Synthetic Curcumin Derivative Research Articles

Evaluating the Therapeutic Potential of Curcumin and Synthetic Derivatives: A Computational Approach to Anti-Obesity Treatments.

Natural compounds such as curcumin, a polyphenolic compound derived from the rhizome of turmeric, have gathered remarkable scientific interest due to their diverse metabolic benefits including anti-obesity potential. However, curcumin faces challenges stemming from its unfavorable pharmacokinetic profile. To address this issue, synthetic curcumin derivatives aimed at enhancing the biological efficacy of curcumin have previously been developed. In silico modelling techniques have gained significant recognition in screening synthetic compounds as drug candidates. Therefore, the primary objective of this study was to assess the pharmacokinetic and pharmacodynamic characteristics of three synthetic derivatives of curcumin. This evaluation was conducted in comparison to curcumin, with a specific emphasis on examining their impact on adipogenesis, inflammation, and lipid metabolism as potential therapeutic targets of obesity mechanisms. In this study, predictive toxicity screening confirmed the safety of curcumin, with the curcumin derivatives demonstrating a safe profile based on their LD50 values. The synthetic curcumin derivative 1A8 exhibited inactivity across all selected toxicity endpoints. Furthermore, these compounds were deemed viable candidate drugs as they adhered to Lipinski's rules and exhibited favorable metabolic profiles. Molecular docking studies revealed that both curcumin and its synthetic derivatives exhibited favorable binding scores, whilst molecular dynamic simulations showed stable binding with peroxisome proliferator-activated receptor gamma (PPARγ), csyclooxygenase-2 (COX2), and fatty acid synthase (FAS) proteins. The binding free energy calculations indicated that curcumin displayed potential as a strong regulator of PPARγ (-60.2 ± 0.4 kcal/mol) and FAS (-37.9 ± 0.3 kcal/mol), whereas 1A8 demonstrated robust binding affinity with COX2 (-64.9 ± 0.2 kcal/mol). In conclusion, the results from this study suggest that the three synthetic curcumin derivatives have similar molecular interactions to curcumin with selected biological targets. However, in vitro and in vivo experimental studies are recommended to validate these findings.

Therapeutic Effects of Curcumin Derivatives against Obesity and Associated Metabolic Complications: A Review of In Vitro and In Vivo Studies.

Obesity is a major cause of morbidity and mortality globally, increasing the risk for chronic diseases. Thus, the need to identify more effective anti-obesity agents has spurred significant interest in the health-promoting properties of natural compounds. Of these, curcumin, the most abundant and bioactive constituent of turmeric, possesses a variety of health benefits including anti-obesity effects. However, despite its anti-obesity potential, curcumin has demonstrated poor bioavailability, which limits its clinical applicability. Synthesizing curcumin derivatives, which are structurally modified analogs of curcumin, has been postulated to improve bioavailability while maintaining therapeutic efficacy. This review summarizes in vitro and in vivo studies that assessed the effects of curcumin derivatives against obesity and its associated metabolic complications. We identified eight synthetic curcumin derivatives that were shown to ameliorate obesity and metabolic dysfunction in diet-induced obese animal models, while five of these derivatives also attenuated obesity and associated metabolic complications in cell culture models. These curcumin derivatives modulated adipogenesis, lipid metabolism, insulin resistance, steatosis, lipotoxicity, inflammation, oxidative stress, endoplasmic reticulum stress, apoptosis, autophagy, fibrosis, and dyslipidemia to a greater extent than curcumin. In conclusion, the findings from this review show that compared to curcumin, synthetic curcumin derivatives present potential candidates for further development as therapeutic agents to modulate obesity and obesity-associated metabolic complications.

CLEFMA induces intrinsic and extrinsic apoptotic pathways through ERK1/2 and p38 signalling in uterine cervical cancer cells.

Although concurrent chemoradiotherapy is the cornerstone of treatment for locally advanced or recurrent uterine cervical cancer, treatment fails at a high rate. Therefore, the development of novel targeting agents is critical. This study investigated the action of CLEFMA, a potent, synthetic curcumin derivative, on cervical cancer cells and its mechanism of action. We found that CLEFMA negatively regulated the viability of cervical cancer cells, involving induction of cell apoptosis. Cleaved caspase-3, cleaved poly(adenosine diphosphate-ribose) polymerase, cleaved caspase-8, and cleaved caspase-9 expression were increased by treatment with CLEFMA. After U0126 (ERK1/2 inhibitor) and SB203580 (p38 inhibitor) were applied as cotreatment with CLEFMA, the expression of cleaved caspase-8, -9, and -3 was reduced significantly. In conclusion, CLEFMA activates both extrinsic and intrinsic apoptotic pathways through ERK1/2 and p38 signal transduction in cervical cancer cells.

Anti-amnesic effect of CUD 003, a novel synthetic derivative of curcumin, on scopolamine-induced memory impairment in rats

Anti-amnesic effect of CUD 003, a novel synthetic derivative of curcumin, on scopolamine-induced memory impairment in rats

JM-17 Induces G0/G1 Cell cycle arrest in human breast cancer cells through the downregulation of androgen receptors and cyclin-dependent kinase 4 protein expression

Background: Locally advanced breast cancer (BC) remains a clinical challenge for patients as many will eventually develop distant metastases despite receiving appropriate therapies. Materials and Methods: In this study, we have analyzed the expression of androgen receptors (AR) in a series of BC cell lines and found their expressions rather ubiquitous across many different cell lines. Moreover, we have demonstrated that JM-17 [(1E,4Z,6E)-4-(cyclobutylmethyl)-1,7-bis (3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one], a synthetic curcumin derivative, exhibited suitable antitumor activities on most of the BC cell lines tested. Results: Human MDA-MB-231 cells were treated with JM-17, and the results demonstrated that JM-17-induced cell cycle proliferation arrested at the G0/G1 phase in a dose-dependent manner. Cell cycle-regulated proteins, such as cyclin-dependent kinases 4 (CDK4), were downregulated and p21 was upregulated. We further demonstrated that JM-17 treatment reduced AR expressions in MDA-MB-231 cells. The AR/CDK4 protein complex was demonstrated for the first time using a fluorescence resonance energy transfer (FRET) activity assay and immunohistochemistry (IHC) staining. JM-17 reduced the FRET activity in vitro. An in vivo study further demonstrated that JM-17 (20 mg/kg) decreased considerably MDA-MB-231 xenograft tumor growth. Conclusion: AR-mediated BC formation is a factor that clinicians often neglect. Our study demonstrated that JM-17 could be a promising agent against specific targets in AR-positive BC patients.

Synthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities.

Natural phenolic products from herbal medicines and dietary plants constitute the main source of lead compounds for the development of the new drug. 4,4-Dimethylcurcumin (DMCU) is a synthetic curcumin derivative and exhibits anticancer activities against breast, colon, lung, and liver cancers. However, further development of DMCU is limited by unfavorable compound properties such as very low aqueous solubility and moderate stability. To increase its solubility, we installed either or both of the ethylene-carbonate-linked L-valine side chains to DMCU phenolic groups and produced targeted 1-trifluoroacetic acid (1-TFA) and 2-trifluoroacetic acid (2-TFA) derivatives. The terminus L-valine of ethylene-carbonate-linked side chain is known to be a L-type amino acid transporter 1 (LAT1) recognition element and therefore, these two derivatives were expected to readily enter into LAT1-expressing cancer cells. In practice, 1-TFA or 2-TFA were synthesized from DMCU in four steps with 34–48% overall yield. Based on the corresponding LC-MS analysis, water solubility of DMCU, 1-TFA, and 2-TFA at room temperature (25 ± 1 °C) were 0.018, 249.7, and 375.8 mg/mL, respectively, indicating >10,000-fold higher solubility of 1-TFA and 2-TFA than DMCU. Importantly, anti-proliferative assay demonstrated that 2-TFA is a potent anti-cancer agent against LAT1-expressing lung cancer cells NCI-H460, NCI-H358, and A549 cells due to its high intracellular uptake compared to DMCU and 1-TFA. In this study, we logically designed and synthesized the targeted compounds, established the LC-MS analytical methods for evaluations of drug solubility and intracellular uptake levels, and showed improved solubility and anti-cancer activities of 2-TFA. Our results provide a strategical direction for the future development of curcuminoid-like phenolic compounds.

C1 Inhibits Liquid-Liquid Phase Separation and Oligomerization of Tau and Protects Neuroblastoma Cells against Toxic Tau Oligomers.

The pathological aggregation of tau is one of the major contributing factors for several neurodegenerative tauopathies, including Alzheimer's disease. Here, we report that C1, a synthetic derivative of curcumin, strongly inhibited both the aggregation and filament formation of purified tau and protected neuroblastoma cells from the deleterious effects of the tau oligomers. Using confocal microscopy, C1 was found to reduce both the size and number of the tau droplets and increased the critical concentration of tau required for the droplet formation in vitro indicating that C1 suppressed the liquid-liquid phase separation of tau. C1 inhibited the aggregation of tau with a half-maximal inhibitory concentration of 1.5 ± 0.1 μM. An analysis of the aggregation kinetics data indicated that C1 strongly reduced the initial rate of the aggregation of tau. A dot blot analysis using tau-oligomer-specific antibody indicated that C1 inhibited the oligomerization of tau. Furthermore, dynamic light scattering experiments suggested that C1 strongly reduced the mean diameter of the tau oligomers. Atomic force microscopy experiments showed that C1 treatment reduced both the size and number of tau oligomers, suppressed the transition of tau oligomers into filaments, and also disintegrated preformed tau filaments. Also, the binding interaction of C1 with tau was monitored using absorbance and fluorescence spectroscopy. C1 bound to Y310W-tau with a dissociation constant of 2.0 ± 0.5 μM. The findings suggested that C1 is a potent inhibitor of tau aggregation and provided insights into the inhibitory mechanism of C1 on the oligomerization and fibril formation of tau.

CUD003, a novel synthetic derivative of curcumin, can mitigate middle cerebral artery occlusion (MCAO)-induced ischemic injury by suppressing inflammation in rats

CUD003, a novel synthetic derivative of curcumin, can mitigate middle cerebral artery occlusion (MCAO)-induced ischemic injury by suppressing inflammation in rats

The assessment of antidiabetic properties of novel synthetic curcumin analogues: α-amylase and α-glucosidase as the target enzymes.

The online version contains supplementary material available at 10.1007/s40200-020-00685-z.

Synthesis of new curcumin derivatives as influential antidiabetic α-glucosidase and α-amylase inhibitors with anti-oxidant activity

In this study, a new class of curcumin derivatives was synthesized using a multicomponent reaction containing curcumin, aldehydes, and malononitrile. This new protocol afforded a novel class of 4H-pyran heterocycles incorporating curcumin moiety. The products were obtained in the presence of p-toluenesulfonic acid (PTSA) as a catalyst in ethanol solvent in good to excellent yields. The synthetic compounds indicated a notable inhibitory activity against α-glucosidase (α-Gls) and revealed a weak inhibitory property against α–amylase (α-Amy). Also, these synthetic compounds indicated significant antioxidant activity. The new curcumin derivatives were also discovered to display no significant effect against the growth of two bacterial microflora in the human intestine. A molecular docking study was done to realize the binding interaction of the synthetic curcumin derivatives with the α-Gls enzyme. The results of our study introduced new synthetic curcumin derivatives as potential antidiabetic drugs.

Cyclodextrins Increase the Cytotoxicity of Curcumin Derivatives in Osteosarcoma Cell Culture

Cyclodextrins (CDs), a group of oligosaccharides formed by glucose units bound togetherin a ring, showed a promising ability to form supramolecular complexes with drug molecules and improved theirphysicochemical properties without any molecular modifications. On the other hand, a large number of synthetic curcumin derivatives showed promising anticancer results on malignant cell cultures in recent years. This study presents the advantages and limitations of CDs (potential enhancers of solubility and stability) when are used together with a series of curcumin complexes. All the CD-curcumin complex mixtures were tested as potential anticancer agents on a human osteosarcoma cell culture. A variant of beta-cyclodextrin (monochlorotriazinyl-β-cyclodextrin sodium salt) was found to exhibit the best results in terms of solubility and cytotoxicity enhancements. The results(expressed as inhibitory concentrations for 50 % cell viability - IC50) showed significant improvements for manganese and cooper curcumin complexes and had no effects for boron and thorium complexes.

Hydrazinocurcumin Induces Apoptosis of Hepatocellular Carcinoma Cells Through the p38 MAPK Pathway.

Hydrazinocurcumin (HZC), a synthetic derivative of curcumin (CUR), has been documented to show anticancer potential in impeding tumor growth in several cancers, including hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms remain unclear. This study aimed to explore the function and underlying mechanisms of HZC on HCC cells, which may involve the p38 mitogen activated protein kinase (MAPK) pathway. HZC was first purified and identified. HepG2 cells were then subjected to treatment with HZC or CUR of different concentrations and p38 MAPK signaling inhibitor (SB203580) to verify their effects on HCC cell apoptosis and proliferation. Furthermore, the functional relevance between HZC and the p38 MAPK pathway in HCC was examined. It was observed that 40 μM HZC exhibited the best pro‐apoptosis effect in HCC cells. HZC was found to inhibit HCC cell proliferation and promote apoptosis, the effect of which was stronger than 5‐fluorouracil (5‐FU). More importantly, the anti‐oncogenic effect of HZC and 5‐FU was implicated with activation of the p38 MAPK pathway. In vivo experimental results showed that HZC inhibited tumor growth more effectively than 5‐FU through the p38 MAPK pathway. These results provide evidence that HZC exerted anti‐oncogenic and pro‐apoptosis effects in HCC cells through activation of the p38 MAPK pathway.

Effects of CNB-001, a synthetic curcumin derivative, on thrombin-induced phosphorylation of MAP kinases in primary cultured rat microglia

Effects of CNB-001, a synthetic curcumin derivative, on thrombin-induced phosphorylation of MAP kinases in primary cultured rat microglia

The Synthetic Curcumin Derivative CNB-001 Attenuates Thrombin-Stimulated Microglial Inflammation by Inhibiting the ERK and p38 MAPK Pathways.

We have recently found that the synthetic curcumin derivative CNB-001 suppresses lipopolysaccharide (LPS)-induced nitric oxide (NO) production in cultured microglia, demonstrating that it exerts anti-neuroinflammatory effects by regulating microglial activation. To explore the molecular mechanisms underlying the anti-inflammatory effect of CNB-001, the present study investigated whether CNB-001 is also effective for microglial NO production induced by other stimulants than LPS. Treatment of primary cultured rat microglia with thrombin, a serine protease that has been proposed as a mediator of cerebrovascular injuries, caused the expression of inducible NO synthase (iNOS) and the production of NO. The thrombin-induced NO production was completely blocked by the presence of SCH-79797, a selective protease-activated receptor 1 (PAR-1) antagonist, suggesting that the effect of thrombin is mediated by PAR-1. CNB-001 (1-10 µM) attenuated the thrombin-induced iNOS expression and NO production without affecting the PAR-1 expression. In addition, thrombin treatment caused rapid phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). The changes in ERK and p38 MAPK were significantly suppressed by the presence of CNB-001. These results demonstrate that CNB-001 suppresses thrombin-stimulated microglial activation by inhibiting the ERK and p38 MAPK pathways.

Inhibition of amyloid fibrillation of lysozyme by bisdemethoxycurcumin and diacetylbisdemethoxycurcumin

Amyloid deposition, arising from the fibrillogenesis of proteins in organs and tissues of the body, causes several neurodegenerative disorders. One therapeutic approach is based on the use of polyphenols and their derivatives for suppressing and inhibiting the accumulation of these toxic fibrils in tissues. In the present study, the anti-amyloidogenic activities of bisdemethoxycurcumin (BDMC), a natural polyphenolic compound, and diacetylbisdemethoxycurcumin (DABC), a synthetic derivative of curcumin, on the amyloid fibrillation of hen egg white lysozyme (HEWL) is studied in depth using thioflavin T (ThT) fluorescence, atomic force microscopy (AFM), circular dichroism spectroscopy (CD), molecular docking and Ligplot calculations. The binding parameters such as binding constants and the number of substantive binding sites were obtained experimentally. It could be shown from docking simulation that four hydrogen bonds via the two phenolic OH groups of BDMC and two β-diketone moiety of BDMC are formed with the Asp-101, Trp-63, Asn-59 and Glu-35 of HEWL, whereas, two hydrogen bonds formed via two β-diketone moiety of DABC with Asn-39 and Trp-63 of HEWL. The short Fӧrster's distance (r) between donor and acceptor, the binding constant values and also the nature of interaction, demonstrate strong interaction between these two curcuminoids and lysozyme. According to amyloid fibrillation and binding results, the interaction of BDMC with HEWL is stronger than that of DABC and amyloid fibrillation of HEWL was inhibited more effectively by BDMC than DABC. It can be suggested that the more inhibitory activity of BDMC than DABC is correlated to the stronger interaction of BDMC with HEWL. These natural polyphenolic compounds are thus good candidates for inhibiting of amyloid formation. The inhibitory activities of BDMC and DABC can be used in drug formulation against the dangerous amyloid-related diseases and provide health promotion for organs and tissues of the body.

Curcumin Derivative Epigenetically Reactivates Nrf2 Antioxidative Stress Signaling in Mouse Prostate Cancer TRAMP C1 Cells.

The carcinogenesis of prostate cancer (PCa) in TRAMP model is highly correlated with hypermethylation in the promoter region of Nrf2 and the accompanying reduced transcription of Nrf2 and its regulated detoxifying genes. We aimed to investigate the effects of (3E,5E)-3,5-bis-(3,4,5-trimethoxybenzylidene)-tetrahydro-thiopyran-4-one (F10) and (3E,5E)-3,5-bis-(3,4,5-trimethoxy-benzylidene)-tetrahydropyran-4-one (E10), two synthetic curcumin derivatives, on restoring Nrf2 activity in TRAMP C1 cells. HepG2-C8 cells transfected with an antioxidant-response element (ARE)-luciferase vector were treated with F10, E10, curcumin, and sulforaphane (SFN) to compare their effects on Nrf2-ARE pathways. We performed real-time quantitative PCR and Western blotting to investigate the effects of F10 and E10 on Nrf2, correlated phase II detoxification genes. We also measured expression and activity of DNMTand HDAC enzymes. Enrichment of H3K27me3 on the promoter region of Nrf2 was explored with a chromatin immunoprecipitation (ChIP) assay. Methylation of the CpG region in Nrf2 promoter was doubly examined by bisulfite genomic sequencing (BGS) and methylation DNA immunoprecipitation (MeDIP). Compared with curcumin and SFN, F10 is more potent in activating Nrf2-ARE pathways. Both F10 and E10 enhanced level of Nrf2 and the correlated phase II detoxifying genes. BGS and MeDIP assays indicated that F10 but not E10 hypomethylated the Nrf2 promoter. F10 also downregulated the protein level of DNMT1, DNMT3a, DNMT3b, HDAC1, HDAC4, and HDAC7 and the activity of DNMTs and HDACs. F10 but not E10 effectively reduced the accumulation of H3k27me3 on the promoter of Nrf2. F10 and E10 can activate the Nrf2-ARE pathway and increase the level of Nrf2 and correlated phase II detoxification genes. The reactivation effect on Nrf2 by F10 in TRAMP C1 may come from demethylation, decrease of HDACs, and inhibition of H3k27me3 accumulation.

CNB-001, a synthetic pyrazole derivative of curcumin, suppresses lipopolysaccharide-induced nitric oxide production through the inhibition of NF-κB and p38 MAPK pathways in microglia

CNB-001, a pyrazole derivative of curcumin, has been found to exert neuroprotective and memory-enhancing effects that may be effective for the treatment of Alzheimer's disease. Since aberrant activation of microglia is involved in the pathogenesis of Alzheimer's disease, the present study was undertaken to investigate the effect of CNB-001 on microglia-mediated inflammatory responses. In primary cultured rat microglia, CNB-001 (1–10µM) suppressed the lipopolysaccharide (LPS)-induced nitric oxide (NO) production and expression of inducible NO synthase (iNOS), and the potency of CNB-001 was stronger than curcumin. CNB-001 also suppressed the LPS-induced nuclear translocation of nuclear factor κB (NF-κB), which is essential for the expression of iNOS. LPS treatment promoted phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). CNB-001 significantly suppressed the LPS-induced phosphorylation of p38 MAPK, but not ERK and JNK. The suppressive effect of CNB-001 on NO production was mimicked by blockade of the p38 MAPK signaling pathway with SB203580. These results suggest that CNB-001 exerts anti-inflammatory effects through inhibition of NF-κB and p38 MAPK pathways in microglia.

Synthetic curcumin derivative DK1 possessed G2/M arrest and induced apoptosis through accumulation of intracellular ROS in MCF-7 breast cancer cells

AimsCurcumin is a lead compound of the rhizomes of Curcuma longa and possess a broad range of pharmacological activities. Chemically, curcumin is 1,3-dicarbonyl class of compound, which exhibits keto-enol tautomerism. Despite of its strong biological properties, curcumin has yet been recommended as a therapeutic agent because of its poor bioavailability.Main methodsA curcumin derivative (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (DK1) was synthesized and its cytotoxicity was tested on breast cancer cell MCF-7 and normal cell MCF-10A using MTT assay. Meanwhile, cell cycle regulation and apoptosis on MCF-7 cell were evaluated using flow cytometry. Regulation of cell cycle and apoptosis related genes expression was investigated by quantitative real time polymerase chain reaction (qRT-PCR), western blot and caspases activity analyses. Activation of oxidative stress on MCF-7 were evaluated by measuring ROS and GSH levels.Key findingsDK1 was found to possess selective cytotoxicity on breast cancer MCF-7 cell than normal MCF-10A cell. Flow cytometry cell cycle and AnnexinV/PI analyses reported that DK1 effectively arrested MCF-7 at G2/M phase and induced apoptosis after 72 h of incubation than curcumin. Upregulation of p53, p21 and downregulation of PLK-1 subsequently promote phosphorylation of CDC2 which were found contributed to the arrest of G2/M phase. Moreover, increased of reactive oxygen species and reduced of antioxidant glutathione level correlate with apoptosis observed with raised of cytochrome c and active caspase 9.SignificanceDK1 was found to be more effective in inducing cell cycle arrest and apoptosis against MCF-7 cell with much higher selectivity index of MCF-10A/MCF-7 than curcumin, which might be contributed by the overexpression of p53 protein.

Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines

BackgroundMultidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF–CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000. Material and methodsCytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptake values, IC50 values and binding energies. ResultsThe compounds displayed IC50 values between 0.7±0.03 and 20.2±0.25μM. CEM/ADR5000 cells exhibited cross-resistance to 10 compounds, collateral sensitivity to three compounds and regular sensitivity to the remaining six curcumins. Molecular docking studies at the intra-channel transmembrane domain of human P-gp resulted in lowest binding energies ranging from −9.00±0.10 to −6.20±0.02kcal/mol and pKi values from 0.24±0.04 to 29.17±0.88μM. At the ATP-binding site of P-gp, lowest binding energies ranged from −9.78±0.17 to −6.79±0.01kcal/mol and pKi values from 0.07±0.02 to 0.03±0.03μM. CEM/ADR5000 cells accumulated approximately 4-fold less doxorubicin than CCRF–CEM cells. The control P-gp inhibitor, verapamil, partially increased doxorubicin uptake in CEM/ADR5000 cells. Six curcumins increased doxorubicin uptake in resistant cells or even exceeded uptake levels compared to sensitive one. QSAR yielded good activity prediction (R=0.797 and R=0.794 for training and test sets). ConclusionSelected derivatives may serve to guide future design of novel P-gp inhibitors and collateral sensitive drugs to combat MDR.

Syntheses And Evaluation Of Asymmetric Curcumin Analogues As Potential Multifunctional Agents For The Treatment Of Alzheimer's Disease.

A series of new asymmetric curcumin analogues were synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. Our results showed that most of these synthetic compounds had better inhibitory properties against Aβ aggregation compared with curcumin, and better anti-oxidative properties compared with the reference compound Trolox through the study of oxygen radical absorbance capacity (ORAC). Some compounds showed good properties in selectively chelating metal ions such as copper and iron. Besides, some compounds were found to be able to dissociate Aβ protein which had already aggregated. The structure-activity relationships (SAR) of these synthetic compounds were studied. The present investigation indicated that our synthetic asymmetric curcumin derivatives could be potential multifunctional agents for the treatment of Alzheimer's disease (AD).