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11 pages, 2562 KiB

Open AccessArticle

Determining Antiradical Capacity of Medicinal Plant Extract Individual Constituents Using Post-Column Reaction Method

by Jarosław L. Przybył, Jan Stefaniak, Anna Jaroszewicz, Amanda Gawrońska, Marcin Łapiński, Katarzyna Barbara Bączek and Zenon Węglarz

Int. J. Mol. Sci. 2024, 25(10), 5461; https://doi.org/10.3390/ijms25105461 - 17 May 2024

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Abstract

The post-column reaction method enables the evaluation of the antiradical capacity of individual components in a mixture by separating the components using HPLC and measuring stable free radical (e.g., DPPH●) scavenging that occurs after the chromatography column. The equipment typically consists of two [...] Read more.

The post-column reaction method enables the evaluation of the antiradical capacity of individual components in a mixture by separating the components using HPLC and measuring stable free radical (e.g., DPPH●) scavenging that occurs after the chromatography column. The equipment typically consists of two detectors. The first records signals of the analytes leaving the column. The second records radical scavenging by the analytes, which appears as a negative band. The recorded signals are found on two separate chromatograms, which must be combined to interpret the results. In this study, a single DAD detector was used behind the post-column reactor, enabling the simultaneous recording of the analyte bands and negative signals, indicating radical scavenging. The objective of this study was to evaluate the antiradical capacity of key compounds found in two herbal raw materials used in traditional Chinese medicine. Saposhnikovia divaricata roots contain phenolic acids, chromones, and furanocoumarins. Chlorogenic acid, rosmarinic acid, and imperatorin demonstrated strong radical scavenging, while prim-O-glucoslocimifugin showed a weaker response, both in standards and in root extracts. However, scavenging was not observed for cimifugin and 4′-O-β-D-glucosyl-5-O-methylvisamminol. Astragalus mongholicus roots contain astragalosides I-IV (triterpene saponins). None of these showed DPPH● scavenging. Furthermore, additional signals were observed, indicating the presence of unidentified radical scavenging compounds. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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26 pages, 24035 KiB

Open AccessArticle

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

by Marakiya T. Moetlediwa, Babalwa U. Jack, Sithandiwe E. Mazibuko-Mbeje, Carmen Pheiffer, Salam J. J. Titinchi, Elliasu Y. Salifu and Pritika Ramharack

Int. J. Mol. Sci. 2024, 25(5), 2603; https://doi.org/10.3390/ijms25052603 - 23 Feb 2024

Cited by 1 | Viewed by 1053

Abstract

Natural compounds such as curcumin, a polyphenolic compound derived from the rhizome of turmeric, have gathered remarkable scientific interest due to their diverse metabolic benefits including anti-obesity potential. However, curcumin faces challenges stemming from its unfavorable pharmacokinetic profile. To address this issue, synthetic [...] Read more.

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

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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24 pages, 15897 KiB

Open AccessArticle

Rosavin Alleviates LPS-Induced Acute Lung Injure by Modulating the TLR-4/NF-κB/MAPK Singnaling Pathways

by Qiao-Hui Liu, Ke Zhang, Shu-Shu Feng, Li-Juan Zhang, Shun-Ying Li, Hang-Yu Wang and Jin-Hui Wang

Int. J. Mol. Sci. 2024, 25(3), 1875; https://doi.org/10.3390/ijms25031875 - 3 Feb 2024

Cited by 1 | Viewed by 1198

Abstract

Acute lung injury (ALI) is a serious inflammatory disease with high morbidity and mortality. Rosavin is an anti-inflammatory and antioxidant phenylpropanoid and glucoside, which is isolated from Rhodiola rosea L. However, its potential molecular mechanisms and whether it has protective effects against lipopolysaccharide [...] Read more.

Acute lung injury (ALI) is a serious inflammatory disease with high morbidity and mortality. Rosavin is an anti-inflammatory and antioxidant phenylpropanoid and glucoside, which is isolated from Rhodiola rosea L. However, its potential molecular mechanisms and whether it has protective effects against lipopolysaccharide (LPS)-induced ALI remain to be elucidated. To assess the in vitro anti-inflammatory effects and anti-lung injury activity of rosavin, RAW264.7 and A549 cells were stimulated using 1 μg/mL LPS. Rosavin attenuated LPS-induced activation of the TLR-4/NF-κB signaling pathway in RAW264.7 cells and inhibited LPS-induced release of inflammatory factors in A549 cells. A mouse model of acute lung injury was constructed by intraperitoneal injection of 5 mg/kg LPS to observe the therapeutic effect of rosavin. Transcriptomics analysis and Western blot assays were utilized to verify the molecular mechanism, rosavin (20, 40, and 80 mg/kg) dose-dependently ameliorated histopathological alterations, reduced the levels of inflammatory factors, and inhibited the TLR-4/NF-κB/MAPK signaling pathway and apoptosis activation. Rosavin is a promising therapeutic candidate for acute lung injury by inhibiting the TLR-4/NF-κB/MAPK pathway. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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17 pages, 3028 KiB

Open AccessArticle

Carvacrol Encapsulation in Chitosan–Carboxymethylcellulose–Alginate Nanocarriers for Postharvest Tomato Protection

by Eva Sánchez-Hernández, Alberto Santiago-Aliste, Adriana Correa-Guimarães, Jesús Martín-Gil, Rafael José Gavara-Clemente and Pablo Martín-Ramos

Int. J. Mol. Sci. 2024, 25(2), 1104; https://doi.org/10.3390/ijms25021104 - 16 Jan 2024

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Abstract

Advancements in polymer science and nanotechnology hold significant potential for addressing the increasing demands of food security, by enhancing the shelf life, barrier properties, and nutritional quality of harvested fruits and vegetables. In this context, biopolymer-based delivery systems present themselves as a promising [...] Read more.

Advancements in polymer science and nanotechnology hold significant potential for addressing the increasing demands of food security, by enhancing the shelf life, barrier properties, and nutritional quality of harvested fruits and vegetables. In this context, biopolymer-based delivery systems present themselves as a promising strategy for encapsulating bioactive compounds, improving their absorption, stability, and functionality. This study provides an exploration of the synthesis, characterization, and postharvest protection applications of nanocarriers formed through the complexation of chitosan oligomers, carboxymethylcellulose, and alginate in a 2:2:1 molar ratio. This complexation process was facilitated by methacrylic anhydride and sodium tripolyphosphate as cross-linking agents. Characterization techniques employed include transmission electron microscopy, energy-dispersive X-ray spectroscopy, infrared spectroscopy, thermal analysis, and X-ray powder diffraction. The resulting hollow nanospheres, characterized by a monodisperse distribution and a mean diameter of 114 nm, exhibited efficient encapsulation of carvacrol, with a loading capacity of approximately 20%. Their suitability for phytopathogen control was assessed in vitro against three phytopathogens—Botrytis cinerea, Penicillium expansum, and Colletotrichum coccodes—revealing minimum inhibitory concentrations ranging from 23.3 to 31.3 μg·mL⁻¹. This indicates a higher activity compared to non-encapsulated conventional fungicides. In ex situ tests for tomato (cv. ‘Daniela’) protection, higher doses (50–100 μg·mL⁻¹, depending on the pathogen) were necessary to achieve high protection. Nevertheless, these doses remained practical for real-world applicability. The advantages of safety, coupled with the potential for a multi-target mode of action, further enhance the appeal of these nanocarriers. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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19 pages, 5811 KiB

Open AccessArticle

Carvacrol as a Stimulant of the Expression of Key Genes of the Ginsenoside Biosynthesis Pathway and Its Effect on the Production of Ginseng Saponins in Panax quinquefolium Hairy Root Cultures

by Ewa Kochan, Monika Sienkiewicz, Dagmara Szmajda-Krygier, Ewa Balcerczak and Grażyna Szymańska

Int. J. Mol. Sci. 2024, 25(2), 909; https://doi.org/10.3390/ijms25020909 - 11 Jan 2024

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Abstract

The accumulation of ginsenosides (triterpenic saponins) was determined in Panax quinquefolium hairy root cultures subjected to an elicitation process using carvacrol at 5, 10, 25, 50, 100, 250, and 500 μM concentrations during 24 and 72 h exposure. This study was the first [...] Read more.

The accumulation of ginsenosides (triterpenic saponins) was determined in Panax quinquefolium hairy root cultures subjected to an elicitation process using carvacrol at 5, 10, 25, 50, 100, 250, and 500 μM concentrations during 24 and 72 h exposure. This study was the first one in which carvacrol was applied as an elicitor. The content of eight ginsenosides, Rb1, Rb2, Rb3, Rc, Rd, Rg1, Rg2, and Re, was determined using HPLC analysis. Moreover, the quantitative RT-PCR method was applied to assess the relative expression level of farnesyl diphosphate synthase, squalene synthase, and dammarenediol synthase genes in the studied cultures. The addition of carvacrol (100 μM) was an effective approach to increase the production of ginsenosides. The highest content and productivity of all detected saponins were, respectively, 20.01 mg∙g⁻¹ d.w. and 5.74 mg∙L⁻¹∙day⁻¹ after 72 h elicitation. The production profile of individual metabolites in P. quinquefolium cultures changed under the influence of carvacrol. The biosynthesis of most examined protopanaxadiol derivatives was reduced under carvacrol treatment. In contrast, the levels of ginsenosides belonging to the Rg group increased. The strongest effect of carvacrol was noticed for Re metabolites, achieving a 7.72-fold increase in comparison to the control. Saponin Rg2, not detected in untreated samples, was accumulated after carvacrol stimulation, reaching its maximum concentration after 72 h exposure to 10 μM elicitor. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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20 pages, 3544 KiB

Open AccessArticle

Design of Two New Sulfur Derivatives of Perezone: In Silico Study Simulation Targeting PARP-1 and In Vitro Study Validation Using Cancer Cell Lines

by Alejandro Rubiales-Martínez, Joel Martínez, Elvia Mera-Jiménez, Javier Pérez-Flores, Guillermo Téllez-Isaías, René Miranda Ruvalcaba, Maricarmen Hernández-Rodríguez, Teresa Mancilla Percino, Martha Edith Macías Pérez and María Inés Nicolás-Vázquez

Int. J. Mol. Sci. 2024, 25(2), 868; https://doi.org/10.3390/ijms25020868 - 10 Jan 2024

Cited by 1 | Viewed by 791

Abstract

Poly-ADP-Ribose Polymerase (PARP-1) is an overexpressed enzyme in several carcinomas; consequently, the design of PARP-1 inhibitors has acquired special attention. Hence, in the present study, three compounds (8–10) were produced through a Michael addition protocol, using phenylmethanethiol, 5-fluoro-2-mercaptobenzyl alcohol, [...] Read more.

Poly-ADP-Ribose Polymerase (PARP-1) is an overexpressed enzyme in several carcinomas; consequently, the design of PARP-1 inhibitors has acquired special attention. Hence, in the present study, three compounds (8–10) were produced through a Michael addition protocol, using phenylmethanethiol, 5-fluoro-2-mercaptobenzyl alcohol, and 4-mercaptophenylacetic acid, respectively, as nucleophiles and perezone as the substrate, expecting them to be convenient candidates that inhibit PARP-1. It is convenient to note that in the first stage of the whole study, the molecular dynamics (MD) simulations and the quantum chemistry studies of four secondary metabolites, i.e., perezone (1), perezone angelate (2), hydroxyperezone (3), and hydroxyperezone monoangelate (4), were performed, to investigate their interactions in the active site of PARP-1. Complementarily, a docking study of a set of eleven sulfur derivatives of perezone (5–15) was projected to explore novel compounds, with remarkable affinity to PARP-1. The molecules 8–10 provided the most adequate results; therefore, they were evaluated in vitro to determine their activity towards PARP-1, with 9 having the best IC₅₀ (0.317 µM) value. Additionally, theoretical calculations were carried out using the density functional theory (DFT) with the hybrid method B3LYP with a set of base functions 6-311++G(d,p), and the reactivity properties were compared between the natural derivatives of perezone and the three synthesized compounds, and the obtained results exhibited that 9 has the best properties to bind with PARP-1. Finally, it is important to mention that 9 displays significant inhibitory activity against MDA-MB-231 and MCF-7 cells, i.e., 145.01 and 83.17 µM, respectively. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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14 pages, 2733 KiB

Open AccessArticle

Separation of Antioxidants from Trace Fraction of Ribes himalense via Chromatographic Strategy and Their Antioxidant Activity Supported with Molecular Simulations

by Youyi Liu, Chuang Liu, Yuqing Lei, Jingrou Guo, Xingyi Chen and Minchen Wu

Int. J. Mol. Sci. 2024, 25(1), 227; https://doi.org/10.3390/ijms25010227 - 22 Dec 2023

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Abstract

Antioxidants from natural sources have long been of interest to researchers. In this paper, taking the traditional Tibetan medicine Ribes himalense as an example, an integrated approach was used to identify and isolate its chemical composition with free-radical-scavenging properties from its ethanol extract. [...] Read more.

Antioxidants from natural sources have long been of interest to researchers. In this paper, taking the traditional Tibetan medicine Ribes himalense as an example, an integrated approach was used to identify and isolate its chemical composition with free-radical-scavenging properties from its ethanol extract. First, the ethanol extract of Ribes himalense was pretreated using polyamide medium-pressure liquid chromatography (polyamide-MPLC), and the target fraction (Fr4) was obtained. Then, a combined HPLC mode was utilized to purify antioxidants in Fr4 under the guidance of an online HPLC-1,1-diphenyl-2-picrylhydrazyl (HPLC-DPPH) activity screening system. Finally, three antioxidants (3-caffeoylquinic acid methyl ester, rutin, and myricetin-3′-α-L-rhamnopyranoside) were isolated, and this is the first report of their presence in R. himalense. Further molecular docking studies showed that the antioxidants exhibited good binding with HO-1, Nrf2, and iNOS. In conclusion, this comprehensive approach is capable of extracting high-purity antioxidants from trace fractions of Ribes himalense and holds promise for future applications in the exploration of the chemical compositions and bioactivity of natural products. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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13 pages, 3010 KiB

Open AccessArticle

Discovery and Characterization of MaK: A Novel Knottin Antimicrobial Peptide from Monochamus alternatus

by Xiaohong Han, Tong Zhou, Xinran Hu, Yukun Zhu, Zengzeng Shi, Shi Chen, Yunfei Liu, Xiaoqian Weng, Feiping Zhang and Songqing Wu

Int. J. Mol. Sci. 2023, 24(24), 17565; https://doi.org/10.3390/ijms242417565 - 17 Dec 2023

Cited by 1 | Viewed by 1111

Abstract

Knottin-type antimicrobial peptides possess exceptional attributes, such as high efficacy, low vulnerability to drug resistance, minimal toxicity, and precise targeting of drug sites. These peptides play a crucial role in the innate immunity of insects, offering protection against bacteria, fungi, and parasites. Knottins [...] Read more.

Knottin-type antimicrobial peptides possess exceptional attributes, such as high efficacy, low vulnerability to drug resistance, minimal toxicity, and precise targeting of drug sites. These peptides play a crucial role in the innate immunity of insects, offering protection against bacteria, fungi, and parasites. Knottins have garnered considerable interest as promising contenders for drug development due to their ability to bridge the gap between small molecules and protein-based biopharmaceuticals, effectively addressing the therapeutic limitations of both modalities. This work presents the isolation and identification of a novel antimicrobial peptide derived from Monochamus alternatus. The cDNA encodes a 56-amino acid knottin propeptide, while the mature peptide comprises only 34 amino acids. We have labeled this knottin peptide as MaK. Using chemically synthesized MaK, we evaluated its hemolytic activity, thermal stability, antibacterial properties, and efficacy against nematodes. The results of this study indicate that MaK is an exceptionally effective knottin-type peptide. It demonstrates low toxicity, superior stability, potent antibacterial activity, and the ability to suppress pine wood nematodes. Consequently, these findings suggest that MaK has potential use in developing innovative therapeutic agents to prevent and manage pine wilt disease. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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18 pages, 8414 KiB

Open AccessArticle

Molecular Mechanism of the Asarum–Angelica Drug Pair in the Treatment of Periodontitis Based on Network Pharmacology and Experimental Verification

by Qianyang Chen, Yuhan Wang, Chun Shi, Meichen Tong, Haibo Sun, Ming Dong, Shuo Liu and Lina Wang

Int. J. Mol. Sci. 2023, 24(24), 17389; https://doi.org/10.3390/ijms242417389 - 12 Dec 2023

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Abstract

(1) To examine the potential mechanism of the Asarum–Angelica drug pair against periodontitis and provide an experimental basis for the treatment of periodontitis with herbal medicine. (2) The core components and core targets of the Asarum–Angelica drug pair in the treatment of periodontitis [...] Read more.

(1) To examine the potential mechanism of the Asarum–Angelica drug pair against periodontitis and provide an experimental basis for the treatment of periodontitis with herbal medicine. (2) The core components and core targets of the Asarum–Angelica drug pair in the treatment of periodontitis were detected according to network pharmacology methods. Finally, the effect of the Asarum–Angelica drug pair on osteogenic differentiation was observed in mouse embryonic osteoblast precursor cells. (3) According to the results of network pharmacology, there are 10 potential active ingredients in the Asarum–Angelica drug pair, and 44 potential targets were obtained by mapping the targets with periodontitis treatment. Ten potential active ingredients, such as kaempferol and β-sitosterol, may play a role in treating periodontitis. Cell experiments showed that the Asarum–Angelica drug pair can effectively promote the expression of osteoblast markers alkaline phosphatase (ALP), Runt-related Transcription Factor 2 (RUNX2), and BCL2 mRNA and protein in an inflammatory environment (p < 0.05). (4) Network pharmacology effectively analyzed the molecular mechanism of Asarum–Angelica in the treatment of periodontitis, and the Asarum–Angelica drug pair can promote the differentiation of osteoblasts. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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16 pages, 6513 KiB

Open AccessArticle

Anti-Biofilm Activity of Cocultimycin A against Candida albicans

by Xiaohong Zhu, Anqi Wang, Yifan Zheng, Dan Li, Yuanjuan Wei, Maoluo Gan, Yan Li and Shuyi Si

Int. J. Mol. Sci. 2023, 24(23), 17026; https://doi.org/10.3390/ijms242317026 - 1 Dec 2023

Cited by 2 | Viewed by 1328

Abstract

Candida albicans (C. albicans), the most common fungal pathogen, has the ability to form a biofilm, leading to enhanced virulence and antibiotic resistance. Cocultimycin A, a novel antifungal antibiotic isolated from the co-culture of two marine fungi, exhibited a potent inhibitory [...] Read more.

Candida albicans (C. albicans), the most common fungal pathogen, has the ability to form a biofilm, leading to enhanced virulence and antibiotic resistance. Cocultimycin A, a novel antifungal antibiotic isolated from the co-culture of two marine fungi, exhibited a potent inhibitory effect on planktonic C. albicans cells. This study aimed to evaluate the anti-biofilm activity of cocultimycin A against C. albicans and explore its underlying mechanism. Crystal violet staining showed that cocultimycin A remarkably inhibited biofilm formation in a dose-dependent manner and disrupted mature biofilms at higher concentrations. However, the metabolic activity of mature biofilms treated with lower concentrations of cocultimycin A significantly decreased when using the XTT reduction method. Cocultimycin A could inhibit yeast-to-hypha transition and mycelium formation of C. albicans colonies, which was observed through the use of a light microscope. Scanning electron microscopy revealed that biofilms treated with cocultimycin A were disrupted, yeast cells increased, and hypha cells decreased and significantly shortened. The adhesive ability of C. albicans cells treated with cocultimycin A to the medium and HOEC cells significantly decreased. Through the use of a qRT-PCR assay, the expression of multiple genes related to adhesion, hyphal formation and cell membrane changes in relation to biofilm cells treated with cocultimycin A. All these results suggested that cocultimycin A may be considered a potential novel molecule for treating and preventing biofilm-related C. albicans infections. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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13 pages, 1748 KiB

Open AccessArticle

First Gallium and Indium Crystal Structures of Curcuminoid Homoleptic Complexes: All-Different Ligand Stereochemistry and Cytotoxic Potential

by William Meza-Morales, Yair Alvarez-Ricardo, Leidys L. Pérez-González, Rosario Tavera-Hernández, María Teresa Ramírez-Apan, Rubén A. Toscano, Rubén Sánchez-Obregón, Marco A. Obregón-Mendoza and Raúl G. Enríquez

Int. J. Mol. Sci. 2023, 24(22), 16324; https://doi.org/10.3390/ijms242216324 - 15 Nov 2023

Cited by 1 | Viewed by 984

Abstract

The crystal structure determination of metal complexes of curcuminoids is a relevant topic to assess their unequivocal molecular structure. We report herein the first two X-ray crystal structures of homoleptic metal complexes of a curcuminoid, namely Dimethoxycurcumin (DiMeOC), with gallium and indium. Such [...] Read more.

The crystal structure determination of metal complexes of curcuminoids is a relevant topic to assess their unequivocal molecular structure. We report herein the first two X-ray crystal structures of homoleptic metal complexes of a curcuminoid, namely Dimethoxycurcumin (DiMeOC), with gallium and indium. Such successful achievement can be attributed to the suppression of interactions from the phenolic groups, which favor an appropriate molecular setup, rendering Dimethoxycurcumin gallium ((DiMeOC)₂-Ga) and Dimethoxycurcumin indium ((DiMeOC)₃-In) crystals. Surprisingly, the conformation of ligands in the crystal structures shows differences in each metal complex. Thus, the ligands in the (DiMeOC)₂-Ga complex show two different conformers in the two molecules of the asymmetric unit. However, the ligands in the (DiMeOC)₃-In complex exhibit three different conformations within the same molecule of the asymmetric unit, constituting the first such case described for an ML₃ complex. The cytotoxic activity of the (DiMeOC)₂-Ga complex is 4-fold higher than cisplatin against the K562 cell line and has comparable activity towards U251 and PC-3 cell lines. Interestingly, this complex exhibit three times lesser toxicity than cisplatin and even slightly lesser cytotoxicity than curcumin itself. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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11 pages, 2010 KiB

Open AccessArticle

Mono- and Dimeric Sorbicillinoid Inhibitors Targeting IL-6 and IL-1β from the Mangrove-Derived Fungus Trichoderma reesei BGRg-3

by Yufeng Liu, Tao Chen, Bing Sun, Qi Tan, Hui Ouyang, Bo Wang, Huijuan Yu and Zhigang She

Int. J. Mol. Sci. 2023, 24(22), 16096; https://doi.org/10.3390/ijms242216096 - 8 Nov 2023

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Abstract

Four new sorbicillinoids, named trichodermolide E (1), trichosorbicillin J (2), bisorbicillinolide B (3), and demethylsorbiquinol (5), together with eight known compounds (4, 6–12), were isolated from the cultures of the [...] Read more.

Four new sorbicillinoids, named trichodermolide E (1), trichosorbicillin J (2), bisorbicillinolide B (3), and demethylsorbiquinol (5), together with eight known compounds (4, 6–12), were isolated from the cultures of the mangrove-derived fungus Trichoderma reesei BGRg-3. The structures of the new compounds were determined by analyzing their detailed spectroscopic data, while the absolute configurations were further determined through electronic circular dichroism calculations. Snatzke’s method was additionally used to determine the absolute configurations of the diol moiety in 1. In a bioassay, compounds 7 and 10 performed greater inhibitory activities on interleukin-6 and interleukin-1β than the positive control (dexamethasone) at the concentration of 25 μM. Meanwhile, compounds 5 and 6 showed potent effects with stronger inhibition than dexamethasone on IL-1β at the same concentration. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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15 pages, 5466 KiB

Open AccessArticle

Mechanisms of NMDA Receptor Inhibition by Sepimostat—Comparison with Nafamostat and Diarylamidine Compounds

by Arseniy S. Zhigulin and Oleg I. Barygin

Int. J. Mol. Sci. 2023, 24(21), 15685; https://doi.org/10.3390/ijms242115685 - 27 Oct 2023

Viewed by 989

Abstract

N-methyl-D-aspartate (NMDA) receptors are inhibited by many amidine and guanidine compounds. In this work, we studied the mechanisms of their inhibition by sepimostat—an amidine-containing serine protease inhibitor with neuroprotective properties. Sepimostat inhibited native NMDA receptors in rat hippocampal CA1 pyramidal neurons with IC [...] Read more.

N-methyl-D-aspartate (NMDA) receptors are inhibited by many amidine and guanidine compounds. In this work, we studied the mechanisms of their inhibition by sepimostat—an amidine-containing serine protease inhibitor with neuroprotective properties. Sepimostat inhibited native NMDA receptors in rat hippocampal CA1 pyramidal neurons with IC₅₀ of 3.5 ± 0.3 µM at −80 mV holding voltage. It demonstrated complex voltage dependence with voltage-independent and voltage-dependent components, suggesting the presence of shallow and deep binding sites. At −80 mV holding voltage, the voltage-dependent component dominates, and we observed pronounced tail currents and overshoots evidencing a “foot-in-the-door” open channel block. At depolarized voltages, the voltage-independent inhibition by sepimostat was significantly attenuated by the increase of agonist concentration. However, the voltage-independent inhibition was non-competitive. We further compared the mechanisms of the action of sepimostat with those of structurally-related amidine and guanidine compounds—nafamostat, gabexate, furamidine, pentamidine, diminazene, and DAPI—investigated previously. The action of all these compounds can be described by the two-component mechanism. All compounds demonstrated similar affinity to the shallow site, which is responsible for the voltage-independent inhibition, with binding constants in the range of 3–30 µM. In contrast, affinities to the deep site differed dramatically, with nafamostat, furamidine, and pentamidine being much more active. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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17 pages, 11506 KiB

Open AccessArticle

Design and Synthesis of Novel Chalcone Derivatives: Anti-Breast Cancer Activity Evaluation and Docking Study

by Weihong Lai, Jiaxin Chen, Xinjiao Gao, Xiaobao Jin, Gong Chen and Lianbao Ye

Int. J. Mol. Sci. 2023, 24(21), 15549; https://doi.org/10.3390/ijms242115549 - 25 Oct 2023

Cited by 2 | Viewed by 1322

Abstract

Chalcone is a common simple fragment of natural products with anticancer activity. In a previous study, the research group discovered a series of chalcone derivatives with stronger anticancer activities. To find better anticancer drugs, novel chalcone derivatives A1–A14, B1– [...] Read more.

Chalcone is a common simple fragment of natural products with anticancer activity. In a previous study, the research group discovered a series of chalcone derivatives with stronger anticancer activities. To find better anticancer drugs, novel chalcone derivatives A1–A14, B1–B14 have continuously been designed and synthesized. The antiproliferative activity of these compounds against breast cancer cells (MCF-7) was investigated by the Cell Counting Kit-8 (CCK-8) method with 5-fluorouracil (5-Fu) as the control drug. The results showed that compound A14 exhibited excellent antiproliferative ability compared to the control drug 5-Fu. Scratch experiments and cloning experiments further confirmed that compound A14 could inhibit the proliferation and colony formation activity of MCF-7 cells. In addition, molecular docking primarily explains the interaction between compound and protein. These results suggested that compound A14 could be a promising chalcone derivative for further anti-breast cancer research. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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14 pages, 6195 KiB

Open AccessArticle

Effects of C-Peptide on Dexamethasone-Induced In Vitro and In Vivo Models as a Potential Therapeutic Agent for Muscle Atrophy

by Jinjoo Kim, Youngmo Yang, Eunwon Choi, Sumin Lee and Jiyoung Choi

Int. J. Mol. Sci. 2023, 24(20), 15433; https://doi.org/10.3390/ijms242015433 - 21 Oct 2023

Viewed by 1282

Abstract

This study aimed to investigate the effects of C-peptide on C2C12 myotubes and a mouse model. Both in vitro and in vivo experiments were conducted to elucidate the role of C-peptide in muscle atrophy. Various concentrations (0, 0.01, 0.1, 1, 10, and 100 [...] Read more.

This study aimed to investigate the effects of C-peptide on C2C12 myotubes and a mouse model. Both in vitro and in vivo experiments were conducted to elucidate the role of C-peptide in muscle atrophy. Various concentrations (0, 0.01, 0.1, 1, 10, and 100 nM) of C-peptide were used on the differentiated C2C12 myotubes with or without dexamethasone (DEX). C57BL/6J mice were administered with C-peptide and DEX for 8 days, followed by C-peptide treatment for 12 days. Compared to the DEX group, C-peptide increased the fusion and differentiation indices and suppressed atrophic factor expression in C2C12 myotubes. However, 100 nM C-peptide decreased the fusion and differentiation indices and increased atrophic factor expression regardless of DEX treatment. In C57BL/6J mice, DEX + C-peptide co-treatment significantly attenuated the body and muscle weight loss and improved the grip strength and cross-sectional area of the gastrocnemius (Gas) and quadriceps (Quad) muscles. C-peptide downregulated the mRNA and protein levels of muscle degradation-related markers, particularly Atrogin-1, in Gas and Quad muscles. This study underscores the potential of C-peptides in mitigating muscle weight reduction and preserving muscle function during muscle atrophy via molecular regulation. In addition, the work presents basic data for future studies on the effect of C-peptide on diabetic muscular dystrophy. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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27 pages, 4838 KiB

Open AccessArticle

Development of Novel Class of Phenylpyrazolo[3,4-d]pyrimidine-Based Analogs with Potent Anticancer Activity and Multitarget Enzyme Inhibition Supported by Docking Studies

by Ahmed K. B. Aljohani, Waheed Ali Zaki El Zaloa, Mohamed Alswah, Mohamed A. Seleem, Mohamed M. Elsebaei, Ashraf H. Bayoumi, Ahmed M. El-Morsy, Mohammed Almaghrabi, Aeshah A. Awaji, Ali Hammad, Marwa Alsulaimany and Hany E. A. Ahmed

Int. J. Mol. Sci. 2023, 24(19), 15026; https://doi.org/10.3390/ijms241915026 - 9 Oct 2023

Cited by 2 | Viewed by 1317

Abstract

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. [...] Read more.

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFR^WT, EGFR^T790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC₅₀ value range, i.e., 0.3–24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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18 pages, 12636 KiB

Open AccessArticle

An EGCG Derivative in Combination with Nimotuzumab for the Treatment of Wild-Type EGFR NSCLC

by Yanping Huang, Xiangdan Cuan, Weiwei Zhu, Xingying Yang, Yunli Zhao, Jun Sheng, Chengting Zi and Xuanjun Wang

Int. J. Mol. Sci. 2023, 24(18), 14012; https://doi.org/10.3390/ijms241814012 - 13 Sep 2023

Cited by 1 | Viewed by 1295

Abstract

Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small-molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies is often ineffective in treating cancers harboring wild-type EGFR. Given the fact that EGFR possesses a kinase-independent pro-survival function, more effective inhibition of [...] Read more.

Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small-molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies is often ineffective in treating cancers harboring wild-type EGFR. Given the fact that EGFR possesses a kinase-independent pro-survival function, more effective inhibition of EGFR-mediated signals is therefore necessary. In this study, we investigated the effects of using a combination of low-dose nimotuzumab and theasinensin A to evaluate whether the inhibitory effect of nimotuzumab on NCI-H441 cancer cells was enhanced. Here, theasinensin A, a novel epigallocatechin-3-gallate (EGCG) derivative, was identified and its potent anticancer activity against wild-type EGFR NSCLC was demonstrated in vitro; the anticancer activity was induced through degradation of EGFR. Mechanistic studies further revealed that theasinensin A bound directly to the EGFR extracellular domain, which decreased interaction with its ligand EGF in combination with nimotuzumab. Theasinensin A significantly promoted EGFR degradation and repressed downstream survival pathways in combination with nimotuzumab. Meanwhile, treatment with theasinensin A and nimotuzumab prevented xenograft growth, whereas the single agents had limited effect. Thus, the combination therapy of theasinensin A with nimotuzumab is a powerful candidate for treatment of wild-type EGFR cancers. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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16 pages, 8514 KiB

Open AccessArticle

Black Ginseng Extract Exerts Potentially Anti-Asthmatic Activity by Inhibiting the Protein Kinase Cθ-Mediated IL-4/STAT6 Signaling Pathway

by Yu Na Song, Jae-Won Lee, Hyung Won Ryu, Jae Kyoung Lee, Eun Sol Oh, Doo-Young Kim, Hyunju Ro, Dahye Yoon, Ji-Yoon Park, Sung-Tae Hong, Mun-Ock Kim, Su Ui Lee and Dae Young Lee

Int. J. Mol. Sci. 2023, 24(15), 11970; https://doi.org/10.3390/ijms241511970 - 26 Jul 2023

Cited by 3 | Viewed by 2443

Abstract

Asthma is a chronic inflammatory lung disease that causes respiratory difficulties. Black ginseng extract (BGE) has preventative effects on respiratory inflammatory diseases such as asthma. However, the pharmacological mechanisms behind the anti-asthmatic activity of BGE remain unknown. To investigate the anti-asthmatic mechanism of [...] Read more.

Asthma is a chronic inflammatory lung disease that causes respiratory difficulties. Black ginseng extract (BGE) has preventative effects on respiratory inflammatory diseases such as asthma. However, the pharmacological mechanisms behind the anti-asthmatic activity of BGE remain unknown. To investigate the anti-asthmatic mechanism of BGE, phorbol 12-myristate 13-acetate plus ionomycin (PMA/Iono)-stimulated mouse EL4 cells and ovalbumin (OVA)-induced mice with allergic airway inflammation were used. Immune cells (eosinophils/macrophages), interleukin (IL)-4, -5, -13, and serum immunoglobulin E (IgE) levels were measured using an enzyme-linked immunosorbent assay. Inflammatory cell recruitment and mucus secretion in the lung tissue were estimated. Protein expression was analyzed via Western blotting, including that of inducible nitric oxide synthase (iNOS) and the activation of protein kinase C theta (PKCθ) and its downstream signaling molecules. BGE decreased T helper (Th)2 cytokines, serum IgE, mucus secretion, and iNOS expression in mice with allergic airway inflammation, thereby providing a protective effect. Moreover, BGE and its major ginsenosides inhibited the production of Th2 cytokines in PMA/Iono-stimulated EL4 cells. In EL4 cells, these outcomes were accompanied by the inactivation of PKCθ and its downstream transcription factors, such as nuclear factor of activated T cells (NFAT), nuclear factor kappa B (NF-κB), activator of transcription 6 (STAT6), and GATA binding protein 3 (GATA3), which are involved in allergic airway inflammation. BGE also inhibited the activation of PKCθ and the abovementioned transcriptional factors in the lung tissue of mice with allergic airway inflammation. These results highlight the potential of BGE as a useful therapeutic and preventative agent for allergic airway inflammatory diseases such as allergic asthma. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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31 pages, 7187 KiB

Open AccessArticle

Implications of the Cultivation of Rosemary and Thyme (Lamiaceae) in Plant Communities for the Development of Antioxidant Therapies

by Emanuela-Alice Luță, Andrei Biță, Alina Moroșan, Dan Eduard Mihaiescu, Dragoș Paul Mihai, Liliana Popescu, Ludovic Everard Bejenaru, Cornelia Bejenaru, Violeta Popovici, Octavian Tudorel Olaru and Cerasela Elena Gîrd

Int. J. Mol. Sci. 2023, 24(14), 11670; https://doi.org/10.3390/ijms241411670 - 19 Jul 2023

Cited by 4 | Viewed by 1770

Abstract

Oxidative stress is the most critical factor in multiple functional disorders’ development, and natural antioxidants could protect the human body against it. Our study aims to investigate the polyphenol content of four extracts of two medicinal plants (Rosmarinus officinalis L. and Thymus [...] Read more.

Oxidative stress is the most critical factor in multiple functional disorders’ development, and natural antioxidants could protect the human body against it. Our study aims to investigate the polyphenol content of four extracts of two medicinal plants (Rosmarinus officinalis L. and Thymus vulgaris L.) and analyze the correlation with their antioxidant activity. The research was carried out on extracts of rosemary and thyme obtained from species cultivated together in plant communities. Both were compared with extracts from species cultivated in individual crops (control crops). Their polyphenols were determined by spectrophotometric methods (dosage of flavones, phenol carboxylic acids, and total polyphenols) and chromatography (UHPLC–MS and FT–ICR MS). Triterpenic acids were also quantified, having a higher concentration in the thyme extract from the culture. The antioxidant activity of the dry extracts was evaluated in vitro (DPPH, ABTS, and FRAP) and in silico (prediction of interactions with BACH1/BACH2 transcription factors). The concentrations of polyphenols are higher in the extracts obtained from the sources collected from the common crops. These observations were also validated following the chromatographic analysis for some compounds. Statistically significant differences in the increase in the antioxidant effect were observed for the extracts from the common batches compared to those from the individual ones. Following the Pearson analysis, the IC₅₀ values for each plant extract were strongly correlated with the concentration of active phytoconstituents. Molecular docking studies revealed that quercetin could bind to BTB domains of BACH1 and BACH2 transcription factors, likely translating into increased antioxidant enzyme expression. Future studies must validate the in silico findings and further investigate phytosociological cultivation’s effects. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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Review

Jump to: Research

46 pages, 9361 KiB

Open AccessReview

Electrophilic Compounds in the Human Diet and Their Role in the Induction of the Transcription Factor NRF2

by Celia María Curieses Andrés, José Manuel Pérez de la Lastra, Elena Bustamante Munguira, Celia Andrés Juan, Francisco J. Plou and Eduardo Pérez Lebeña

Int. J. Mol. Sci. 2024, 25(6), 3521; https://doi.org/10.3390/ijms25063521 - 20 Mar 2024

Cited by 1 | Viewed by 1244

Abstract

The phrase “Let food be thy medicine…” means that food can be a form of medicine and medicine can be a form of food; in other words, that the diet we eat can have a significant impact on our health and well-being. Today, [...] Read more.

The phrase “Let food be thy medicine…” means that food can be a form of medicine and medicine can be a form of food; in other words, that the diet we eat can have a significant impact on our health and well-being. Today, this phrase is gaining prominence as more and more scientific evidence suggests that one’s diet can help prevent and treat disease. A diet rich in fruits, vegetables, whole grains, and lean protein can help reduce the risk of heart disease, cancer, diabetes, and other health problems and, on the other hand, a diet rich in processed foods, added sugars, and saturated fats can increase the risk of the same diseases. Electrophilic compounds in the diet can have a significant impact on our health, and they are molecules that covalently modify cysteine residues present in the thiol-rich Keap1 protein. These compounds bind to Keap1 and activate NRF2, which promotes its translocation to the nucleus and its binding to DNA in the ARE region, triggering the antioxidant response and protecting against oxidative stress. These compounds include polyphenols and flavonoids that are nucleophilic but are converted to electrophilic quinones by metabolic enzymes such as polyphenol oxidases (PPOs) and sulfur compounds present in foods such as the Brassica genus (broccoli, cauliflower, cabbage, Brussel sprouts, etc.) and garlic. This review summarizes our current knowledge on this subject. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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27 pages, 17762 KiB

Open AccessReview

Binding Pattern and Structural Interactome of the Anticancer Drug 5-Fluorouracil: A Critical Review

by En-Shyh Lin and Cheng-Yang Huang

Int. J. Mol. Sci. 2024, 25(6), 3404; https://doi.org/10.3390/ijms25063404 - 17 Mar 2024

Viewed by 1065

Abstract

5-Fluorouracil (5-FU) stands as one of the most widely prescribed chemotherapeutics. Despite over 60 years of study, a systematic synopsis of how 5-FU binds to proteins has been lacking. Investigating the specific binding patterns of 5-FU to proteins is essential for identifying additional [...] Read more.

5-Fluorouracil (5-FU) stands as one of the most widely prescribed chemotherapeutics. Despite over 60 years of study, a systematic synopsis of how 5-FU binds to proteins has been lacking. Investigating the specific binding patterns of 5-FU to proteins is essential for identifying additional interacting proteins and comprehending their medical implications. In this review, an analysis of the 5-FU binding environment was conducted based on available complex structures. From the earliest complex structure in 2001 to the present, two groups of residues emerged upon 5-FU binding, classified as P- and R-type residues. These high-frequency interactive residues with 5-FU include positively charged residues Arg and Lys (P type) and ring residues Phe, Tyr, Trp, and His (R type). Due to their high occurrence, 5-FU binding modes were simplistically classified into three types, based on interactive residues (within <4 Å) with 5-FU: Type 1 (P-R type), Type 2 (P type), and Type 3 (R type). In summary, among 14 selected complex structures, 8 conform to Type 1, 2 conform to Type 2, and 4 conform to Type 3. Residues with high interaction frequencies involving the N1, N3, O4, and F5 atoms of 5-FU were also examined. Collectively, these interaction analyses offer a structural perspective on the specific binding patterns of 5-FU within protein pockets and contribute to the construction of a structural interactome delineating the associations of the anticancer drug 5-FU. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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43 pages, 5158 KiB

Open AccessReview

The Genus Cladosporium: A Prospective Producer of Natural Products

by Yanjing Li, Yifei Wang, Han Wang, Ting Shi and Bo Wang

Int. J. Mol. Sci. 2024, 25(3), 1652; https://doi.org/10.3390/ijms25031652 - 29 Jan 2024

Viewed by 1191

Abstract

Cladosporium, a genus of ascomycete fungi in the Dematiaceae family, is primarily recognized as a widespread environmental saprotrophic fungus or plant endophyte. Further research has shown that the genus is distributed in various environments, particularly in marine ecosystems, such as coral reefs, [...] Read more.

Cladosporium, a genus of ascomycete fungi in the Dematiaceae family, is primarily recognized as a widespread environmental saprotrophic fungus or plant endophyte. Further research has shown that the genus is distributed in various environments, particularly in marine ecosystems, such as coral reefs, mangroves and the polar region. Cladosporium, especially the marine-derived Cladosporium, is a highly resourceful group of fungi whose natural products have garnered attention due to their diverse chemical structures and biological activities, as well as their potential as sources of novel leads to compounds for drug production. This review covers the sources, distribution, bioactivities, biosynthesis and structural characteristics of compounds isolated from Cladosporium in the period between January 2000 and December 2022, and conducts a comparative analysis of the Cladosporium isolated compounds derived from marine and terrestrial sources. Our results reveal that 34% of Cladosporium-derived natural products are reported for the first time. And 71.79% of the first reported compounds were isolated from marine-derived Cladosporium. Cladosporium-derived compounds exhibit diverse skeletal chemical structures, concentrating in the categories of polyketides (48.47%), alkaloids (19.21%), steroids and terpenoids (17.03%). Over half of the natural products isolated from Cladosporium have been found to have various biological activities, including cytotoxic, antibacterial, antiviral, antifungal and enzyme-inhibitory activities. These findings testify to the tremendous potential of Cladosporium, especially the marine-derived Cladosporium, to yield novel bioactive natural products, providing a structural foundation for the development of new drugs. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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25 pages, 2122 KiB

Open AccessReview

Statins—From Fungi to Pharmacy

by Anna Sadowska, Patryk Osiński, Alicja Roztocka, Karolina Kaczmarz-Chojnacka, Ewa Zapora, Diana Sawicka and Halina Car

Int. J. Mol. Sci. 2024, 25(1), 466; https://doi.org/10.3390/ijms25010466 - 29 Dec 2023

Cited by 1 | Viewed by 2348

Abstract

Statins have been used in the treatment of hyperlipidemia, both as monotherapy and in combination therapy. Natural fermentation processes of fungi such as Monascus spp., Penicillium spp., Aspergillus terreus, and Pleurotus ostreatus have given rise to natural statins. Compactin (mevastatin), the original [...] Read more.

Statins have been used in the treatment of hyperlipidemia, both as monotherapy and in combination therapy. Natural fermentation processes of fungi such as Monascus spp., Penicillium spp., Aspergillus terreus, and Pleurotus ostreatus have given rise to natural statins. Compactin (mevastatin), the original naturally occurring statin, is the primary biotransformation substrate in the manufacturing process of marketed drugs. Statins are classified into natural, semi-synthetic derivatives of natural statins, and synthetic ones. Synthetic statins differ from natural statins in their structural composition, with the only common feature being the HMG-CoA-like moiety responsible for suppressing HMG-CoA reductase. Statins do not differ significantly regarding their pleiotropic and adverse effects, but their characteristics depend on their pharmacokinetic parameters and chemical properties. This paper focuses on describing the processes of obtaining natural statins, detailing the pharmacokinetics of available statins, divided into natural and synthetic, and indicating their pleiotropic effects. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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16 pages, 2668 KiB

Open AccessReview

The Potential Role of Gossypetin in the Treatment of Diabetes Mellitus and Its Associated Complications: A Review

by Karishma Naidoo and Andile Khathi

Int. J. Mol. Sci. 2023, 24(24), 17609; https://doi.org/10.3390/ijms242417609 - 18 Dec 2023

Cited by 1 | Viewed by 1155

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder caused by insulin resistance and dysfunctional beta (β)-cells in the pancreas. Hyperglycaemia is a characteristic of uncontrolled diabetes which eventually leads to fatal organ system damage. In T2DM, free radicals are continuously produced, causing [...] Read more.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder caused by insulin resistance and dysfunctional beta (β)-cells in the pancreas. Hyperglycaemia is a characteristic of uncontrolled diabetes which eventually leads to fatal organ system damage. In T2DM, free radicals are continuously produced, causing extensive tissue damage and subsequent macro-and microvascular complications. The standard approach to managing T2DM is pharmacological treatment with anti-diabetic medications. However, patients’ adherence to treatment is frequently decreased by the side effects and expense of medications, which has a detrimental impact on their health outcomes. Quercetin, a flavonoid, is a one of the most potent anti-oxidants which ameliorates T2DM. Thus, there is an increased demand to investigate quercetin and its derivatives, as it is hypothesised that similar structured compounds may exhibit similar biological activity. Gossypetin is a hexahydroxylated flavonoid found in the calyx of Hibiscus sabdariffa. Gossypetin has a similar chemical structure to quercetin with an extra hydroxyl group. Furthermore, previous literature has elucidated that gossypetin exhibits neuroprotective, hepatoprotective, reproprotective and nephroprotective properties. The mechanisms underlying gossypetin’s therapeutic potential have been linked to its anti-oxidant, anti-inflammatory and immunomodulatory properties. Hence, this review highlights the potential role of gossypetin in the treatment of diabetes and its associated complications. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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13 pages, 321 KiB

Open AccessReview

The Potential of Sheep or Camel Milk Constituents to Contribute to Novel Dressings for Diabetic Wounds

by Zuzanna Flis, Piotr Szatkowski, Kinga Pielichowska and Edyta Molik

Int. J. Mol. Sci. 2023, 24(24), 17551; https://doi.org/10.3390/ijms242417551 - 16 Dec 2023

Viewed by 1121

Abstract

Impaired wound healing is a complication of diabetes, which constitutes a serious problem in clinical practice. Currently, there is a high demand on the market for local treatment options for difficult-to-heal wounds caused by diabetes. The development of dressings that accelerate wound healing [...] Read more.

Impaired wound healing is a complication of diabetes, which constitutes a serious problem in clinical practice. Currently, there is a high demand on the market for local treatment options for difficult-to-heal wounds caused by diabetes. The development of dressings that accelerate wound healing has recently been the subject of much research. Sheep and camel milk is gaining importance due to the content of many bioactive substances with health-promoting effects, such as insulin, LF, proline, or CLA. Sheep and camel milk proteins are a promising source of insulin, antidiabetic, and antihypertensive peptides. Numerous studies show that local administration of insulin has a significant impact on the healing of diabetic wounds. Sheep and camel milk, due to the highest LF content among ruminants, reduces autoimmune inflammatory processes and protects against bacterial and viral infections in the wound environment. Sheep’s milk has the highest content of proline and CLA, and their addition to a hydrogel dressing can help in the development of an effective dressing material. The production of hydrogel dressings containing sheep and camel milk, which are naturally rich in the bioactive substances presented in this review, may be a promising step in the market of specialized dressings for difficult-to-heal diabetic wounds. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

24 pages, 3705 KiB

Open AccessReview

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

by Marakiya T. Moetlediwa, Rudzani Ramashia, Carmen Pheiffer, Salam J. J. Titinchi, Sithandiwe E. Mazibuko-Mbeje and Babalwa U. Jack

Int. J. Mol. Sci. 2023, 24(18), 14366; https://doi.org/10.3390/ijms241814366 - 21 Sep 2023

Cited by 4 | Viewed by 2137

Abstract

Obesity is a major cause of morbidity and mortality globally, increasing the risk for chronic diseases. Thus, the need to identify more effective anti-obesity agents has spurred significant interest in the health-promoting properties of natural compounds. Of these, curcumin, the most abundant and [...] Read more.

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

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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29 pages, 10658 KiB

Open AccessReview

An Updated Review on Developing Small Molecule Kinase Inhibitors Using Computer-Aided Drug Design Approaches

by Linwei Li, Songtao Liu, Bi Wang, Fei Liu, Shu Xu, Pirui Li and Yu Chen

Int. J. Mol. Sci. 2023, 24(18), 13953; https://doi.org/10.3390/ijms241813953 - 11 Sep 2023

Cited by 6 | Viewed by 2443

Abstract

Small molecule kinase inhibitors (SMKIs) are of heightened interest in the field of drug research and development. There are 79 (as of July 2023) small molecule kinase inhibitors that have been approved by the FDA and hundreds of kinase inhibitor candidates in clinical [...] Read more.

Small molecule kinase inhibitors (SMKIs) are of heightened interest in the field of drug research and development. There are 79 (as of July 2023) small molecule kinase inhibitors that have been approved by the FDA and hundreds of kinase inhibitor candidates in clinical trials that have shed light on the treatment of some major diseases. As an important strategy in drug design, computer-aided drug design (CADD) plays an indispensable role in the discovery of SMKIs. CADD methods such as docking, molecular dynamic, quantum mechanics/molecular mechanics, pharmacophore, virtual screening, and quantitative structure–activity relationship have been applied to the design and optimization of small molecule kinase inhibitors. In this review, we provide an overview of recent advances in CADD and SMKIs and the application of CADD in the discovery of SMKIs. Full article

(This article belongs to the Special Issue Natural Products and Synthetic Compounds for Drug Development)

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