcumin has shown promising therapeutic utilities for many diseases, including cancer; however, its clinical application is severely limited because of its poor stability under physiological conditions. Here we find that curcumin also loses its activity instantaneously in a reducing environment. Curcumin can exist in solution as a tautomeric mixture of keto and enol forms, and the enol form was found to be responsible for the rapid degradation of the compound. To increase the stability of curcumin, several analogues were synthesized in which the diketone moiety of curcumin was replaced by isoxazole (compound 2) and pyrazole (compound 3) groups. Isoxazole and pyrazole curcumins were found to be extremely stable at physiological pH, in addition to reducing atmosphere, and they can kill cancer cells under serum-depleted condition. Using molecular modeling, we found that both compounds 2 and 3 could dock to the same site of tubulin as the parent molecule, curcumin. Interestingly, compounds 2 and 3 also show better free radical scavenging activity than curcumin. Altogether, these results strongly suggest that compounds 2 and 3 could be good replacements for curcumin in future drug development.

Stable and potent analogues derived from the modification of the dicarbonyl moiety of curcumin

Blood compatible N-maleyl chitosan-graft-PAMAM copolymer for enhanced gene transfection.

In the present study, a carboxymethylated guar gum-grafted-polyethyleneimine copolymer (CMGG-g-PEI) was synthesized and characterized by FT-IR, 1H NMR, XRD and zeta potential analyses. CMGG-g-PEI exhibited good binding ability with plasmid DNA (pDNA) and formed complexes with sizes ranging from 150 to 200 nm when the polymer/pDNA weight ratio was above 10:1. SEM analysis revealed a compact and spherical morphology of CMGG-g-PEI/pDNA complexes. The results from cytotoxicity and blood compatibility studies revealed the less toxic profile of CMGG-g-PEI. The in vitro gene transfection efficiency of the CMGG-g-PEI/pDNA complex was optimized in A549 cell and CMGG-g-PEI showed better transfection efficiency compared to the well-known standard polymer, polyethyleneimine (PEI). All the results suggested that the CMGG-g-PEI could find application as an alternative efficient gene delivery vehicle in the future.

Gopal Chakraborti

Papers

Curcumin recognizes a unique binding site of tubulin.

Stable and potent analogues derived from the modification of the dicarbonyl moiety of curcumin

Blood compatible N-maleyl chitosan-graft-PAMAM copolymer for enhanced gene transfection.

Synthesis of a carboxymethylated guar gum grafted polyethyleneimine copolymer as an efficient gene delivery vehicle