Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates.

A cascade inter-intramolecular double Michael strategy for the synthesis of highly functionalized cyclohexanones from curcumins and arylidenemalonates is reported. This strategy works in the presence of aqueous KOH using TBAB as a suitable phase transfer catalyst at room temperature. The functionalized cyclohexanones are formed as major products in moderate to excellent yields with complete diastereoselectivity in most cases. A triple Michael adduct, tetrahydrochromen-4-one, is also formed as a side product in a few cases with excellent diastereoselectivity.

Half-Curcuminoids Encapsulated in Alginate-Glucosamine Hydrogel Matrices as Bioactive Delivery Systems.

The therapeutic effects of curcumin and its derivatives, based on research in recent years, are limited by their low bioavailability. To improve bioavailability and develop the medical field of application, different delivery systems have been developed that are adapted to certain environments or the proposed target type. This study presents some half-curcuminoids prepared by the condensation of acetylacetone with 4-hydroxybenzaldehyde (C1), 4-hydroxy-3-methoxybenzaldehyde (C2), 4-acetamidobenzaldehyde (C3), or 4-diethylaminobenzaldehyde (C4), at microwaves as a simple, solvent-free, and eco-friendly method. The four compounds obtained were characterized in terms of morphostructural and photophysical properties. Following the predictions of theoretical studies on the biological activities related to the molecular structure, in vitro tests were performed for compounds C1-C3 to evaluate the antitumor properties and for C4's possible applications in the treatment of neurological diseases. The four compounds were encapsulated in two types of hydrogel matrices. First, the alginate-glucosamine network was generated and then the curcumin analogs were loaded (G1, G3, G5-G7, and G9). The second type of hydrogels was obtained by loading the active compound together with the generation of the hydrogel carrier matrices, by simply dissolving (G4 and G10) or by chemically binding half-curcuminoid derivatives to glucosamine (G2 and G8). Thus, two types of curcumin analog delivery systems were obtained, which could be applied in various types of medical treatments.

Bioassay-guided separation and identification of the anticancer composition from Curcuma longa L. by the combination strategy of methanol gradient countercurrent chromatography and ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry.

In this study, a combined strategy with methanol gradient countercurrent chromatography and ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry was introduced for the fractionation and identification of active constituents from Curcuma longa L. The gradient countercurrent chromatography separation was performed using the heptane-ethyl acetate-methanol-water (5:5:2:8, v/v) solvent system, in which the lower phase and methanol were used as the mobile phases. Constituents of turmeric with large partition coefficients were well resolved. Subsequent cytotoxicity analysis showed that the fractions 10, 11, 12, and 15 expressed significantly higher cytotoxicity against B16 mouse melanoma than the other fractions. Four compounds with potent activity, curcumin, demethoxycurcumin, and bisdemethoxycurcumin from fraction 11 and galanal A from fraction 15, were purified, and the half-maximal inhibitory concentrations were 18.5 ± 1.3, 7.8 ± 0.4, 20.4 ± 1.3, and 14.1 ± 0.8 µM, respectively. Ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry was then applied for compound identification from fraction 10 with constituents in very low content. A total of 14 diarylheptanoids were identified, which are supposed to be cytotoxic constituents. It proved that the strategy based on the combination of bioassay-guided methanol gradient countercurrent chromatography separation and ultra-high-performance liquid chromatography coupled with tandem mass spectrometry-assisted peak identification could be an efficient method for natural product screening and new drug discovery.

Some Natural Photosensitizers and Their Medicinal Properties for Use in Photodynamic Therapy.

Despite significant advances in early diagnosis and treatment, cancer is one of the leading causes of death. Photodynamic therapy (PDT) is a therapy for the treatment of many diseases, including cancer. This therapy uses a combination of a photosensitizer (PS), light irradiation of appropriate length and molecular oxygen. The photodynamic effect kills cancer cells through apoptosis, necrosis, or autophagy of tumor cells. PDT is a promising approach for eliminating various cancers but is not yet as widely applied in therapy as conventional chemotherapy. Currently, natural compounds with photosensitizing properties are being discovered and identified. A reduced toxicity to healthy tissues and a lower incidence of side effects inspires scientists to seek natural PS for PDT. In this review, several groups of compounds with photoactive properties are presented. The use of natural products has been shown to be a fruitful approach in the discovery of novel pharmaceuticals. This review focused on the anticancer activity of furanocoumarins, polyacetylenes, thiophenes, tolyporphins, curcumins, alkaloid and anthraquinones in relation to the light-absorbing properties. Attention will be paid to their phototoxic and anti-cancer effects on various types of cancer.

Novel Chemically Modified Curcumin (CMC) Analogs Exhibit Anti-Melanogenic Activity in Primary Human Melanocytes.

Hyperpigmentation is a dermatological condition characterized by the overaccumulation and/or oversecretion of melanin pigment. The efficacy of curcumin as an anti-melanogenic therapeutic has been recognized, but the poor stability and solubility that have limited its use have inspired the synthesis of novel curcumin analogs. We have previously reported on comparisons of the anti-melanogenic activity of four novel chemically modified curcumin (CMC) analogs, CMC2.14, CMC2.5, CMC2.23 and CMC2.24, with that of parent curcumin (PC), using a B16F10 mouse melanoma cell model, and we have investigated mechanisms of inhibition. In the current study, we have extended our findings using normal human melanocytes from a darkly pigmented donor (HEMn-DP) and we have begun to study aspects of melanosome export to human keratinocytes. Our results showed that all the CMCs downregulated the protein levels of melanogenic paracrine mediators, endothelin-1 (ET-1) and adrenomedullin (ADM) in HaCaT cells and suppressed the phagocytosis of FluoSphere beads that are considered to be melanosome mimics. All the three CMCs were similarly potent (except CMC2.14, which was highly cytotoxic) in inhibiting melanin production; furthermore, they suppressed dendricity in HEMn-DP cells. CMC2.24 and CMC2.23 robustly suppressed cellular tyrosinase activity but did not alter tyrosinase protein levels, while CMC2.5 did not suppress tyrosinase activity but significantly downregulated tyrosinase protein levels, indicative of a distinctive mode of action for the two structurally related CMCs. Moreover, HEMn-DP cells treated with CMC2.24 or CMC2.23 partially recovered their suppressed tyrosinase activity after cessation of the treatment. All the three CMCs were nontoxic to human dermal fibroblasts while PC was highly cytotoxic. Our results provide a proof-of-principle for the novel use of the CMCs for skin depigmentation, since at low concentrations, ranging from 5 to 25 µM, the CMCs (CMC2.24, CMC2.23 and CMC2.5) were more potent anti-melanogenic agents than PC and tetrahydrocurcumin (THC), both of which were ineffective at melanogenesis at similar doses, as tested in HEMn-DP cells (with PC being highly toxic in dermal fibroblasts and keratinocytes). Further studies to evaluate the efficacy of CMCs in human skin tissue and in vivo studies are warranted.

Synthesis and photophysical properties of ditrifluoroacetoxyboron complexes with curcumin analogues.

A new class of ditrifluoroacetoxyboron complexes were designed and synthesized by chelation reaction of curcumins with boron trifluoroacetate. Their photophysical behaviors were studied in different solvents, powder state and PMMA polymer films. The results indicated that these complexes revealed a green to yellow emission at 486-595 nm in solution or PMMA films and an orange to red emission at 598-710 nm in powder state. Especially, complex 2c displayed the strongest emission intensity, the highest quantum yield in solution and the longest fluorescence lifetime in powder state in these complexes. In addtion, the emission bathochromic shifts of these complexes as a function of the solvent polarity parameter ET(30) were investigated by Lippert-Mataga approximation. It was observed that these complexes exhibited the higher values of the dipole moment difference (Δµ) between the ground and excited states, which implied an intense intramolecular charge transfer characteristics and a noticeable emission solvatochromic effect.

Role of Curcuminoids and Tricalcium Phosphate Ceramic in Rat Spinal Fusion.

Despite considerable research effort, there is a significant need for safe agents that stimulate bone formation. Treatment of large or complex bone defects remains a challenge. Implantation of small molecule-induced human bone marrow-derived mesenchymal stromal cells (hBMSCs) on an appropriate tricalcium phosphate (TCP) scaffold offers a robust system for noninvasive therapy for spinal fusion. To show the efficacy of this approach, we identified a small molecule curcuminoid that when combined with TCP ceramic in the presence of hBMSCs selectively induced growth of bone cells: after 8- or 25-day incubations, alkaline phosphatase was elevated. Treatment of hBMSCs with curcuminoid 1 and TCP ceramic increased osteogenic target gene expression (i.e., Runx2, BMP2, Osteopontin, and Osteocalcin) over time. In the presence of curcuminoid 1 and TCP ceramic, osteogenesis of hBMSCs, including proliferation, differentiation, and mineralization, was observed. No evidence of chondrogenic or adipogenic potential using this protocol was observed. Transplantation of curcuminoid 1-treated hBMSC/TCP mixtures into the spine of immunodeficient rats showed that it achieved spinal fusion and provided greater stability of the spinal column than untreated hBMSC-TCP implants or TCP alone implants. On the basis of histological analysis, greater bone formation was associated with curcuminoid 1-treated hBMSC implants manifested as contiguous growth plates with extensive hematopoietic territories. Stimulation of hBMSCs by administration of small molecule curcuminoid 1 in the presence of TCP ceramic afforded an effective noninvasive strategy that increased spinal fusion repair and provided greater stability of the spinal column after 8 weeks in immunodeficient rats. Impact statement Bone defects only slowly regenerate themselves in humans. Current procedures to restore spinal defects are not always effective. Some have side effects. In this article, a new method to produce bone growth within 8 weeks in rats is presented. In the presence of tricalcium phosphate ceramic, curcuminoid-1 small molecule-stimulated human bone marrow-derived mesenchymal stromal cells showed robust bone cell growth in vitro. Transplantation of this mixture into the spine showed efficient spinal fusion in rats. The approach presented herein provides an efficient biocompatible scaffold for delivery of a potentially clinically useful system that could be applicable in patients.

Different Processed Products of Curcumae Radix Regulate Pain-Related Substances in a Rat Model of Qi Stagnation and Blood Stasis.

BACKGROUND: Curcumae blood Radix (Yujin) has been widely used to treat Qi stagnation and stasis in TCM. According to the Chinese Pharmacopoeia, the tuberous roots of Curcuma longed L. (i.e., Huangsiyujin, HSYJ) is one of the major species of Yujin. According to the processing theory of TCM, stir-frying HSYJ with vinegar might strengthen the effect of dispersing stagnated hepatoqi to relieve pain, and stir-frying HSYJ with wine might strengthen the effect of promoting blood circulation in order to remove blood stasis. However, the mechanism for the enhancement of clinical efficacy by processing is unclear. AIM/HYPOTHESIS: This study was aimed at evaluating the effect of different processed products of HSYJ on chemical constituents and pain-related substances to explore underlying mechanisms of HSYJ in treating pain caused by Qi stagnation and blood stasis. METHODS: The effects of different processing methods on the paste yield of water decoction were analyzed, and the content of the main constituents were detected by HPLC. A rat model of Qi stagnation and blood stasis was established by tail clamp stimulation combined with subcutaneous adrenaline injection. After treatment and intervention with HSYJ and its processed products, ß-endorphin (ß-EP) and 5-hydroxytryptamine (5-HT) were measured by ELISA, and the expression of c-fos was evaluated by immunohistochemistry. RESULTS: After stir-frying with vinegar or wine, the extract yield and curcumin content increased. Compared with model group, raw HSYJ could significantly improve the abnormality of 5-HT in plasma (P < 0.05) and ß-EP in brain (P < 0.01). Stir-frying HSYJ with vinegar or wine could significantly improve the abnormality of 5-HT in plasma, ß-EP in brain, and the expression of c-fos (P < 0.01). Stir-frying HSYJ with vinegar could also significantly increase the level of ß-EP in plasma (P < 0.05). CONCLUSION: These results showed that different processing methods have certain effects on the chemical constituents of HSYJ, mainly in increasing the decoction rate and curcumin content. HSYJ and its processed products can reduce 5-HT levels, increase ß-EP levels, and inhibit the expression of c-fos in model rats. The effects of stir-frying HSYJ with vinegar on ß-EP levels in plasma was superior to others.

Study on curcumins from Curcuma phaeocaulis / 中草药

Objective: To study the chemical constituents and the cytotoxic activity of curcumins from the rhizome of Curcuma phaeocaulis. Methods: The 95% ethanol extract from the rhizome of C. phaeocaulis was extracted with petroleum ether, ethyl acetate, and n-butanol. The separation and purification of ethyl acetate fraction was carried out by silica gel column, sephadex LH-20 column, reversed-phase medium pressure chromatography, preparative thin-layer chromatography, and semi-preparative high performance liquid chromatography. The structures of the isolated components were identified by modern spectroscopy techniques. The isolated compounds were screened for cytotoxic activity by MTT assay. Results: Four curcuminoids were isolated from the ethyl acetate extract of the rhizome of C. phaeocaulis, and identified as 1,7-bis (4-hydroxyphenyl)-1E,6E-heptadien-3-one (1), 1,7-bis (4-hydroxyphenyl)-1,4,6-heptatrien-3-one (2), 1,7-bis (4-hydroxyphenyl)-4E,6E-heptadien-3-one (3), and (1R,5S,6S)-1,5-epoxy-6- hydroxy-1,7-bis (3-methoxy-4-hydroxy-phenyl)-heptane (4). MTT experiments showed that compounds 1-3 inhibited HGC-27 cells proliferation, and only compound 2 inhibited MDA-MB-231 cells proliferation. Compounds 2 and 3 also showed strong toxic effects on human normal liver cells. Conclusion: Four curcuminoids were isolated from C. phaeocaulis. Compound 1 was a new compound named curcumin P. Compounds 1-3 had a certain inhibitory effect on the proliferation of HGC-27 cells. Notably, compound 1 selectively inhibited the proliferation of HGC-27 cells and showed no obvious toxic effects on L-02 cells.

Curcumin and Novel Synthetic Analogs in Cell-Based Studies of Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is associated with the most common type of dementia and is characterized by the presence of deposits of the protein fragment amyloid beta (Aß) in the brain. The natural product mixture of curcuminoids that improves certain defects in innate immune cells of AD patients may selectively enhance Aß phagocytosis by alteration of gene transcription. In this work, we evaluated the protective effects of curcuminoids in cells from AD patients by investigating the effect on NF-κB and BACE1 signaling pathways. These results were compared to the gene expression profile of the clearance of Aß. The minor curcumin constituent, bisdemethoxycurcumin (BDC) showed the most potent protective action to decrease levels of NF-κB and BACE1, decrease the inflammatory cascade and diminish Aß aggregates in cells from AD patients. Moreover, mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3) and vitamin D receptor (VDR) gene mRNAs were up-regulated in peripheral blood mononuclear cells from AD patients treated with BDC. BDC treatment impacts both gene expression including Mannosyl (Beta-1,4-)-Glycoprotein Beta-1,4-N-Acetylglucosaminyltransferase, Vitamin D and Toll like receptor mRNA and Aß phagocytosis. The observation of down-regulation of BACE1 and NF-κB following administration of BDC to cells from AD patients as a model system may have utility in the treatment of asymptomatic AD patients.

Evaluation of the antioxidant properties of curcumin derivatives by genetic function algorithm.

The prevalence of degenerative diseases in recent time has triggered extensive research on their control. This condition could be prevented if the body has an efficient antioxidant mechanism to scavenge the free radicals which are their main causes. Curcumin and its derivatives are widely employed as antioxidants. The free radical scavenging activities of curcumin and its derivatives have been explored in this research by the application of quantitative structure activity relationship (QSAR). The entire data set was optimized at the density functional theory (DFT) level using the Becke's three-parameter Lee-Yang-Parr hybrid functional (B3LYP) in combination with the 6-311G∗ basis set. The training set was subjected to QSAR studies by genetic function algorithm (GFA). Five predictive QSAR models were developed and statistically subjected to both internal and external validations. Also the applicability domain of the developed model was accessed by the leverage approach. Furthermore, the variation inflation factor, (VIF), mean effect (MF) and the degree of contribution (DC) of each descriptor in the resulting model were calculated. The developed models met all the standard requirements for acceptability upon validation with highly impressive results ( R=0.965,R2=0.931,Q2(RCV2)=0.887,Rpred2=0.844,cRp2=0.842s=0.226,rmsep=0.362 ). Based on the results of this research, the most crucial descriptor that influence the free radical scavenge of the curcumins is the nsssN (count of atom-type E-state: >N-) descriptor with DC and MF values of 12.980 and 0.965 respectively.

Photodynamic activity of plant extracts from Sarawak, Borneo.

Photodynamic therapy (PDT) is a medical treatment that involves the irradiation of an administered photosensitizing drug with light of a particular wavelength to activate the photosensitizer to kill abnormal cells. To date, only a small number of photosensitizers have been clinically approved for PDT, and researchers continue to look for new molecules that have more desirable properties for clinical applications. Natural products have long been important sources of pharmaceuticals, and there is a great potential for discovery of novel chemotypes from under-explored biodiversities in the world. The objective of this study is to mine the terrestrial plants in Sarawak, Borneo Island, for new photosensitizers for PDT. In a screening program from 2004 to 2008, we prepared and studied 2,400 extracts from 888 plants for their photosensitizing activities. This report details the bioprospecting process, preparation and testing of extracts, analysis of the active samples, fractionation of four samples, and isolation and characterization of photosensitizers.

Synthesis of Light-Induced Expandable Photoresponsive Polymeric Nanoparticles for Triggered Release.

High stability of drug-delivery nanocarriers during blood circulation is critical for effective drug delivery and low systematic toxicity, although destabilization of these nanocarriers is required for efficient release when they reach target sites. To develop efficient polymeric nanocarriers, we intended to synthesize and characterize a group of cross-linked, light-induced, expandable, polymeric nanoparticles through miniemulsion polymerization. These synthesized nanoparticles were stable in aqueous solutions, although light irradiation led to particle uncaging and further particle expansion up to 315-fold in volume. This resulted in the efficient release of the encapsulated contents in aqueous solutions and three cell lines (HeLa, RAW264.7, and MCF-7). Selective triggered release was also successfully achieved with spatial resolution in cell monolayers. In addition, curcumin encapsulation and photoregulation of its release were realized. Further cell viability of encapsulated curcumin was successfully achieved with light activation.