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1.
ChemMedChem ; 19(9): e202400055, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38351738

ABSTRACT

Inspired by potent antiproliferative xanthone natural products and so far limited examples of derived bioactive agents, a structure activity study of architecturally novel types of xanthones is reported. Their preparation was enabled in a short and divergent manner by a modular chlorination in combination with optimized protocols for a polar condensation and a hetero-cyclization. Application of these procedures allowed for the synthesis of various polyhalogenated representatives (including mixed bromo/chloro xanthones) that were obtained in up to fourfold improved yields as compared to previous procedures. Subsequent Suzuki coupling of either halide enabled access to phenyl- and chloro-bearing xanthones, which may be functionalized at four out of five non-hydroxylated positions. Antiproliferative assays against breast cancer cell lines revealed potent activities of some of these simplified analogs that are in the range of pharmaceutically used anticancer drug doxorubicin.


Subject(s)
Antineoplastic Agents , Cell Proliferation , Doxorubicin , Drug Screening Assays, Antitumor , Xanthones , Xanthones/chemistry , Xanthones/chemical synthesis , Xanthones/pharmacology , Humans , Doxorubicin/pharmacology , Doxorubicin/chemistry , Doxorubicin/chemical synthesis , Cell Proliferation/drug effects , Structure-Activity Relationship , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Molecular Structure , Dose-Response Relationship, Drug
2.
Anticancer Agents Med Chem ; 24(6): 454-463, 2024.
Article in English | MEDLINE | ID: mdl-38204259

ABSTRACT

BACKGROUND: Gambogic acid (GA) is a natural product from the resin of the Garcinia species, which showed significant activity in the induction of apoptosis. .t can be one promising lead compound for the design and synthesis of new anticancer drugs. OBJECTIVE: The objective of the current study is to design novel nitrogen-contained GA derivatives with better anti-cancer activities and study the effect of the introduction of different nitrogen-contained groups on the activity of GA. METHODS: The designed 15 derivatives were synthesized via esterification or amidation of 30-carboxylate. The synthetic compounds were characterized via different spectroscopic techniques, including X-ray single crystal diffraction, MS and NMR. The cytotoxic activity of the designed derivatives was evaluated in vitro against A549, HepG-2, and MCF-7 cell lines using methyl thiazolyl tetrazolium (MTT) test. RESULTS: 15 nitrogen-contained GA derivatives were successfully synthesized and established. Based on the IC50 values, compounds 9, 10, 11 and 13 showed stronger inhibitory effects on A549, HepG-2, MCF-7 cell lines than GA, while 9 is the most active compound with IC50 value of 0.64-1.49 µM. Most derivatives of GA with esterification of C-30 including cyano-benzene ring were generally weaker than those of pyrimidinyl-substituted derivatives. In addition, length of alkyl linkers between C-30 of GA and nitrogen-contained group produced different effects on A549, HepG-2 and MCF-7 cell lines. CONCLUSION: The structure-activity relationship results show that aromatic substituent and linker length play important roles to improve the anticancer activities, while compound 9 with pyrimidine substituent and C-C-C linkers is the most active derivative against tested cell lines, and is a promising anti-cancer agent for further development.


Subject(s)
Antineoplastic Agents , Cell Proliferation , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Nitrogen , Xanthones , Humans , Xanthones/chemistry , Xanthones/pharmacology , Xanthones/chemical synthesis , Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Molecular Structure , Nitrogen/chemistry , Cell Line, Tumor
3.
Molecules ; 27(2)2022 Jan 13.
Article in English | MEDLINE | ID: mdl-35056797

ABSTRACT

Moreollic acid, a caged-tetraprenylated xanthone from Gamboge, has been indicated as a potent antitumor molecule. In the present study, a series of moreollic acid derivatives with novel structures were designed and synthesized, and their antitumor activities were determined in multifarious cell lines. The preliminary screening results showed that all synthesized compounds selectively inhibited human colon cancer cell proliferation. TH12-10, with an IC50 of 0.83, 1.10, and 0.79 µM against HCT116, DLD1, and SW620, respectively, was selected for further antitumor mechanism studies. Results revealed that TH12-10 effectively inhibited cell proliferation by blocking cell-cycle progression from G1 to S. Besides, the apparent structure-activity relationships of target compounds were discussed. To summarize, a series of moreollic acid derivatives were discovered to possess satisfactory antitumor potentials. Among them, TH12-10 displays the highest antitumor activities against human colon cancer cells, in which the IC50 values in DLD1 and SW620 are lower than that of 5-fluorouracil.


Subject(s)
Antineoplastic Agents , Colonic Neoplasms , Garcinia , Xanthones , Humans , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Colonic Neoplasms/drug therapy , Garcinia/chemistry , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Structure-Activity Relationship , Xanthones/chemical synthesis , Xanthones/chemistry , Xanthones/pharmacology
4.
Molecules ; 27(2)2022 Jan 15.
Article in English | MEDLINE | ID: mdl-35056861

ABSTRACT

Diabetes mellitus is characterized by chronic hyperglycemia that promotes ROS formation, causing severe oxidative stress. Furthermore, prolonged hyperglycemia leads to glycation reactions with formation of AGEs that contribute to a chronic inflammatory state. This research aims to evaluate the inhibitory activity of α-mangostin and four synthetic xanthenone derivatives against glycation and oxidative processes and on α-glucosidase, an intestinal hydrolase that catalyzes the cleavage of oligosaccharides into glucose molecules, promoting the postprandial glycemic peak. Antiglycation activity was evaluated using the BSA assay, while antioxidant capacity was detected with the ORAC assay. The inhibition of α-glucosidase activity was studied with multispectroscopic methods along with inhibitory kinetic analysis. α-Mangostin and synthetic compounds at 25 µM reduced the production of AGEs, whereas the α-glucosidase activity was inhibited only by the natural compound. α-Mangostin decreased enzymatic activity in a concentration-dependent manner in the micromolar range by a reversible mixed-type antagonism. Circular dichroism revealed a rearrangement of the secondary structure of α-glucosidase with an increase in the contents of α-helix and random coils and a decrease in ß-sheet and ß-turn components. The data highlighted the anti-α-glucosidase activity of α-mangostin together with its protective effects on protein glycation and oxidation damage.


Subject(s)
Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Xanthones/chemistry , Xanthones/pharmacology , alpha-Glucosidases/metabolism , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Circular Dichroism , Glycation End Products, Advanced/drug effects , Glycation End Products, Advanced/metabolism , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycosylation , Kinetics , Nitrophenylgalactosides/metabolism , Oxidation-Reduction , Spectrometry, Fluorescence , Xanthones/antagonists & inhibitors , Xanthones/chemical synthesis
5.
Molecules ; 26(21)2021 Nov 01.
Article in English | MEDLINE | ID: mdl-34771042

ABSTRACT

Type 2 diabetes mellitus has been a major health issue with increasing morbidity and mortality due to macrovascular and microvascular complications. The urgent need for improved methods to control hyperglycemic complications reiterates the development of innovative preventive and therapeutic treatment strategies. In this perspective, xanthone compounds in the pericarp of the mangosteen fruit, especially α-mangostin (MGN), have been recognized to restore damaged pancreatic ß-cells for optimal insulin release. Therefore, taking advantage of the robust use of nanotechnology for targeted drug delivery, we herein report the preparation of MGN loaded nanosponges for anti-diabetic therapeutic applications. The nanosponges were prepared by quasi-emulsion solvent evaporation method. Physico-chemical characterization of formulated nanosponges with satisfactory outcomes was performed with Fourier transform infra-red (FTIR) spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Zeta potential, hydrodynamic diameter, entrapment efficiency, drug release properties, and stability studies at stress conditions were also tested. Molecular docking analysis revealed significant interactions of α-glucosidase and MGN in a protein-ligand complex. The maximum inhibition by nanosponges against α-glucosidase was observed to be 0.9352 ± 0.0856 µM, 3.11-fold higher than acarbose. In vivo studies were conducted on diabetic rats and plasma glucose levels were estimated by HPLC. Collectively, our findings suggest that MGN-loaded nanosponges may be beneficial in the treatment of diabetes since they prolong the antidiabetic response in plasma and improve patient compliance by slowly releasing MGN and requiring less frequent doses, respectively.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Glycoside Hydrolase Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Nanostructures/chemistry , Xanthones/pharmacology , Animals , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/metabolism , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Male , Molecular Docking Simulation , Molecular Structure , Particle Size , Rats , Rats, Sprague-Dawley , Streptozocin/administration & dosage , Xanthones/chemical synthesis , Xanthones/chemistry , alpha-Glucosidases/metabolism
6.
Bioorg Med Chem ; 44: 116292, 2021 08 15.
Article in English | MEDLINE | ID: mdl-34225167

ABSTRACT

Transthyretin is a tetrameric protein which functions as a transporter of thyroxine and retinol-binding protein. Misfolding and amyloid aggregation of transthyretin are known to cause wild-type and hereditary transthyretin amyloidosis. Stabilization of the transthyretin tetramer by low molecular weight compounds is an efficacious strategy to inhibit the aggregation pathway in the amyloidosis. Here, we investigated the inhibitory activities of anthraquinone and xanthone derivatives against amyloid aggregation, and found that xanthone-2-carboxylic acid with one chlorine or methyl group has strong inhibitory activity comparable with that of diflunisal, which is one of the best known stabilizers of transthyretin. X-ray crystallographic structures of transthyretin in complex with the compounds revealed that the introduction of chlorine, which is buried in a hydrophobic region, is important for the strong inhibitory effect of the stabilizer against amyloidogenesis. An in vitro absorption, distribution, metabolism and elimination (ADME) study and in vivo pharmacokinetic study demonstrated that the compounds have drug-like features, suggesting that they have potential as therapeutic agents to stabilize transthyretin.


Subject(s)
Amyloid Neuropathies, Familial/drug therapy , Anthraquinones/therapeutic use , Xanthones/therapeutic use , Anthraquinones/chemical synthesis , Anthraquinones/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Xanthones/chemical synthesis , Xanthones/chemistry
7.
Carbohydr Polym ; 267: 118229, 2021 Sep 01.
Article in English | MEDLINE | ID: mdl-34119182

ABSTRACT

A novel multiple environment-sensitive polymeric prodrug of gambogic acid (GA) based on chitosan graftomer was fabricated for cancer treatment. Folic acid-chitosan conjugates was complexed with thermosensitive amine terminated poly-N-isopropylacrylamide (NH2-PNIPAM) to develop FA-CSPN. Gambogic acid was conjugated with the graftomer via esterification to achieve high drug-loading capacity and controlled drug release. The resulting amphiphilic prodrug, O-(gambogic acid)-N-(folic acid)-N'-(NH2-PNIPAM) chitosan graftomer (GFCP), could self-assemble into micelles. As expected, the micelles were stable and biocompatible, featuring pH-, esterase- and temperature-dependent manner of drug release. Moreover, the anticancer effect studies of GFCP micelles were performed using a tumor-bearing mouse model and cellular assays (tumor cell uptake assay, cytotoxicity and tumor-sphere penetration). Collectively, GFCP micelles show both potential in vivo and in vitro in improving the anticancer effectiveness of GA owing to high loading capacity, targeted tumor accumulation, and multiple tumor microenvironmental responsiveness.


Subject(s)
Antineoplastic Agents/therapeutic use , Chitosan/analogs & derivatives , Chitosan/therapeutic use , Neoplasms/drug therapy , Prodrugs/therapeutic use , Xanthones/therapeutic use , Acrylic Resins/chemical synthesis , Acrylic Resins/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Chitosan/chemical synthesis , Drug Carriers/chemical synthesis , Drug Carriers/chemistry , Drug Liberation , Folic Acid/analogs & derivatives , Folic Acid/chemical synthesis , Humans , Hydrogen-Ion Concentration , Male , Mice , Micelles , Neoplasms/pathology , Prodrugs/chemical synthesis , Temperature , Xanthones/chemical synthesis
8.
Molecules ; 26(4)2021 Feb 12.
Article in English | MEDLINE | ID: mdl-33673146

ABSTRACT

9H-Xanthenes, 9H-thioxanthenes and 9,10-dihydroacridines can be easily oxidized to the corresponding xanthones, thioxanthones and acridones, respectively, by a simple photo-oxidation procedure carried out using molecular oxygen as oxidant under the irradiation of visible blue light and in the presence of riboflavin tetraacetate as a metal-free photocatalyst. The obtained yields are high or quantitative.


Subject(s)
Acridones/chemical synthesis , Oxygen/chemistry , Thioxanthenes/chemical synthesis , Xanthones/chemical synthesis , Acridones/chemistry , Acridones/radiation effects , Light , Metals/chemistry , Oxidants, Photochemical/chemistry , Oxidants, Photochemical/pharmacology , Oxidation-Reduction/radiation effects , Thioxanthenes/chemistry , Thioxanthenes/radiation effects , Xanthones/chemistry , Xanthones/radiation effects
9.
J Enzyme Inhib Med Chem ; 36(1): 627-639, 2021 Dec.
Article in English | MEDLINE | ID: mdl-33557647

ABSTRACT

A new series of 3-O-substituted xanthone derivatives were synthesised and evaluated for their anti-cholinergic activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results indicated that the xanthone derivatives possessed good AChE inhibitory activity with eleven of them (5, 8, 11, 17, 19, 21-23, 26-28) exhibited significant effects with the IC50 values ranged 0.88 to 1.28 µM. The AChE enzyme kinetic study of 3-(4-phenylbutoxy)-9H-xanthen-9-one (23) and ethyl 2-((9-oxo-9H-xanthen-3-yl)oxy)acetate (28) showed a mixed inhibition mechanism. Molecular docking study showed that 23 binds to the active site of AChE and interacts via extensive π-π stacking with the indole and phenol side chains of Trp86 and Tyr337, besides the hydrogen bonding with the hydration site and π-π interaction with the phenol side chain of Y72. This study revealed that 3-O-alkoxyl substituted xanthone derivatives are potential lead structures, especially 23 and 28 which can be further developed into potent AChE inhibitors.


Subject(s)
Acetylcholinesterase/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Xanthones/pharmacology , Animals , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Electrophorus , Horses , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Xanthones/chemical synthesis , Xanthones/chemistry
11.
Bioorg Med Chem Lett ; 36: 127820, 2021 03 15.
Article in English | MEDLINE | ID: mdl-33513389

ABSTRACT

Phosphoglycerate mutase 1 (PGAM1) is a promising target for cancer treatment. Herein, we found that α-mangostin and γ-mangostin exhibited moderate PGAM1 inhibitory activities, with IC50 of 7.2 µM and 1.2 µM, respectively. Based on α-mangostin, a series of 1,3,6,7-tetrahydroxyxanthone derivatives were designed, synthesized and evaluated in vitro for PGAM1 inhibition. The significant structure-activity relationships (SAR) and a fresh binding mode of this kind of new compounds were also clearly described. This study provides valuable information for further optimization of PGAM1 inhibitors with 1,3,6,7-tetrahydroxyxanthone backbone or de novo design of novel inhibitor.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Phosphoglycerate Mutase/antagonists & inhibitors , Xanthones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Phosphoglycerate Mutase/metabolism , Structure-Activity Relationship , Xanthones/chemical synthesis , Xanthones/chemistry
12.
Anticancer Agents Med Chem ; 21(9): 1110-1119, 2021.
Article in English | MEDLINE | ID: mdl-32268871

ABSTRACT

BACKGROUND AND PURPOSE: Gambogic Acid (GA), a promising anti-cancer agent isolated from the resin of Garcinia species in Southeast Asia, exhibits high potency in inhibiting a wide variety of cancer cells' growth. Moreover, the fact that it is amenable to chemical modification makes GA an attractive molecule for the development of anti-cancer agents. METHODS: Gambogic acid-3-(4-pyrimidinyloxy) propyl ester (compound 4) was derived from the reaction between 4-hydroxypropoxy pyrimidine and GA. Its structure was elucidated by comprehensive analysis of ESIMS, HRESIMS, 1 D NMR data. Anti-tumor activities of compound 4 and GA in vitro against HepG-2, A549 and MCF-7 cells were investigated by MTT assay. FITC/PI dye was used to test apoptosis. The binding affinity difference of compound 4 and GA binding to IKKß was studied by using Discovery Studio 2016. RESULTS: Compound 4 was successfully synthesized and showed strong inhibitory effects on HepG-2, A549 and MCF-7 cells lines with an IC50 value of 1.49±0.11, 1.37±0.06 and 0.64±0.16µM, respectively. Molecular docking study demonstrated that four more hydrogen bonds were established between IKKß and compound 4, compared with GA. CONCLUSION: Our results suggested that compound 4 showed significant effects in inducing apoptosis. Further molecular docking study indicated that the introduction of pyrimidine could improve GA's binding affinity to IKKß. Compound 4 may serve as a potential lead compound for the development of new anti-cancer drugs.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Xanthones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tumor Cells, Cultured , Xanthones/chemical synthesis , Xanthones/chemistry
13.
Bioorg Med Chem ; 29: 115873, 2021 01 01.
Article in English | MEDLINE | ID: mdl-33242700

ABSTRACT

The human skin is constantly exposed to external factors that affect its integrity, UV radiation being one of the main stress factors. The repeated exposure to this radiation leads to increased production of Reactive Oxygen Species (ROS) which activate a series of processes involved in photoaging. Excessive UV exposure also exacerbates melanin production leading to a variety of pigmentation disorders. Xanthones are reported to exhibit properties that prevent deleterious effects of UV exposure and high levels of ROS in the organism, so in this work a wide library of xanthones with different patterns of substitution was synthesized and tested for their inhibitory activity against the skin enzymes tyrosinase, elastase, collagenase and hyaluronidase, many of which were evaluated for the first time. Most of the compounds were tyrosinase inhibitors, with the best one (xanthone 27) presenting an IC50 of 1.9 µM, which is approximately 6 times lower than the IC50 of the positive control kojic acid. Concerning the other enzymes, only one compound presented IC50 lower than 150 µM in elastase inhibition (xanthone 14 = 91.8 µM) and none in collagenase and hyaluronidase inhibition. A QSAR model for tyrosinase inhibitory activity was built using six molecular descriptors, with a partial negative surface area descriptor and the relative number of oxygen atoms being positively contributing to the tyrosinase inhibitory activity. Docking using AutoDock Vina shows that all the tested compounds have more affinity to mushroom tyrosinase than kojic acid. Docking results implied that the tyrosinase inhibitory mechanisms of xanthonic derivatives are attributed to an allosteric interaction. Taken together, these data suggest that xanthones might be useful scaffolds for the development of new and promising candidates for the treatment of pigmentation-related disorders and for skin whitening cosmetic products.


Subject(s)
Enzyme Inhibitors/pharmacology , Melanins/antagonists & inhibitors , Molecular Docking Simulation , Monophenol Monooxygenase/antagonists & inhibitors , Quantitative Structure-Activity Relationship , Xanthones/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Melanins/metabolism , Molecular Structure , Monophenol Monooxygenase/metabolism , Xanthones/chemical synthesis , Xanthones/chemistry
14.
Chem Biol Drug Des ; 97(3): 674-685, 2021 03.
Article in English | MEDLINE | ID: mdl-33031630

ABSTRACT

Ten new xanthone derivatives have been designed and synthesized for their potential antibacterial activity. All compounds have been screened against Staphylococcus epidermidis strains ATCC 12228 and clinical K/12/8915. The highest antibacterial activity was observed for compound 3: 5-chloro-2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-9H-xanthen-9-one dihydrochloride, exhibiting MIC of 0.8 µg/ml against ATCC 12228 strain, compared to linezolid (0.8 µg/ml), ciprofloxacin (0.2 µg/ml) or trimethoprim and sulfamethoxazole (0.8 µg/ml). For the most active compound 3, genotoxicity assay with use of Salmonella enterica serovar Typhimurium revealed safety in terms of genotoxicity at concentration 75 µg/ml and antibacterial activity against Salmonella at all higher concentrations. A final in silico prediction of skin metabolism of compound 3 seems promising, indicating stability of the xanthone moiety in the metabolism process.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Drug Design , Xanthones/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Ciprofloxacin/pharmacology , Microbial Sensitivity Tests , Mutagenicity Tests , Salmonella enterica/drug effects , Salmonella enterica/genetics , Staphylococcus epidermidis/drug effects , Structure-Activity Relationship , Xanthones/chemical synthesis , Xanthones/pharmacology
15.
Biomolecules ; 10(8)2020 07 30.
Article in English | MEDLINE | ID: mdl-32751491

ABSTRACT

The development of alternative ecological and effective antifouling technologies is still challenging. Synthesis of nature-inspired compounds has been exploited, given the potential to assure commercial supplies of potential ecofriendly antifouling agents. In this direction, the antifouling activity of a series of nineteen synthetic small molecules, with chemical similarities with natural products, were exploited in this work. Six (4, 5, 7, 10, 15 and 17) of the tested xanthones showed in vivo activity toward the settlement of Mytilus galloprovincialis larvae (EC50: 3.53-28.60 µM) and low toxicity to this macrofouling species (LC50 > 500 µM and LC50/EC50: 17.42-141.64), and two of them (7 and 10) showed no general marine ecotoxicity (<10% of Artemia salina mortality) after 48 h of exposure. Regarding the mechanism of action in mussel larvae, the best performance compounds 4 and 5 might be acting by the inhibition of acetylcholinesterase activity (in vitro and in silico studies), while 7 and 10 showed specific targets (proteomic studies) directly related with the mussel adhesive structure (byssal threads), given by the alterations in the expression of Mytilus collagen proteins (PreCols) and proximal thread proteins (TMPs). A quantitative structure-activity relationship (QSAR) model was built with predictive capacity to enable speeding the design of new potential active compounds.


Subject(s)
Biofouling/prevention & control , Mytilus/drug effects , Xanthones/chemistry , Xanthones/toxicity , Animals , Biological Products/chemical synthesis , Biological Products/chemistry , Biological Products/toxicity , Larva/drug effects , Larva/physiology , Mytilus/physiology , Xanthones/chemical synthesis
16.
Int J Biol Macromol ; 164: 836-844, 2020 Dec 01.
Article in English | MEDLINE | ID: mdl-32693131

ABSTRACT

In this contribution, a novel soluble and antibacterial polymer, O-xanthonyl-chitosan (CTMC-Xan), was synthesized successfully by grafting 1,3-dihydroxy-xanthone (Xan) to the side chains of O-carboxymethyl-N, N, N-trimethyl chitosan (CTMC). The chemical structure and physical properties of the polymer were analyzed by 1H NMR, FT-IR spectra, UV spectra and XRD. The results showed that Xan could covalently bond with the carboxyl groups of CTMC by esterification at a grafting ratio of 9.1%. XRD patterns indicated that CTMC-Xan does not exhibit crystallization. The solubility tests showed that CTMC-Xan was completely dissolved and stable in neutral solution but unstable in acid or basic conditions. Moreover, it was found that the antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) of CTMC-Xan was much stronger than that of Xan and CTMC, and the minimal bactericidal concentration (MBC) was 125 µg·mL-1. Due to the enhanced solubility and antibacterial activity, CTMC-Xan could potentially serve as a desirable biomaterial for food and pharmaceutical applications.


Subject(s)
Anti-Bacterial Agents/pharmacology , Chitosan/chemistry , Polymers/chemistry , Xanthones/chemistry , Anti-Bacterial Agents/chemistry , Chitosan/analogs & derivatives , Chitosan/chemical synthesis , Chitosan/pharmacology , Escherichia coli/drug effects , Humans , Polymers/chemical synthesis , Polymers/pharmacology , Solubility/drug effects , Spectroscopy, Fourier Transform Infrared , Staphylococcus aureus/drug effects , Staphylococcus aureus/pathogenicity , Xanthones/chemical synthesis , Xanthones/pharmacology
17.
Chem Biodivers ; 17(10): e2000442, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32692899

ABSTRACT

Four xanthone derivatives were synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs) with metal chelating ability and antioxidant ability against Alzheimer's disease (AD). Most of them exhibited potential acetylcholinesterase (AChE), butylcholinesterase (BuChE) inhibitory, antioxidant and metal chelating properties. Among them, 1-hydroxy-3-[2-(pyrrolidin-1-yl)ethoxy]-9H-xanthen-9-one had the highest ability to inhibit AChE and displayed high selectivity towards AChE (IC50 =2.403±0.002 µM for AChE and IC50 =31.221±0.002 µM for BuChE), and it was also a good antioxidant (IC50 =2.662±0.003 µM). Enzyme kinetic studies showed that this compound was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. Interestingly, its copper complex showed more significant inhibitory activity for AChE (IC50 =0.934±0.002 µM) and antioxidant activity (IC50 =1.064±0.003 µM). Molecular dockings were carried out for the four xanthone derivatives in order to further investigate the binding modes. Finally, the blood-brain barrier (BBB) penetration prediction indicated that all compounds might penetrate BBB. These results suggested that 1-hydroxy-3-[2-(pyrrolidin-1-yl)ethoxy]-9H-xanthen-9-one was promising AChEI with metal chelating ability and antioxidant ability for the further investigation.


Subject(s)
Alzheimer Disease/drug therapy , Antioxidants/pharmacology , Cholinesterase Inhibitors/pharmacology , Drug Design , Xanthones/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Blood-Brain Barrier/drug effects , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Electrophorus , Horses , Humans , Hydroxyl Radical/antagonists & inhibitors , Molecular Docking Simulation , Xanthones/chemical synthesis , Xanthones/chemistry
18.
Biochim Biophys Acta Biomembr ; 1862(9): 183353, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32407778

ABSTRACT

Semisynthetic γ-mangostin derivative LS02 is a novel cationic amphiphilic peptidomimetic antimicrobial agent containing a hydrophobic scaffold and three hydrophilic and positively charged residues of arginine. LS02 showed low in vitro toxicity, potent activities against Gram-positive bacteria including MRSA (MIC = 1.56-6.25 µg/mL) and avoidance of drug resistance. The mode of action studies indicated that LS02 killed bacteria by disrupting bacterial cell membranes. LS02 not only exhibited good water solubility, low hemolytic activity and cell cytotoxicity, but also displayed excellent in vitro and in vivo antibacterial activity, indicating its great potential of being a lead compound as a novel membrane-active antibacterial agent capable of combating bacterial resistance.


Subject(s)
Anti-Infective Agents , Methicillin-Resistant Staphylococcus aureus/growth & development , Peptidomimetics , Xanthones , Animals , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Female , Humans , MCF-7 Cells , Mice , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Peptidomimetics/pharmacology , Rabbits , Xanthones/chemical synthesis , Xanthones/chemistry , Xanthones/pharmacology
19.
Molecules ; 25(10)2020 May 21.
Article in English | MEDLINE | ID: mdl-32455828

ABSTRACT

A series of thirteen xanthones 3-15 was prepared based on substitutional (appendage) diversity reactions. The series was structurally characterized based on their spectral data and HRMS, and the structures of xanthone derivatives 1, 7, and 8 were determined by single-crystal X-ray diffraction. This series, along with an in-house series of aminated xanthones 16-33, was tested for in-vitro antimicrobial activity against seven bacterial (including two multidrug-resistant) strains and five fungal strains. 1-(Dibromomethyl)-3,4-dimethoxy-9H-xanthen-9-one (7) and 1-(dibromomethyl)-3,4,6-trimethoxy-9H-xanthen-9-one (8) exhibited antibacterial activity against all tested strains. In addition, 3,4-dihydroxy-1-methyl-9H-xanthen-9-one (3) revealed a potent inhibitory effect on the growth of dermatophyte clinical strains (T. rubrum FF5, M. canis FF1 and E. floccosum FF9), with a MIC of 16 µg/mL for all the tested strains. Compounds 3 and 26 showed a potent inhibitory effect on two C. albicans virulence factors: germ tube and biofilm formation.


Subject(s)
Anti-Bacterial Agents/chemistry , Biofilms/drug effects , Small Molecule Libraries/chemistry , Xanthones/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacteria/pathogenicity , Biofilms/growth & development , Candida albicans/drug effects , Candida albicans/pathogenicity , Crystallography, X-Ray , Humans , Microbial Sensitivity Tests , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacology , X-Ray Diffraction , Xanthones/chemical synthesis , Xanthones/pharmacology
20.
Talanta ; 215: 120914, 2020 Aug 01.
Article in English | MEDLINE | ID: mdl-32312458

ABSTRACT

Because of the biological importance of CO, the development of effective probes for the detection of CO in living systems is of great significance. In particular, near-infrared (NIR) fluorescence probes with good water solubility and large Stokes shift are indispensable tools for CO detection in vivo. However, such tools are extremely scarce. Herein, a modified rhodol dye was used to develop a novel NIR fluorescent probe (Rh-NIR-CO) for selective and sensitive detection of CO using the Pd0-mediated Tsuji-Trost reaction. This probe shows good water solubility and rapid CO detecting ability in aqueous buffer at pH 7.4, accompanied by distinct colorimetric and turn-on NIR emission changes at 676 nm with a large Stokes shift (135 nm) and low detection limit (37 nM). Moreover, NIR fluorescence imaging of CO in living cells, zebrafish, and living mice was successfully applied with this probe. These excellent results highlighted Rh-NIR-CO as a promising new tool for in vitro and in vivo detection of CO.


Subject(s)
Carbon Monoxide/analysis , Fluorescent Dyes/chemistry , Optical Imaging , Water/chemistry , Xanthones/chemistry , Animals , Fluorescence , Fluorescent Dyes/administration & dosage , Fluorescent Dyes/chemical synthesis , HeLa Cells , Humans , Hydrogen-Ion Concentration , Infrared Rays , Injections, Intraperitoneal , Mice , Mice, Inbred Strains , Microscopy, Confocal , Molecular Structure , Particle Size , Solubility , Surface Properties , Xanthones/administration & dosage , Xanthones/chemical synthesis , Zebrafish
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