Mono-carbonyl Analogues Of Curcumin Research Articles

Preparation and anti-colon cancer effect of a novel curcumin analogue (CA8): in vivo and in vitro evaluation

Chemotherapy remains the first choice of treatment for colon cancer despite the inevitable adverse effects. Curcumin (CU) possesses antitumor activity but has poor aqueous solubility, low bioavailability, and weak activity. To address this, nine novel monocarbonyl CU analogues were designed, synthesized, and evaluated in the present study. Among them, CA8 exhibited the highest water solubility, which was approximately 2.37 × 106 times that of CU. In addition, compared with CU, its cytotoxicity on Caco-2 cells (19.2 times/48 h) was stronger. Of note, CA8 arrestedthe cell cycle of Caco-2 cells at the G2/M phase and induced apoptosis. Meanwhile, acute toxicity experiments indicated that KM mice tolerated CA8 for up to 300 mg/kg CA8 (oral administration) and 50 mg/kg CA8 (intraperitoneal injection). The oral administration of CA8 to Sprague Dawley rats exhibited higher AUC (0-t) (6.23-fold) and longer MRT (0-t) (3.35-fold) than that of CU. CA8 also inhibited the proliferation and angiogenesis of tumor cells more than CU and tegafur. Finally, CA8 may exert anti-tumor effects through the activation of JNK pathway and inhibition of AKT pathway. These results suggest that CA8 is a safe and highly effective new drug for colon cancer treatment.

6603 Impact of the Monocarbonyl Analogs of Curcumin, C66 and B2BrBC, on the Protein Expression of Epithelial and Mesenchymal Markers in MCF-7 Breast Cancer Cells

Abstract Disclosure: R. Stojchevski: None. A. Lavi: None. J. Bogdanov: None. N. Hadzi-Petrushev: None. M. Mladenov: None. L. Poretsky: None. D.B. Avtanski: None. The synthesis of monocarbonyl analogs of curcumin (MACs) presents a solution to the challenges posed by curcumin, a natural polyphenol extracted from the roots of the turmeric plant (Curcuma longa), which is known for its antioxidant and anti-inflammatory properties. The limitations of curcumin, including poor stability, low bioavailability, and rapid metabolism, hinder its application, and MACs, designed without a β-diketone moiety, address these drawbacks and exhibit enhanced stability and bioavailability. This study aimed to assess the effects of two monocarbonyl analogs of curcumin, (2E,6E)-2,6-bis[(2-trifluoromethyl)benzylidene]cyclohexanone (C66) and (2E,6E)-2,6-bis(2-bromobenzylidene)cyclohexanone (B2BrBC), on epithelial-to-mesenchymal transition (EMT) in MCF-7 breast cancer cells using western blot analysis. Our previous findings indicated that these analogs can potentially affect EMT by modulating the epithelial and mesenchymal gene expression. MCF-7 cells were cultured in complete medium supplemented with EMT-inducing factors for two days, followed by C66 and B2BrBC administration (100 µM) for three additional days. After the experiments, proteins were extracted, and western blot analyses were performed to measure the expression levels of various epithelial and mesenchymal markers (E-cadherin, N-cadherin, SNAI1, and Claudin-1). The results revealed that both C66 and B2BrBC increased the protein levels of the epithelial marker E-cadherin and suppressed those of the mesenchymal marker N-cadherin. Moreover, C66 and B2BrBC decreased the protein expression of the transcription factor SNAI1 and transmembrane protein Claudin-1. Between the two MACs, B2BrBC showed a more pronounced effect on N-cadherin expression, while C66 was more potent in suppressing SNAI1 protein expression. Our findings demonstrate that C66 and B2BrBC counteract EMT, contributing to the potential therapeutic applications of MACs in managing breast cancer progression. Presentation: 6/3/2024

6603 Impact Of The Monocarbonyl Analogs Of Curcumin, C66 And B2BrBC, On The Protein Expression Of Epithelial And Mesenchymal Markers In MCF-7 Breast Cancer Cells

Abstract Disclosure: R. Stojchevski: None. A. Lavi: None. J. Bogdanov: None. N. Hadzi-Petrushev: None. M. Mladenov: None. L. Poretsky: None. D.B. Avtanski: None. The synthesis of monocarbonyl analogs of curcumin (MACs) presents a solution to the challenges posed by curcumin, a natural polyphenol extracted from the roots of the turmeric plant (Curcuma longa), which is known for its antioxidant and anti-inflammatory properties. The limitations of curcumin, including poor stability, low bioavailability, and rapid metabolism, hinder its application, and MACs, designed without a β-diketone moiety, address these drawbacks and exhibit enhanced stability and bioavailability. This study aimed to assess the effects of two monocarbonyl analogs of curcumin, (2E,6E)-2,6-bis[(2-trifluoromethyl)benzylidene]cyclohexanone (C66) and (2E,6E)-2,6-bis(2-bromobenzylidene)cyclohexanone (B2BrBC), on epithelial-to-mesenchymal transition (EMT) in MCF-7 breast cancer cells using western blot analysis. Our previous findings indicated that these analogs can potentially affect EMT by modulating the epithelial and mesenchymal gene expression. MCF-7 cells were cultured in complete medium supplemented with EMT-inducing factors for two days, followed by C66 and B2BrBC administration (100 µM) for three additional days. After the experiments, proteins were extracted, and western blot analyses were performed to measure the expression levels of various epithelial and mesenchymal markers (E-cadherin, N-cadherin, SNAI1, and Claudin-1). The results revealed that both C66 and B2BrBC increased the protein levels of the epithelial marker E-cadherin and suppressed those of the mesenchymal marker N-cadherin. Moreover, C66 and B2BrBC decreased the protein expression of the transcription factor SNAI1 and transmembrane protein Claudin-1. Between the two MACs, B2BrBC showed a more pronounced effect on N-cadherin expression, while C66 was more potent in suppressing SNAI1 protein expression. Our findings demonstrate that C66 and B2BrBC counteract EMT, contributing to the potential therapeutic applications of MACs in managing breast cancer progression. Presentation: 6/3/2024

Monocarbonyl analogs of curcumin C66 and B2BrBC modulate oxidative stress, JNK activity, and pancreatic gene expression in rats with streptozotocin-induced diabetes

The pathogenesis of type 1 diabetes mellitus (T1DM) involves oxidative stress and inflammation. Curcumin, a natural polyphenolic compound found in turmeric, known to exhibit antioxidative and anti-inflammatory properties, is characterized by poor chemical stability, low bioavailability, and rapid metabolism. Monocarbonyl analogs of curcumin (MACs) with a structural absence of β-diketone and enhanced stability and bioavailability present a potential solution to the challenges associated with the use of curcumin. This study aimed to evaluate the effect of two MACs, C66 and B2BrBC, on oxidative stress markers, antioxidant enzyme activity, expression of diabetes-associated genes, and signaling pathway proteins in the context of T1DM. Streptozotocin (STZ)-induced male Wistar rats or rat pancreatic RIN-m cells were used for in vivo and in vitro experiments, respectively. C66 or B2BrBC were given either before or after STZ treatment. Oxidative stress markers and antioxidant enzyme activities were determined in various tissues. Expression of diabetes-associated genes was assessed using RT-qPCR, and the activity of signaling pathway proteins in the pancreas was determined through Western blot analysis. Treatment with C66 and B2BrBC significantly reduced oxidative stress markers and positively influenced antioxidant enzyme activities. Moreover, both compounds inhibited JNK activity in the pancreas while enhancing the expression of genes crucial for β-cell survival and glucose and redox homeostasis. The findings highlight the multifaceted potential of C66 and B2BrBC in ameliorating oxidative stress, influencing gene expression patterns linked to diabetes, and modulating key signaling pathways in the pancreas. The findings suggest that these compounds can potentially address diabetes-related pathological processes.

Anticancer perspectives of monocarbonyl analogs of curcumin: A decade (2014-2024) review.

Monocarbonyl analogs of curcumin (MACs) represent structurally modified versions of curcumin. The existing literature indicates that MACs exhibit enhanced anticancer properties compared with curcumin. Numerous research articles in recent years have emphasized the significance of MACs as effective anticancer agents. This review focuses on the latest advances in the anticancer potential of MACs, from 2014 to 2024, including discussions on their mechanism of action, structure-activity relationship (SAR), and in silico molecular docking studies.

Discovery of cinnamylaldehyde-derived mono-carbonyl curcumin analogs as anti-gastric cancer agents via suppression of STAT3 and AKT pathway

The structural modification of curcumin has always been a hotspot in drug development. In this paper, a class of cinnamylaldehyde-derived mono-carbonyl curcumin analogs (MCAs) with 7-carbon-links were designed and synthesized and their anticancer properties were evaluated. Through screening anti-gastric cancer activity of these compounds, H1 exhibited the strongest cytotoxic activity by inhibiting cell viability and colony formation, inducing cell cycle G2/M phase arrest in vitro (SGC-7901 and AGS gastric cancer cells). Moreover, the SGC-7901 subcutaneous tumor-bearing mice studies revealed that H1 significantly inhibited the tumor growth of gastric cancer. We explored the possible potential targets of H1 through network pharmacology. Mechanistically, our results demonstrated that H1 showed potential anti-gastric cancer activity through suppression of the STAT3 and AKT signaling pathway in vitro and in vivo, which was validated by molecular docking. Overall, our results indicate the potential of H1 as a potent chemotherapeutic drug against gastric cancer.

Identification of β-cycloidal-derived mono-carbonyl curcumin analogs as potential interleukin-6 inhibitor to treat wound healing through QSAR, molecular docking, MD simulation, MM-GBSA calculation

Interleukin-6 (IL-6) is a cytokine that involved in the different phases of wound healing. It is responsible for promoting inflammation, regulating tissue repair scar formation, stimulating the production of extracellular matrix components and recruiting immune cells to the wound site. Therefore, suppressing IL-6 is beneficial for wound healing. However, no small molecules are currently available in the market against the IL-6. As a result, this research gap motivates us to find a potential inhibitor. This study aimed to investigate the wound healing potential of novel β-cycloidal-derived mono-carbonyl curcumin analogs reported in the literature through screening a series of computational studies. The calculated pIC50 value of 18 compounds (below 10) showed that all compounds may have potential therapeutic efficacy. Molecular docking studies revealed that compound C12 (−45.6044 kcal/mol) bound most strongly in the active site of IL-6 compared to the FDA-approved drug clindamycin (−42.3223). The Molecular Dynamic (MD) simulation displayed that lead compound C12 had the highest stability in the active site of IL-6 compared to the reference drug clindamycin. Furthermore, MMGBSA results indicated that C12 (−20.28 kcal/mol) had the highest binding energy compared to clindamycin (−8.36 kcal/mol). The ADMET analysis predicted that C12 are favourable for drug candidates. This study recommended compound C12 as a lead IL-6 inhibitor for future testing and development as therapeutics for wound healing. Communicated by Ramaswamy H. Sarma

Design, synthesis, and evaluation of cyclic C7-bridged monocarbonyl curcumin analogs containing an o-methoxy phenyl group as potential agents against gastric cancer

The structure-activity relationship (SAR) between toxicity and the types of linking ketones of C7 bridged monocarbonyl curcumin analogs (MCAs) was not clear yet. In the pursuit of effective and less cytotoxic chemotherapeutics, we conducted a SAR analysis using various diketene skeletons of C7-bridged MCAs, synthesized cyclic C7-bridged MCAs containing the identified low-toxicity cyclopentanone scaffold and an o-methoxy phenyl group, and assessed their anti-gastric cancer activity and safety profile. Most compounds exhibited potent cytotoxic activities against gastric cancer cells. We developed a quantitative structure-activity relationship model (R 2 > 0.82) by random Forest method, providing important information for optimizing structure. An optimized compound 2 exhibited in vitro and in vivo anti-gastric cancer activity partly through inhibiting the AKT and STAT3 pathways, and displayed a favorable in vivo safety profile. In summary, this paper provided a promising class of MCAs and a potential compound for the development of chemotherapeutic drugs.

Correction of mitochondrial dysfunction with trimethoxy-substituted monocarbonyl curcumin analogues in experimental Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease that is a terminal form of dementia with an alarming spread rate. The treatment of AD usually involves symptomatic therapy, but the research field for new medicines to correct AD focus on the pathogenetic keys of the disease, i.e., a mitochondrial dysfunction.The aim of the work was to evaluate the effect of trimethoxy-substituted monocarbonyl curcumin analogues on changes in the mitochondrial function of the hippocampus in AD rats.Materials and methods. AD was modeled in female Wistar rats by the injection of β-amyloid aggregates 1-42 into the CA1 part of the hippocampus. The tested compounds AZBAX4 and AZBAX6 at a dose of 20 mg/kg each, as well as the reference donepezil at a dose of 50 mg/kg, were administered orally for 30 days after the surgery. After the specified time had passed, the changes in the cellular respiration, a citrate synthase activity, cytochrome-c-oxidase, succinate dehydrogenase, and adenosine triphosphate (ATP) concentrations were evaluated in the mitochondrial fraction of the rat hippocampus.Results. During the study, it was shown that the use of AZBAX4 and AZBAX6 compounds contributed to an increase in the intensity of aerobic metabolism by 83.9 (p <0.05) and 35.9% (p <0.05), respectively, while reducing the activity of anaerobic one by 27.7 (p <0.05) and 20.6% (p <0.05), respectively. Against the background of the tested compounds AZBAX4 and AZBAX6 administration, there was also a significant increase in the activity of citrate synthase, succinate dehydrogenase and cytochrome-c-oxidase, as well as the level of ATP in the hippocampal tissue by 112.8 (p <0.05) and 117.1% (p <0.05), respectively. The use of donepezil led to a significant increase in the intensity of aerobic reactions – by 24.0% (p <0.05), a citrate synthase activity– by 80.0% (p <0.05) and the ATP concentration – by 68.5% (p <0.05). Against the background of the use of the analyzed substances, a decrease in the apoptosis-inducing factor and mitochondrial hydrogen peroxide is also worth noting.Conclusion. Based on the obtained data, it can be assumed that the use of AZBAX4 and AZBAX6 compounds contributes to an increase in the functional activity of the mitochondria of hippocampal cells of AD rats, while surpassing the reference donepezil. It is perspective to continue a further study of AZBAX4 and AZBAX6 compounds as possible medicines of a pathogenetic correction of AD.

Anti-apoptotic effects of trimethoxy-substituted monocarbonyl curcumin analogues in experimental Alzheimer’s disease

Anti-apoptotic effects of trimethoxy-substituted monocarbonyl curcumin analogues in experimental Alzheimer’s disease

Experimental and theoretical studies on (2E,5E)-2,5-bis(2-methoxybenzylidene)cyclopentanone: Structural, electrochemical, spectroscopic features, solid-state interactions, molecular docking and adsorption studies onto 2D carbon nanomaterials

A monocarbonyl analog of curcumin, (2E,5E)-2,5-bis(2-methoxybenzylidene)-cyclopentanone (B2MBCP), was prepared and characterized via spectroscopic methods (NMR, UV-Vis, FT-IR, and MS). Furthermore, density functional calculations were implemented to study the molecular structure and spectroscopic features, as well as adsorption properties. In addition, Hirshfeld surface and NBO theoretical analysis were carried out. The reduced density gradient (RDG) analysis via non-covalent interactions (NCI) and interaction region indicator (IRI) indicate the presence of extensive Van der Waals interactions. These interactions are classified in different contributions and energy stabilization from Hirshfeld surface analysis where the dominant type of contacts are H···H contacts. The molecular docking studies of B2MBCP with DNA revealed cooperative interactions that led to intercalation. The results from the cyclic voltammetry (CV) measurements agreed with the calculated energies of the frontier orbitals and the compound structure. Theoretical studies indicated that the relatively flat B2MBCP is adsorbed onto a graphene surface, with a significant adsorption energy of –41.19 kcal/mol. The results of this study provide a better overall picture of the properties of MAC with a cyclopentanone core and can be taken as a useful guide in the search for new biologically active compounds and new possible means of delivery.

Molecular Docking, Pharmacokinetic and Molecular Simulation Analysis of Novel Mono-Carbonyl Curcumin Analogs as L858R/T790M/C797S Mutant EGFR Inhibitors.

Curcumin, an anticancer natural compound with multiple pharmacological activities, has a weak pharmacokinetic and instability due to diketone moiety. Curcumin's stability challenges can be overcome by removing the diketone moiety and shortening the 7-carbon chain, resulting in mono-carbonyl analogs. Cancer proliferation is caused by the activation of Epidermal Growth Factor (EGFR) pathways. Current available EGFR inhibitors have an issue of resistance. Thus, we aimed to design new mono-carbonyl curcumin derivatives and analyse their drug likeness properties. Further, to investigate them on three distinct crystal structures, namely two wild-type and L858R/T790M/C797S mutant generations for EGFR inhibitory activity. Ten New Molecular Entities (NME's) were designed using literature survey. These molecules were subjected to comparative molecular docking, on the EGFR crystal structures viz. wild-type (PDB: 1M17 and 4I23) and L858R/T790M/C797S mutant (PDB: 6LUD) using Schrodinger software. The molecules were also tested for Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties. The docked complex of the hit molecule was studied for molecular simulation. In molecular docking studies, NMEs 1, 2, and 3 were found to have good binding affinity with 1st , 2nd , and 3rd generation EGFR crystal structures and a greater dock score than standard curcumin. All molecules have shown a good ADMET profile. Since L858R/T790M/C797S is currently being explored more, we decided to take the best molecule, NME 3, for molecular dynamics with 6LUD, and the results were compared with those of the co-crystallized ligand S4 (Osimertinib). It was found that the Relative mean square standard deviation (RMSD) (1.8 Å), Relative mean standard Fluctuation (RMSF) (1.45 Å) and radius of gyration (4.87 Å) values of NME 3 were much lower than those of reference S4. All these confirm that our designed NME 3 is more stable than reference S4. NME 1 and NME 2 have shown better binding against wild type of EGFR. NME 3 have shown comparable binding and more stability as compared to Osimertinib against L858R/T790M/C797S mutated protein structure. The hit compound can be further explored for its Molecular mechanics with generalised Born and surface area solvation (MM-GBSA) and discrete Fourier transform (DFT) studies to find out the energy and atomic level study. In the future, this molecule could be taken for wet lab studies and can be tested for mutated EGFR inhibitory activity.

THU557 Effects Of Two Experimental Monocarbonyl Analogs Of Curcumin (MACs) On Breast Cancer Growth, Migration, And Epithelial-To-Mesenchymal Transition (EMT)

Abstract Disclosure: R. Stojchevski: None. N. Hadzi-Petrushev: None. M. Mladenov: None. J. Bogdanov: None. S. Velichkovikj: None. L. Poretsky: None. D.B. Avtanski: None. Curcumin, a polyphenol found in turmeric (Curcuma longa), has been reported to have a range of potential therapeutic effects, including anti-inflammatory and antioxidant properties. However, curcumin’s poor bioavailability has limited its use in medicine. Monocarbonyl analogs of curcumin (MACs) have been developed to overcome this challenge and have shown promise in various medical applications, including cancer. Our previous experiments in animals showed that these two analogs possess potent antioxidant properties. The aim of this study was to investigate the in vitro effects of two experimental MACs (C66 (C22H16F6O) and B2BrBC (C20H16Br2O)) on breast cancer cell growth and epithelial-to-mesenchymal transition (EMT). Both C66 and B2BrBC significantly suppressed MCF-7 and BT-474 viability shown by MTT assay. These two analogs also suppressed breast cancer cell migration, demonstrated by scratch migration wound-healing assay using MCF-7 and MDA-MB-231 cells. Further, using qRT-PCR, we investigated the effects of C66 and B2BrBC on the expression of various epithelial (E-cadherin, cytokeratin-18) and mesenchymal (snail, slug, fibronectin, and vimentin) genes in MCF-7 cells subjected to EMT induction (a media supplement containing Wnt-5a, TGFβ1, anti-E-cadherin, anti-sFRP1, and anti-Dkk-1 antibodies). Since the EMT-induction media significantly downregulated the epithelial markers’ and upregulated the mesenchymal markers’ mRNA expression, these effects were significantly abolished when C66 or B2BrBC were introduced. Taken together, these data demonstrate that C66 and B2BrBC are potent agents for suppressing breast cancer cell growth and EMT in vitro. Further investigation is needed to determine the potential clinical use of these compounds in breast cancer treatment. Presentation: Thursday, June 15, 2023

Phytoconstituents of two Gleditsia L. species and cytotoxic activity of the isolated curcumin analogues

Methanolic extracts of Gleditsia triacanthos L. fruits and Gleditsia caspica Desf. leaves yielded two mono-carbonyl curcumin analogues; (1E,4E)-1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one [1], (1E,4E)-1,5-bis(4-hydroxyphenyl)penta-1,4-dien-3-one [2], in addition to β-sitosterol [3], apigenin [4], quercetin-3`-O-methyl ether [5], rutin [6], quercetin [7], naringenin [8], eriodictyol [9], vitexin [10], isovitexin [11], gleditsin A [12]. The isolation of these compounds was reported here for the first time from the named plants. The separation and identification of curcumin analogues from genus Gleditsia in addition to 13C NMR data of compound 2 were reported here for the first time. Compounds 1 and 2 were assayed in two hepatic cancer cells; HepG-2 and Huh-7. Compound 1 showed high cytotoxic activity against HepG-2 with an IC50 value of 14.39 µM, compared with the standard, IC50 = 12.44 μM.

Synthesis, Characterization and Thermal Study of Some new Copolyesters from mono-carbonyl analogues of Curcumin and Thymol blue dye

A series of copolyesters were prepared from a dicarboxylic acid, curcumin analogues (monocarbonyl) and thymol blue dye in the mole ratio of 2:1:1 by direct polycondensation using triethylamine (Et3N) as the condensation agent. The dicarboxylic used is 2,6-Pyridine dicarbonyl dichloride acid. The curcumin analogues were prepared by acid catalyzed Aldol condensation reaction. These copolyesters were characterized by FT-IR. The fluorescence of the synthesized copolyesters was also investigated. Furthermore, Thermo gravimetric analysis (TGA) was used to investigate the thermal stability of these copolymers

Design, synthesis, in vitro and in silico evaluation of anti-colorectal cancer activity of curcumin analogues containing 1,3-diphenyl-1H-pyrazole targeting EGFR tyrosine kinase

Recent studies have shown that monocarbonyl analogues of curcumin (MACs) and 1H-pyrazole heterocycle both demonstrated promising anticancer activities, in which several compounds containing these scaffolds could target EGFR. In this research, 24 curcumin analogues containing 1H-pyrazole (a1-f4) were synthesized and characterized by using modern spectroscopic techniques. Firstly, synthetic MACs were screened for cytotoxicity against human cancer cell lines such as SW480, MDA-MB-231 and A549, from which the 10 most potential cytotoxic compounds were identified and selected. Subsequently, the selected MACs were further screened for their inhibition against tyrosine kinases, which showed that a4 demonstrated the most significant inhibitory effects on EGFRWT and EGFRL858R. Based on the results, a4 further demonstrated its ability to cause morphological changes, to increase the percentage of apoptotic cells, and to increase caspase-3 activity, suggesting its apoptosis-inducing activity on SW480 cells. In addition, the effect of a4 on the SW480 cell cycle revealed its ability to arrest SW480 cells at G2/M phase. In subsequent computer-based assessments, a4 was predicted to possess several promising physicochemical, pharmacokinetic, and toxicological properties. Via molecular docking and molecular dynamics simulation, a reversible binding mode between a4 and EGFRWT, EGFRL858R, or EGFRG719S, remained stable within the 100-ns simulation due to effective interactions especially the hydrogen bonding with M793. Finally, free binding energy calculations suggested that a4 could inhibit the activity of EGFRG719S more effectively than other EGFR forms. In conclusion, our work would provide the basis for the future design of promising synthetic compounds as anticancer agents targeting EGFR tyrosine kinase.

Development of a spectrophotometric method for assessment of the relative reactivity of monocarbonyl analogs of curcumin with 2-(dimethylamino)ethanethiol

In order to improve the bioavailability of curcumin, studies have been undertaken to prepare the so-called monocarbonyl analogs of curcumin (MACs) and assess their biological activity. These analogs contain an electrophilic α,β-unsaturated carbonyl moiety (Michael acceptor). Several key biological processes are connected/controlled with thiol alkylation (glutathione, cysteine, cysteine peptide residues). The most likely reaction is the Michael addition between the α,β-unsaturated acceptor and a corresponding thiol. 2,6-Bisarylidenecyclohexanone and 3,5-bisarylidenepiperidin-4-one scaffolds offer convenient tunability of electrophilicity and redox properties of the Michael acceptor by the introduction of various substituents. In this study, several MACs were prepared by Claisen-Schmidt condensation reaction, and their reactivity with 2-(dimethylamino)ethanethiol was evaluated. For this purpose, based on the UV-Vis spectra of the analogs and thiol(s), a proper method for spectrophotometric evaluation of their reactivity with 2-(dimethylamino)ethanethiol was optimized. The relative reactivity of the analogs was 7 > 2 > 5 > 4 > 1 ≈ 6. The developed method is simple, and it can be extended to assess the reactivity of other MACs.

Mono-Carbonyl Curcumin Analogs for Cancer Therapy.

Curcumin has long been recognized for its anti-inflammatory properties. An antitumor effect has been recently reported in curcumin and clinical trials are being conducted. However, a large amount of required intake to obtain the antitumor effect of curcumin has been regarded as a problem. Therefore, curcumin analogs have been created by many researchers to enhance the effects of curcumin. We have synthesized >50 curcumin analogs and revealed greater growth suppression of various tumor cells with mono-carbonyl analogs than curcumin. Mechanistically, mono-carbonyl analogs inhibited transcriptional activity (e.g., nuclear factor kappa B, signal transducer, and activator of transcription 3) or activated caspase-3. Additionally, mono-carbonyl analogs of curcumin control tumor cell metabolism. Herein, we summarize the current knowledge about mono-carbonyl curcumin analogs and discuss their potential clinical applications.

Synthesis, molecular docking study, and in vivo biological evaluation of pyrazolopyridines derived from monocarbonyl curcumin analogues as potential anti-inflammatory agents

Background: Pyrazolopyridines are heterocyclic compounds with nitrogen atoms in the ring, and they have been used as one of the important pharmacophores in drug design. Pyrazole derivatives have been synthesised and applied in the pharmaceutical industry as active drugs. The recent commercial success of pyrazole COX-2 inhibitors has brought even more attention to the significance of this heterocyclic ring in medicinal chemistry. Objective: This study aimed to synthesise new compounds as anti-inflammatory candidates from the pyrazolopyridine group. Method: Synthesis was carried out using the Claisen-Schmidt reaction through condensation of substituted benzaldehyde and 4-piperidone to produce mono-ketone curcumin analogues, which were then cyclised with phenylhydrazine. The results of the synthesis were characterised using FT-IR, 1H-NMR, and MS. Docking analysis was performed on the 3LN1 protein with MOE 2021.0901. Furthermore, an in vivo anti-inflammatory test was applied using a plethysmometer. Results: The synthesis results obtained two pyrazolopyridine compounds, and the docking results showed that both of these synthesised compounds could interact with the COX-2 receptor binding site. Conclusion: Compound 2 demonstrated good anti-inflammatory activities. This strategy is in the preliminary stages of identifying novel substances that may be used as anti-inflammatory agents in the future.

Theoretical Analysis of the Properties of Monocarbonyl Curcumin Analogs

Curcumin is found in the medicinal plant turmeric and has a wide range of pharmacological activities. To improve their low stability, poor solubility, and low bioavailability, their monocarbonyl derivatives (MACs) modification has received much attention from researchers. In this study, MACs (1a–1e) were investigated with the help of density functional theory (DFT). The equilibrium geometries were optimized and then the predictions of vibration frequencies, conceptual density functional indices, antioxidant activity, and aromaticity were carried out. The results showed that the hydroxyl substitution at o- and p-positions in MACs exhibited strong reactivity, especially the substitution at the p-position significantly improved the electrophilic and antioxidant activity of compounds. This work also found that aqueous solutions had a booster effect on the reactivity of MACs. In contrast, the effect of hydroxyl at the m-position on the structure and properties was not significant. Furthermore, the molecular docking results show that the presence of hydroxyl group in MACs facilitates the enhancement of the interaction between MACs and the receptor. Results of this work introduce new and important information that contributes to the understanding of the potential properties of MACs and provides references and directions for the design of this type of drugs.