Design and Synthesis of Dimethylaminomethyl-Substituted Curcumin Derivatives: Potent Anti-Inflammatory, Anti-Oxidant, and Radioprotection Activity, Improved Aqueous Solubility Compared with Curcumin.

Although the wide variety of bioactivities of curcumin has been reported by researchers, the clinical application of curcumin is still limited due to its poor aqueous solubility. In view of this, a series of dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized (compounds 1-15). Acetate of these derivatives were prepared (compounds 1a-15a). The Mannich reaction and aldol condensation reaction are the main reactions involved in this study. Compounds 6, 10, 12, 3a, 5a, 6a, 7a, 8a, 10a, 11a, 12a, 13a, 14a, and 15a exhibited better in vitro anti-inflammatory activity compared to curcumin in the RAW264.7 cell line. Compounds 5, 1a, 5a, 8a, and 12a exhibited better in vitro antioxidant activity compared to curcumin in the PC 12 cell line. Compounds 11, 13, 5a, 7a, and 13a exhibited better in vitro radiation protection compared to curcumin in the PC 12 cell line. The aqueous solubilities of all the curcumin derivative acetates were greatly improved compared to curcumin.

Anti-Lung Cancer Activities of 1,2,3-Triazole Curcumin Derivatives via Regulation of the MAPK/NF-κB/STAT3 Signaling Pathways.

In this study, a series of curcumin derivatives containing 1,2,3-triazole were designed and synthesized, and their inhibitory activities against the proliferation of lung cancer cells were studied. Compound 5 k (3,4-dichlorobenzyltriazole methyl curcumin) had the best activity against A549 cells, with a half-maximal inhibitory concentration (IC50 ) of 2.27 µM, which was approximately 10 times higher than that of the lead curcumin and higher than that of gefitinib (IC50 =8.64 µM). Western blotting revealed that 5 k increased the phosphorylation levels of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). Compound 5 k also promoted the expression of the inhibitor of nuclear factor-κB (IκBα) and decreased that of nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), and ß-catenin. Therefore, 5 k suppresses A549 cell proliferation by activating the mitogen-activated protein kinases and suppressing NF-κB/STAT3 signaling pathways. So, 5 k can potentially be used for treating non-small cell lung cancer.

Biotinylated curcumin as a novel chemosensitizer enhances naphthalimide-induced autophagic cell death in breast cancer cells.

Achieving selective release of chemical anticancer agents and improving therapeutic efficacy has always been a hot spot in the field of cancer research, yet how to achieve this remains a great challenge. In this work, we constructed a novel chemical anticancer agent (named MCLOP) by introducing naphthalimide into the skeleton of methylene blue (MB). Under the stimulation by cellular hypochlorous acid (HClO) and visible light, selective release of active naphthalimide can be achieved within breast cancer cell lines, the release process of which can be tracked visually using near-infrared fluorescence of MB (685 nm). More importantly, we developed biotinylated curcumin (Cur-Bio) as a new chemosensitizer, which significantly enhanced the ability of MCLOP to induce autophagic cell death of breast cancer cells. This synergistic treatment strategy exhibited an excellent anti-proliferation effect on breast cancer cells in vitro, three-dimensional (3D) cell sphere model, and mouse tumor model in vivo. This work provides a new strategy for the treatment of breast cancer and also opens new opportunities for the efficient treatment of cancer with curcumin-based chemosensitizer.

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.

Novel Bio-Based Amphiphilic Ionic Liquids for the Efficient Demulsification of Heavy Crude Oil Emulsions.

In the last few decades, there has been an increasing trend for the usage of natural products and their derivatives as green and renewable oil-filed chemicals. Use of these compounds or their derivatives contributes to reducing the use of traditional chemicals, and enhances green chemistry principles. Curcumin (CRC) is one of the most popular natural products and is widely available. The green character, antioxidant action, and low cost of CRC prompt its use in several applications. In the present study, Curcumin was used to synthesize two new amphiphilic ionic liquids (AILs) by reacting with 1,3-propanesultone or bromoacetic acid to produce corresponding sulfonic and carboxylic acids, CRC-PS and CRC-BA, respectively. Following this, the formed CRC-PS and CRC-BA were allowed to react with 12-(2-hydroxyethyl)-15-(4-nonylphenoxy)-3,6,9-trioxa-12-azapentadecane-1,14-diol (HNTA) to form corresponding AILs, GCP-IL and GRB-IL, respectively. The chemical structures, surface tension, interfacial tension, and relative solubility number (RSN) of the synthesized AILs were investigated. The efficiency of GCP-IL and GRB-IL to demulsify water in heavy crude oil (W/O) emulsions was also investigated, where we observed that both GCP-IL and GRB-IL served as high-efficiency demulsifiers and the efficiency increased with a decreased ratio of water in W/O emulsion. Moreover, the data showed an increased efficiency of these AILs with an increased concentration. Among the two AILs, under testing conditions, GCP-IL exhibited a higher efficiency, shorter demulsification time, and cleaner demulsified water.

The AMPA receptor biophysical gating properties and binding site: Focus on novel curcumin-based diazepines as non-competitive antagonists.

INTRODUCTION: Investigating the binding site of six novel curcumin-based diazepine compounds as a non-competitive antagonist on ionotropic, AMPA-type glutamate receptors, including homomeric and heteromeric subunits. These receptors play a pivotal role in neurodegenerative diseases such as Alzheimer's and epilepsy due to excitotoxicity. Furthermore, it appears that AMPAR signaling plays a significant role in disease development outside the nervous system, as a potential relationship between AMPAR activation and cancer development may exist. OBJECTIVES: Study the biophysical gating effects of the curcumin-based diazepine on AMPAR variants and identify CBD binding sites on AMPARs with the hopes of discovering more potent drug candidates with less undesirable side effects. METHODS: Our current study uses patch-clamp electrophysiology technology to estimate whole-cell amplitudes changes when exposing HEK293T cells expressing AMPAR subunits to different curcumin-based diazepines. RESULTS: The non-competitive antagonist curcumin-based compounds successfully reduced AMPAR activation currents and increased the rate of desensitization and deactivation. CBD-4 and CBD-5 show the most significant impact on AMPARs, reducing the current by 7-fold. The results contrast with those obtained by the halogenated benzodiazepine-fused curcumins reported previously and lake pyrimidine and pyrazine moieties. This indicates that the N's presence in the effused rings plays a significant role in binding to receptors. CBD-4 showed the highest effect on GluA2 subunits in receptors, while CBD-5 most dramatically impacting GluA1 homomeric receptors, demonstrating that the compounds are more selective towards AMPA-type glutamate receptors. The compounds also showed significant cytotoxic activities against breast cancer cell line (MCF-7), with CBD-4 having the most significant impact. CONCLUSION: Curcumin-based compounds (i.e., CBD-4 and CBD-5) yield significant neurodegenerative drug potential, and it creates a novel structure with significant activities in reducing AMPAR excitation compared to traditional benzodiazepine analogs, yet their binding mechanisms are still not fully understood. Moreover, AMPARs appear to have a potential influence on cancer development, and the curcumin-based compounds might provide insight into the nature of this relationship.

Tailored Functionalization of Natural Phenols to Improve Biological Activity.

Phenols are widespread in nature, being the major components of several plants and essential oils. Natural phenols' anti-microbial, anti-bacterial, anti-oxidant, pharmacological and nutritional properties are, nowadays, well established. Hence, given their peculiar biological role, numerous studies are currently ongoing to overcome their limitations, as well as to enhance their activity. In this review, the functionalization of selected natural phenols is critically examined, mainly highlighting their improved bioactivity after the proper chemical transformations. In particular, functionalization of the most abundant naturally occurring monophenols, diphenols, lipidic phenols, phenolic acids, polyphenols and curcumin derivatives is explored.

A Small Molecule Strategy for Targeting Cancer Stem Cells in Hypoxic Microenvironments and Preventing Tumorigenesis.

Breast cancer consists of heterogenic subpopulations, which determine the prognosis and response to chemotherapy. Among these subpopulations, a very limited number of cancer cells are particularly problematic. These cells, known as breast cancer stem cells (BCSCs), are thought responsible for metastasis and recurrence. They are thus major contributor to the unfavorable outcomes seen for many breast cancer patients. BCSCs are more prevalent in the hypoxic niche. This is an oxygen-deprived environment that is considered crucial to their proliferation, stemness, and self-renewal but also one that makes BCSCs highly refractory to traditional chemotherapeutic regimens. Here we report a small molecule construct, AzCDF, that allows the therapeutic targeting of BCSCs and which is effective in normally refractory hypoxic tumor environments. A related system, AzNap, has been developed that permits CSC imaging. Several design elements are incorporated into AzCDF, including the CAIX inhibitor acetazolamide (Az) to promote localization in MDA-MB-231 CSCs, a dimethylnitrothiophene subunit as a hypoxia trigger, and a 3,4-difluorobenzylidene curcumin (CDF) as a readily released therapeutic payload. This allows AzCDF to serve as a hypoxia-liable molecular platform that targets BCSCs selectively which decreases CSC migration, retards tumor growth, and lowers tumorigenesis rates as evidenced by a combination of in vitro and in vivo studies. To the best of our knowledge, this is the first time a CSC-targeting small molecule has been shown to prevent tumorigenesis in an animal model.

Synthetic curcumin analog: inhibiting the invasion, angiogenesis, and metastasis in human laryngeal carcinoma cells via NF-kB pathway.

BACKGROUND: Laryngeal carcinoma, the most common among head and neck squamous cell carcinoma (HNSCC), induces 1% of all cancer deaths. Curcumin the active constituent of turmeric, is shown to be effective in the treatment of various cancers. In the present study, we explored the mechanistic role of bis-demethoxy curcumin analog (BDMC-A) as a chemotherapeutic agent. We investigated its inhibitory effect on invasion, angiogenesis, and metastasis in human laryngeal carcinoma (Hep-2) cells in comparison with curcumin. METHODS: The effect of curcumin and BDMC-A on transcription factors (NF-κB, p65, c-Jun, c-Fos, STAT3, 5, PPAR-γ, ß-catenin, COX-2, MMP-9, VEGF, TIMP-2) involved in signal transduction cascade, invasion, and angiogenesis in Hep-2 cells were quantified using Western blotting and RT-PCR technique. ELISA was used to measure the pro-inflammatory markers in Hep-2 cells treated with curcumin and BDMC-A. RESULTS: The results showed that BDMC-A inhibits the transcription factors NF-κB, p65, c-Jun, c-Fos, STAT3, STAT5, PPAR-γ and ß-catenin, which are responsible for tumor progression and malignancy. Moreover, BDMC-A treatment downregulated MMP-9, VEGF, TGF- ß, IL-6 and IL-8 and upregulated TIMP-2 levels. The effects were more significant compared to curcumin. CONCLUSION: Our overall results revealed that BDMC-A more effectively inhibited the markers of invasion, angiogenesis and metastasis in comparison with curcumin.

A New Pentafluorothio-Substituted Curcuminoid with Superior Antitumor Activity.

A new and readily available pentafluorothiophenyl-substituted N-methyl-piperidone curcuminoid 1a was prepared and investigated for its anti-proliferative, pro-apoptotic and cancer stem cell-differentiating activities against a panel of human tumor cell lines derived from various tumor entities. The compound 1a was highly anti-proliferative and reached IC50 values in the nanomolar concentration range. 1a was superior to the known anti-tumorally active curcuminoid EF24 (2) and its known N-ethyl-piperidone analog 1b in all tested tumor cell lines. Furthermore, 1a induced a noticeable increase of intracellular reactive oxygen species in HT-29 colon adenocarcinoma cells, which possibly leads to a distinct increase in sub-G1 cells, as assessed by cell cycle analysis. A considerable activation of the executioner-caspases 3 and 7 as well as nuclei fragmentation, cell rounding, and membrane protrusions suggest the triggering of an apoptotic mechanism. Yet another effect was the re-organization of the actin cytoskeleton shown by the formation of stress fibers and actin aggregation. 1a also caused cell death in the adherently cultured glioblastoma cell lines U251 and Mz54. We furthermore observed that 1a strongly suppressed the stem cell properties of glioma stem-like cell lines including one primary line, highlighting the potential therapeutic relevance of this new compound.

New Hybrids Based on Curcumin and Resveratrol: Synthesis, Cytotoxicity and Antiproliferative Activity against Colorectal Cancer Cells.

We synthesized twelve hybrids based on curcumin and resveratrol, and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620, along with the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids 3e and 3i (for SW480) and 3a, 3e and 3k (for SW620) displayed the best cytotoxic activity with IC50 values ranging from 11.52 ± 2.78 to 29.33 ± 4.73 µM for both cell lines, with selectivity indices (SI) higher than 1, after 48 h of treatment. Selectivity indices were even higher than those reported for the reference drug, 5-fluorouracil (SI = 0.96), the starting compound resveratrol (SI = 0.45) and the equimolar mixture of curcumin plus resveratrol (SI = 0.77). The previous hybrids showed good antiproliferative activity.

Solid-phase synthesis of curcumin mimics and their anticancer activity against human pancreatic, prostate, and colorectal cancer cell lines.

Curcumin is a bioactive natural compound with a wide range of pharmacological properties, including antitumor activity; however, its clinical application has been limited because of its low solubility, stability, and bioavailability. In this study, a solid phase approach was proposed for the combinatorial synthesis of a mini library of the mimics of curcumin in good purity and yield. The non-effective findings in pancreatic cancer cells switched to strong growth inhibition and cell death efficacy for PC3 prostate cancer cells, and mimic 9, in which tyrosol (TYR) and homovanillyl alcohol (HVA) units were linked by a phosphodiester bond, was quite effective not only in cell growth inhibition but also in causing strong cell death under the study conditions and treatments that were not effective in PANC1 cells. The results got more exciting when we also consider the findings in SW480 human colorectal carcinoma cell line, where the growth inhibitor effects were more in line with that of the PC3 cells, but the lack of cell death effect was more in line with the PANC1 cells.

Perspectives for synthetic curcumins in chemoprevention and treatment of cancer: An update with promising analogues.

Curcumin, a pure compound extracted from the flowering plant, turmeric (Curcuma longa. Zingiberaceae), is a common dietary ingredient found in curry powder. It has been studied extensively for its anti-inflammatory, antioxidant, antimicrobial and anti-tumour activities. Evidence is accumulating demonstrating its potential in chemoprevention and as an anti-tumour agent for the treatment of cancer. Despite demonstrated safety and tolerability, the clinical application of curcumin is frustrated by its poor solubility, metabolic instability and low oral bioavailability. Consequently researchers have tried novel techniques of formulation and delivery as well as synthesis of analogues with enhanced properties to overcome these barriers. This review presents the synthetic analogues of curcumin that have proven their anticancer potential from different studies. It also highlights studies that combined these analogues with approved chemotherapies and delivered them via novel techniques. Currently, there are no reports of clinical studies on any of the synthetic congeners of curcumin and this presents an opportunity for future research. This review presents the synthetic analogues of curcumin and makes a compelling argument for their potential application in the management of cancerous disease.

A novel selective mitochondrial-targeted curcumin analog with remarkable cytotoxicity in glioma cells.

Naturally occurring polyphenol curcumin (4) or demethoxycurcumin (5) and their synthetic derivatives display promising anticancer activities. However, their further development is limited by low bioavailability and poor selectivity. Thus, a mitochondria-targeted compound 14 (DMC-TPP) was prepared in the present study by conjugating a triphenylphosphine moiety to the phenolic hydroxyl group of demethoxycurcumin to enhance its bioavailability and treatment efficacy. The in vitro biological experiments of DMC-TPP showed that it not only displayed higher cytotoxicity as compared with its parent compound 5, but also exhibited superior mitochondria accumulation ability. Glioma cells were more sensitive to DMC-TPP, which inhibited the proliferation of U251 cells with an IC50 of 0.42 µM. The mechanism studies showed that DMC-TPP triggers mitochondria-dependent apoptosis, caused by caspase activation, production of reactive oxygen species (ROS) and decrease of mitochondrial membrane potential (MMP). In addition, DMC-TPP efficiently inhibited cellular thioredoxin reductase, which contributed to its cytotoxicity. Significantly, DMC-TPP delayed tumor progression in a mouse xenograft model of human glioma cancer. Taken together, the potent in vitro and in vivo antitumor activity of DMC-TPP warrant further comprehensive evaluation as a novel anti-glioma agent.

The potency of heterocyclic curcumin analogues: An evidence-based review.

Curcumin, a potent phytochemical, has been a significant lead compound and has been extensively investigated for its multiple bioactivities. Owing to its natural origin, non-toxic, safe, and pleiotropic behavior, it has been extensively explored. However, several limitations such as its poor stability, bioavailability, and fast metabolism prove to be a constraint to achieve its full therapeutic potential. Many approaches have been adopted to improve its profile, amongst which, structural modifications have indicated promising results. Its symmetric structure and simple chemistry have prompted organic and medicinal chemists to manipulate its arrangement and study its implications on the corresponding activity. One such recurring and favorable modification is at the diketo moiety with the aim to achieve isoxazole and pyrazole analogues of curcumin. A modification at this site is not only simple to achieve, but also has indicated a superior activity consistently. This review is a comprehensive and wide-ranged report of the different methods adopted to achieve several cyclized curcumin analogues along with the improvement in the efficacy of the corresponding activities observed.

Selective targeting of the inactive state of hematopoietic cell kinase (Hck) with a stable curcumin derivative.

Hck, a Src family nonreceptor tyrosine kinase (SFK), has recently been established as an attractive pharmacological target to improve pulmonary function in COVID-19 patients. Hck inhibitors are also well known for their regulatory role in various malignancies and autoimmune diseases. Curcumin has been previously identified as an excellent DYRK-2 inhibitor, but curcumin's fate is tainted by its instability in the cellular environment. Besides, small molecules targeting the inactive states of a kinase are desirable to reduce promiscuity. Here, we show that functionalization of the 4-arylidene position of the fluorescent curcumin scaffold with an aryl nitrogen mustard provides a stable Hck inhibitor (Kd = 50 ± 10 nM). The mustard curcumin derivative preferentially interacts with the inactive conformation of Hck, similar to type-II kinase inhibitors that are less promiscuous. Moreover, the lead compound showed no inhibitory effect on three other kinases (DYRK2, Src, and Abl). We demonstrate that the cytotoxicity may be mediated via inhibition of the SFK signaling pathway in triple-negative breast cancer and murine macrophage cells. Our data suggest that curcumin is a modifiable fluorescent scaffold to develop selective kinase inhibitors by remodeling its target affinity and cellular stability.

One Pot Green Synthesis of Doxorubicin and Curcumin Loaded Magnetic Nanoparticles and Cytotoxicity Studies.

BACKGROUND: Green synthesis, an alternative method for synthesizing nanoparticles, is cheaper, environmentally friendly, and does not show toxic effects. Doxorubicin is a chemotherapeutic agent used in lung cancer. Curcumin is a bioactive compound with properties, such as an anticancer obtained from Curcuma longa. OBJECTIVE: The objective of this study was to develop Doxorubicin and Curcumin loaded magnetic nanoparticles that could be synthesized by green tea leaves and to investigate cytotoxic effects against the A549-luc-C8, non-small cell lung cancer line. METHODS: Magnetic nanoparticles were synthesized with the green synthesis method. Furthermore, Doxorubicin and Curcumin were encapsulated into magnetic nanoparticles with the one-pot method and obtained magnetic nanoparticles characterized using FTIR, SEM/EDX, XRD, and UV-VIS spectrophotometric techniques. After that, The drug release test was performed by dialysis using pH 7.4 phosphate-buffered saline at 37 °C. MTT assay was performed to test the cytotoxicity effect in the A549-luc-C8 cell line. RESULTS: FTIR analysis verified the magnetic structure and drug loading. SEM images of magnetic nanoparticle revealed that they had a size of about 50-60 nm in a mono-disperse manner. Drug release after 24 h was found to be 5.8% for doxorubicin and 3.4% for curcumin, showing controlled release. CONCLUSION: Results showed that the prepared magnetic nanoparticles had a synergistic antitumor activity for A549-luc-C8.

Therapeutic Applications of Curcumin and its Novel Formulations in the Treatment of Bladder Cancer: A Review of Current Evidence.

Bladder cancer, a life-threatening serious disease, is responsible for thousands of cancer-associated deaths worldwide. Similar to other malignancies, standard treatments of bladder cancer, such as Chemoradiotherapy, are not efficient enough in the affected patients. It means that, according to recent reports in the case of life quality as well as the survival time of bladder cancer patients, there is a critical requirement for exploring effective treatments. Recently, numerous investigations have been carried out to search for appropriate complementary treatments or adjuvants for bladder cancer therapy. Curcumin, a phenolic component with a wide spectrum of biological activities, has recently been introduced as a potential anti-cancer agent. It has been shown that this agent exerts its therapeutic effects via targeting a wide range of cellular and molecular pathways involved in bladder cancer. Herein, the current data on curcumin therapy for bladder cancer are summarized.

Film-Forming Nanogels: Effects of Nanocarriers and Film-Forming Gel on the Sustained Release of Curcumin.

BACKGROUND: Although film-forming hydrogels possess the advantages of both film and hydrogel dosage forms, certain limitations still remain. OBJECTIVE: This study aims to investigate the use of film-forming hydrogels and the effects of nanocarriers on the sustained release of a poorly water-soluble drug, curcumin. METHODS: The film-forming hydrogels contained either zein or polyvinylpyrrolidone as a film former, in addition to hydroxypropyl methylcellulose, oleic acid, ethanol and water. Curcumin was encapsulated in poly(lacticco- glycolic acid) and gelatine nanoparticles using a sonoprecipitation method. Free drug and drug-loaded nanoparticles were later dispersed into blank hydrogels to produce the film-forming nanogels. RESULTS: The results suggested that the encapsulation of curcumin in nanoparticles could reduce the drug particle size to less than 200nm for easier diffusion and could shield curcumin from chemical interactions that limit its topical permeability. Curcumin was more compatible with gelatine nanoparticles than with poly(lactic-coglycolic acid) nanoparticles, and gelatine nanoparticles, in turn, were more compatible with zein than with polyvinylpyrrolidone film-forming nanogels. Therefore, gelatine nanoparticles in zein film-forming nanogels greatly elevated the permeability of curcumin by over five times that afforded by gelatine nanoparticles in polyvinylpyrrolidone film-forming nanogels. CONCLUSION: This research suggested that film-forming nanogel is a promising drug delivery system for both improved permeability and sustained topical diffusion of the extremely hydrophobic drug curcumin depending on the compatibility between the nanocarrier and the film-forming hydrogel.

Preparation, Characterization and In Vitro Biological Evaluation of Novel Curcumin Derivatives as Cytotoxic and Apoptosis-Inducing Agents.

BACKGROUND: Curcumin is a natural polyphenol and lead compound of the rhizomes of curcuma longa and it has been widely used for pharmacological activities. OBJECTIVE: In this study, a series of novel derivatives of curcumin, with this group linked to a 2-amino-4- phenylpyran-3-carbonitrile system, have been synthesized and tested for their antitumor activities in vitro against a panel of three human cancer cell lines (MCF-7, A2780, and U-87MG). METHODS: The in vitro cytotoxic activity of the synthesized compounds was tested on three cancer cell lines (MCF-7, A2780, and U-87MG) using MTT colorimetric assay. Meanwhile, the ability of the active compounds to induce apoptosis in cancer cells was investigated by examination of caspase-3 and caspase-9 and mitochondrial membrane potential assay. RESULTS: Under relatively mild conditions in ethanol, the reaction of a series of substrates afforded the corresponding derivatives of curcumin mostly in good yields (13 analogues, 48-94% yields). Bioassay results indicated that compounds L6 (para-Bromo), L9 (para-Nitro) and L12 (meta-Methoxy) were the most active members in this study demonstrating potent activities against A2780 cancer cells and experimental results of fluorescent staining and flow cytometry analysis revealed that L6 and L9 could induce apoptosis in A2780 cells with apoptosis ratios of about 40% and 46%, respectively at 24h of treatment at 15.35µM and 23µM in A2780 cells. On the other hand, they could increase the caspase-3 activity slightly (10%), while having no significant impact on the activities of caspase-9. CONCLUSION: Those two derivatives could be considered as useful templates for future development to obtain more potent antitumor agents.