Important chemical structural features of curcumin and its derivatives: How do they influence their anticancer activity?

Curcumin is the active component of the Indian spice turmeric, known since ancient times for medicinal properties. Extensive research in the last two to three decades has confirmed its promising pharmacological properties such as anti-cancer, anti-oxidant, anti-inflammatory etc., leading to several ongoing/completed clinical trials. Curcumin has three reactive functional groups: one diketone moiety, and two phenolic groups. Curcumin interacts with several biomolecules through non-covalent and covalent binding. However, the properties limiting its potential are low bioavailability and fast degradation. The metabolites as well as degradation products of curcumin show biological activities but not as much as curcumin. To overcome these limitations, new analogues with modifications on both o-methoxy group and the diketo structures of curcumin have been developed. Of several analogues, dimethyl curcumin, where the phenolic OH is absent showed better anti-tumor activity. Also, the isoxazole and pyrazole derivatives of curcumin, derivatized at the diketo moiety have been investigated in our group. Hispolon, which is a half curcumin analogue also showed interesting cellular activity. Here in the present manuscript, the comparative cytotoxic effect of curcumin and some of these derivatives in cancer cells is presented. The results indicated that specific structural modifications on curcumin can be adopted to fine-tune its desired anticancer activity

Important chemical structural features of curcumin and its derivatives: How do they influence their anticancer activity?

228-235Curcumin is the active component of the Indian spice turmeric, known since ancient times for medicinal properties. Extensive research in the last two to three decades has confirmed its promising pharmacological properties such as anti-cancer, anti-oxidant, anti-inflammatory etc., leading to several ongoing/completed clinical trials. Curcumin has three reactive functional groups: one diketone moiety, and two phenolic groups. Curcumin interacts with several biomolecules through non-covalent and covalent binding. However, the properties limiting its potential are low bioavailability and fast degradation. The metabolites as well as degradation products of curcumin show biological activities but not as much as curcumin. To overcome these limitations, new analogues with modifications on both o-methoxy group and the diketo structures of curcumin have been developed. Of several analogues, dimethyl curcumin, where the phenolic OH is absent showed better anti-tumor activity. Also, the isoxazole and pyrazole derivatives of curcumin, derivatized at the diketo moiety have been investigated in our group. Hispolon, which is a half curcumin analogue also showed interesting cellular activity. Here in the present manuscript, the comparative cytotoxic effect of curcumin and some of these derivatives in cancer cells is presented. The results indicated that specific structural modifications on curcumin can be adopted to fine-tune its desired anticancer activity

The antioxidant activity of some curcuminoids and chalcones

The antioxidant properties of the synthetic compound (C1)–(C8), which comprised 7 curcuminoids and a chalcone, were evaluated by two complementary assays, DPPH and β-carotene/linoleic acid. It was found that, in general, the free radical scavenging ability of (C1)–(C8) was concentration-dependent. Compounds (C1) and (C4), which contained (4-OH) phenolic groups, were found to be highly potent antioxidants with higher antioxidant values than BHT suggesting that synthetic curcuminoids are more potent antioxidants than standard antioxidants like BHT. Using β-carotene-linoleic acid assay, only the water-soluble 2, 4,6-trihydroxyphenolic chalcone (C5) showed 85.2 % inhibition of the formation of conjugated dienes reflecting on its potent antioxidant activity

Curcumin supplementation could improve diabetes-induced endothelial dysfunction associated with decreased vascular superoxide production and PKC inhibition

<p>Abstract</p> <p>Background</p> <p>Curcumin, an Asian spice and food-coloring agent, is known for its anti-oxidant properties. We propose that curcumin can improve diabetes-induced endothelial dysfunction through superoxide reduction.</p> <p>Methods</p> <p>Diabetes (DM) was induced in rats by streptozotocin (STZ). Daily curcumin oral feeding was started six weeks after the STZ injection. Twelve weeks after STZ injection, mesenteric arteriolar responses were recorded in real time using intravital fluorescence videomicroscopy. Superoxide and vascular protein kinase C (PKC-βII) were examined by hydroethidine and immunofluorescence, respectively.</p> <p>Results</p> <p>The dilatory response to acetylcholine (ACh) significantly decreased in DM arterioles as compared to control arterioles. There was no difference among groups when sodium nitroprusside (SNP) was used. ACh responses were significantly improved by both low and high doses (30 and 300 mg/kg, respectively) of curcumin supplementation. An oxygen radical-sensitive fluorescent probe, hydroethidine, was used to detect intracellular superoxide anion (O₂^●-) production. O₂^●-production was markedly increased in DM arterioles, but it was significantly reduced by supplementation of either low or high doses of curcumin. In addition, with a high dose of curcumin, diabetes-induced vascular PKC-βII expression was diminished.</p> <p>Conclusion</p> <p>Therefore, it is suggested that curcumin supplementation could improve diabetes-induced endothelial dysfunction significantly in relation to its potential to decrease superoxide production and PKC inhibition.</p

Reactivity of Metal-Free and Metal-Associated Amyloid-?? with Glycosylated Polyphenols and Their Esterified Derivatives

Both amyloid-?? (A??) and transition metal ions are shown to be involved in the pathogenesis of Alzheimer???s disease (AD), though the importance of their interactions remains unclear. Multifunctional molecules, which can target metal-free and metal-bound A?? and modulate their reactivity (e.g., A?? aggregation), have been developed as chemical tools to investigate their function in AD pathology; however, these compounds generally lack specificity or have undesirable chemical and biological properties, reducing their functionality. We have evaluated whether multiple polyphenolic glycosides and their esterified derivatives can serve as specific, multifunctional probes to better understand AD. The ability of these compounds to interact with metal ions and metal-free/-associated A??, and further control both metal-free and metal-induced A?? aggregation was investigated through gel electrophoresis with Western blotting, transmission electron microscopy, UV-Vis spectroscopy, fluorescence spectroscopy, and NMR spectroscopy. We also examined the cytotoxicity of the compounds and their ability to mitigate the toxicity induced by both metal-free and metal-bound A??. Of the polyphenols investigated, the natural product (Verbascoside) and its esterified derivative (VPP) regulate the aggregation and cytotoxicity of metal-free and/or metal-associated A?? to different extents. Our studies indicate Verbascoside represents a promising structure for further multifunctional tool development against both metal-free A?? and metal-A??.open0

Establishment of a 3D In Vitro Model to Accelerate the Development of Human Therapies against Corneal Diabetes

The authors thank Dr. John M Asara, Min Yuan, and Susanne Breitkopf for their technical help with metabolomics experiments, Dr. Ben Fowler for his technical help with TEM experiments and also Tina B McKay for many thoughtful discussions and scientific insights during the study.Purpose To establish an in vitro model that would mirror the in vivo corneal stromal environment in diabetes (DM) patients. Methods Human corneal fibroblasts from Healthy (HCFs), Type 1DM (T1DM) and Type 2DM (T2DM) donors were isolated and cultured for 4 weeks with Vitamin C stimulation in order to allow for extracellular matrix (ECM) secretion and assembly. Results Our data indicated altered cellular morphology, increased cellular migration, increased ECM assembly, and severe mitochondrial damage in both T1DM and T2DMs when compared to HCFs. Furthermore, we found significant downregulation of Collagen I and Collagen V expression in both T1DM and T2DMs. Furthermore, a significant up regulation of fibrotic markers was seen, including α-smooth muscle actin in T2DM and Collagen III in both T1DM and T2DMs. Metabolic analysis suggested impaired Glycolysis and Tricarboxylic acid cycle (TCA) pathway. Conclusion DM has significant effects on physiological and clinical aspects of the human cornea. The benefits in developing and fully characterizing our 3D in vitro model are enormous and might provide clues for the development of novel therapeutics.Yeshttp://www.plosone.org/static/editorial#pee