International Journal of Molecular Sciences

Editorial

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4 pages, 192 KiB

Open AccessEditorial

Chemistry towards Biology

by Milos Hricovini and Josef Jampilek

Int. J. Mol. Sci. 2023, 24(4), 3998; https://doi.org/10.3390/ijms24043998 - 16 Feb 2023

Viewed by 1171

Abstract

Although it may not seem like it, chemical biology has existed for a long time from today’s perspective [...] Full article

(This article belongs to the Special Issue Chemistry towards Biology)

Research

Jump to: Editorial, Review

14 pages, 2464 KiB

Open AccessArticle

Computational Analysis of the Ligand-Binding Sites of the Molecular Chaperone OppA from Yersinia pseudotuberculosis

by Mirian Becerril Ramírez, Lucía Soto Urzúa, María de los Ángeles Martínez Martínez and Luis Javier Martínez Morales

Int. J. Mol. Sci. 2023, 24(4), 4023; https://doi.org/10.3390/ijms24044023 - 16 Feb 2023

Cited by 1 | Viewed by 1766

Abstract

The function of chaperones is to correct or degrade misfolded proteins inside the cell. Classic molecular chaperones such as GroEL and DnaK have not been found in the periplasm of Yersinia pseudotuberculosis. Some periplasmic substrate-binding proteins could be bifunctional, such as OppA. [...] Read more.

The function of chaperones is to correct or degrade misfolded proteins inside the cell. Classic molecular chaperones such as GroEL and DnaK have not been found in the periplasm of Yersinia pseudotuberculosis. Some periplasmic substrate-binding proteins could be bifunctional, such as OppA. Using bioinformatic tools, we try to elucidate the nature of the interactions between OppA and ligands from four proteins with different oligomeric states. Using the crystal structure of the proteins Mal12 alpha-glucosidase from Saccharomyces cerevisiae S288C, LDH rabbit muscle lactate dehydrogenase, EcoRI endonuclease from Escherichia coli and THG Geotrichum candidum lipase, a hundred models were obtained in total, including five different ligands from each enzyme with five conformations of each ligand. The best values for Mal12 stem from ligands 4 and 5, with conformation 5 for both; for LDH, ligands 1 and 4, with conformations 2 and 4, respectively; for EcoRI, ligands 3 and 5, with conformation 1 for both; and for THG, ligands 2 and 3, with conformation 1 for both. The interactions were analyzed with LigProt, and the length of the hydrogen bridges has an average of 2.8 to 3.0 Å. The interaction within the OppA pocket is energetically favored due to the formation of hydrogen bonds both of OppA and of the selected enzymes. The Asp 419 residue is important in these junctions. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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14 pages, 4299 KiB

Open AccessArticle

Effect of Hydrogel Substrate Components on the Stability of Tetracycline Hydrochloride and Swelling Activity against Model Skin Sebum

by Agnieszka Kostrzębska, Karolina Pączek, Angelika Weselak and Witold Musiał

Int. J. Mol. Sci. 2023, 24(3), 2678; https://doi.org/10.3390/ijms24032678 - 31 Jan 2023

Cited by 8 | Viewed by 2004

Abstract

Due to its high instability and rapid degradation under adverse conditions, tetracycline hydrochloride (TC) can cause difficulties in the development of an effective but stable formulation for the topical treatment of acne. The aim of the following work was to propose a hydrogel [...] Read more.

Due to its high instability and rapid degradation under adverse conditions, tetracycline hydrochloride (TC) can cause difficulties in the development of an effective but stable formulation for the topical treatment of acne. The aim of the following work was to propose a hydrogel formulation that would ensure the stability of the antibiotic contained in it. Additionally, an important property of the prepared formulations was the activity of the alcoholamines contained in them against the components of the model sebum. This feature may help effectively cleanse the hair follicles in the accumulated sebum layer. A series of formulations with varying proportions of anionic polymer and alcoholamine and containing different polymers have been developed. The stability of tetracycline hydrochloride contained in the hydrogels was evaluated for 28 days by HPLC analysis. Formulations containing a large excess of TRIS alcoholamine led to the rapid degradation of TC from an initial concentration of about 10 µg/mL to about 1 µg/mL after 28 days. At the same time, these formulations showed the highest activity against artificial sebum components. Thanks to appropriately selected proportions of the components, it was possible to develop a formulation that assured the stability of tetracycline for ca. one month, while maintaining formulation activity against the components of model sebum. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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14 pages, 3889 KiB

Open AccessArticle

Optimization of Mobile Phase Modifiers for Fast LC-MS-Based Untargeted Metabolomics and Lipidomics

by Tomas Cajka, Jiri Hricko, Lucie Rudl Kulhava, Michaela Paucova, Michaela Novakova and Ondrej Kuda

Int. J. Mol. Sci. 2023, 24(3), 1987; https://doi.org/10.3390/ijms24031987 - 19 Jan 2023

Cited by 26 | Viewed by 5488

Abstract

Liquid chromatography-mass spectrometry (LC-MS) is the method of choice for the untargeted profiling of biological samples. A multiplatform LC-MS-based approach is needed to screen polar metabolites and lipids comprehensively. Different mobile phase modifiers were tested to improve the electrospray ionization process during metabolomic [...] Read more.

Liquid chromatography-mass spectrometry (LC-MS) is the method of choice for the untargeted profiling of biological samples. A multiplatform LC-MS-based approach is needed to screen polar metabolites and lipids comprehensively. Different mobile phase modifiers were tested to improve the electrospray ionization process during metabolomic and lipidomic profiling. For polar metabolites, hydrophilic interaction LC using a mobile phase with 10 mM ammonium formate/0.125% formic acid provided the best performance for amino acids, biogenic amines, sugars, nucleotides, acylcarnitines, and sugar phosphate, while reversed-phase LC (RPLC) with 0.1% formic acid outperformed for organic acids. For lipids, RPLC using a mobile phase with 10 mM ammonium formate or 10 mM ammonium formate with 0.1% formic acid permitted the high signal intensity of various lipid classes ionized in ESI(+) and robust retention times. For ESI(−), the mobile phase with 10 mM ammonium acetate with 0.1% acetic acid represented a reasonable compromise regarding the signal intensity of the detected lipids and the stability of retention times compared to 10 mM ammonium acetate alone or 0.02% acetic acid. Collectively, we show that untargeted methods should be evaluated not only on the total number of features but also based on common metabolites detected by a specific platform along with the long-term stability of retention times. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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14 pages, 5338 KiB

Open AccessArticle

Characterization of a Novel Amphiphilic Cationic Chlorin Photosensitizer for Photodynamic Applications

by Margarita A. Gradova, Oleg V. Gradov, Anton V. Lobanov, Anna V. Bychkova, Elena D. Nikolskaya, Nikita G. Yabbarov, Mariia R. Mollaeva, Anton E. Egorov, Alexey A. Kostyukov, Vladimir A. Kuzmin, Irina S. Khudyaeva and Dmitry V. Belykh

Int. J. Mol. Sci. 2023, 24(1), 345; https://doi.org/10.3390/ijms24010345 - 25 Dec 2022

Cited by 7 | Viewed by 2215

Abstract

A novel amphiphilic cationic chlorin e₆ derivative was investigated as a promising photosensitizer for photodynamic therapy. Two cationic –N(CH₃)₃⁺ groups on the periphery of the macrocycle provide additional hydrophilization of the molecule and ensure its electrostatic binding to [...] Read more.

A novel amphiphilic cationic chlorin e₆ derivative was investigated as a promising photosensitizer for photodynamic therapy. Two cationic –N(CH₃)₃⁺ groups on the periphery of the macrocycle provide additional hydrophilization of the molecule and ensure its electrostatic binding to the mitochondrial membranes and bacterial cell walls. The presence of a hydrophobic phytol residue in the same molecule results in its increased affinity towards the phospholipid membranes while decreasing its stability towards aggregation in aqueous media. In organic media, this chlorin e₆ derivative is characterized by a singlet oxygen quantum yield of 55%. Solubilization studies in different polymer- and surfactant-based supramolecular systems revealed the effective stabilization of this compound in a photoactive monomolecular form in micellar nonionic surfactant solutions, including Tween-80 and Cremophor EL. A novel cationic chlorin e₆ derivative also demonstrates effective binding towards serum albumin, which enhances its bioavailability and promotes effective accumulation within the target tissues. Laser confocal scanning microscopy demonstrates the rapid intracellular accumulation and distribution of this compound throughout the cells. Together with low dark toxicity and a rather good photostability, this compound demonstrates significant phototoxicity against HeLa cells causing cellular damage most likely through reactive oxygen species generation. These results demonstrate a high potential of this derivative for application in photodynamic therapy. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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22 pages, 1266 KiB

Open AccessArticle

Assessment of Small Cellular Particles from Four Different Natural Sources and Liposomes by Interferometric Light Microscopy

by Anna Romolo, Zala Jan, Apolonija Bedina Zavec, Matic Kisovec, Vesna Arrigler, Vesna Spasovski, Marjetka Podobnik, Aleš Iglič, Gabriella Pocsfalvi, Ksenija Kogej and Veronika Kralj-Iglič

Int. J. Mol. Sci. 2022, 23(24), 15801; https://doi.org/10.3390/ijms232415801 - 13 Dec 2022

Cited by 8 | Viewed by 2271

Abstract

Small particles in natural sources are a subject of interest for their potential role in intercellular, inter-organism, and inter-species interactions, but their harvesting and assessment present a challenge due to their small size and transient identity. We applied a recently developed interferometric light [...] Read more.

Small particles in natural sources are a subject of interest for their potential role in intercellular, inter-organism, and inter-species interactions, but their harvesting and assessment present a challenge due to their small size and transient identity. We applied a recently developed interferometric light microscopy (ILM) to assess the number density and hydrodynamic radius (R_h) of isolated small cellular particles (SCPs) from blood preparations (plasma and washed erythrocytes) (B), spruce needle homogenate (S), suspension of flagellae of microalgae Tetraselmis chuii (T), conditioned culture media of microalgae Phaeodactylum tricornutum (P), and liposomes (L). The aliquots were also assessed by flow cytometry (FCM), dynamic light scattering (DLS), ultraviolet-visible spectrometry (UV-vis), and imaging by cryogenic transmission electron microscopy (cryo-TEM). In R_h, ILM showed agreement with DLS within the measurement error in 10 out of 13 samples and was the only method used here that yielded particle density. Cryo-TEM revealed that representative SCPs from Tetraselmis chuii flagella (T) did not have a globular shape, so the interpretation by R_h of the batch methods was biased. Cryo-TEM showed the presence of thin filaments in isolates from Phaeodactylum tricornutum conditioned culture media (P), which provides an explanation for the considerably larger R_h obtained by batch methods than the sizes of particles observed by cryo-TEM images. ILM proved convenient for assessment of number density and R_h of SCPs in blood preparations (e.g., plasma); therefore, its use in population and clinical studies is indicated. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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15 pages, 2268 KiB

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Application of Spectroscopic Methods for the Identification of Superoxide Dismutases in Cyanobacteria

by Monika Kula-Maximenko, Kamil Jan Zieliński, Joanna Depciuch, Janusz Lekki, Marcin Niemiec and Ireneusz Ślesak

Int. J. Mol. Sci. 2022, 23(22), 13819; https://doi.org/10.3390/ijms232213819 - 10 Nov 2022

Cited by 3 | Viewed by 1638

Abstract

Superoxide dismutases (SODs) belong to the group of metalloenzymes that remove superoxide anion radicals and they have been identified in three domains of life: Bacteria, Archaea and Eucarya. SODs in Synechocystis sp. PCC 6803, Gloeobacter violaceus CCALA 979, and Geitlerinema sp. [...] Read more.

Superoxide dismutases (SODs) belong to the group of metalloenzymes that remove superoxide anion radicals and they have been identified in three domains of life: Bacteria, Archaea and Eucarya. SODs in Synechocystis sp. PCC 6803, Gloeobacter violaceus CCALA 979, and Geitlerinema sp. ZHR1A were investigated. We hypothesized that iron (FeSOD) and/or manganese (MnSOD) dominate as active forms in these cyanobacteria. Activity staining and three different spectroscopic methods of SOD activity bands excised from the gels were used to identify a suitable metal in the separated samples. FeSODs or enzymes belonging to the Fe-MnSOD superfamily were detected. The spectroscopic analyses showed that only Fe is present in the SOD activity bands. We found FeSOD in Synechocystis sp. PCC 6803 while two forms in G. violaceus and Geitlerinema sp. ZHR1A: FeSOD1 and FeSOD2 were present. However, no active Cu/ZnSODs were identified in G. violaceus and Geitlerinema sp. ZHR1A. We have shown that selected spectroscopic techniques can be complementary to the commonly used method of staining for SOD activity in a gel. Furthermore, the occurrence of active SODs in the cyanobacteria studied is also discussed in the context of SOD evolution in oxyphotrophs. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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18 pages, 3086 KiB

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Immobilization and Application of the Recombinant Xylanase GH10 of Malbranchea pulchella in the Production of Xylooligosaccharides from Hydrothermal Liquor of the Eucalyptus (Eucalyptus grandis) Wood Chips

by Robson C. Alnoch, Gabriela S. Alves, Jose C. S. Salgado, Diandra de Andrades, Emanuelle N. de Freitas, Karoline M. V. Nogueira, Ana C. Vici, Douglas P. Oliveira, Valdemiro P. Carvalho-Jr, Roberto N. Silva, Marcos S. Buckeridge, Michele Michelin, José A. Teixeira and Maria de Lourdes T. M. Polizeli

Int. J. Mol. Sci. 2022, 23(21), 13329; https://doi.org/10.3390/ijms232113329 - 1 Nov 2022

Cited by 6 | Viewed by 1904

Abstract

Xylooligosaccharides (XOS) are widely used in the food industry as prebiotic components. XOS with high purity are required for practical prebiotic function and other biological benefits, such as antioxidant and inflammatory properties. In this work, we immobilized the recombinant endo-1,4-β-xylanase of Malbranchea pulchella [...] Read more.

Xylooligosaccharides (XOS) are widely used in the food industry as prebiotic components. XOS with high purity are required for practical prebiotic function and other biological benefits, such as antioxidant and inflammatory properties. In this work, we immobilized the recombinant endo-1,4-β-xylanase of Malbranchea pulchella (MpXyn10) in various chemical supports and evaluated its potential to produce xylooligosaccharides (XOS) from hydrothermal liquor of eucalyptus wood chips. Values >90% of immobilization yields were achieved from amino-activated supports for 120 min. The highest recovery values were found on Purolite (142%) and MANAE-MpXyn10 (137%) derivatives, which maintained more than 90% residual activity for 24 h at 70 °C, while the free-MpXyn10 maintained only 11%. In addition, active MpXyn10 derivatives were stable in the range of pH 4.0–6.0 and the presence of the furfural and HMF compounds. MpXyn10 derivatives were tested to produce XOS from xylan of various sources. Maximum values were observed for birchwood xylan at 8.6 mg mL⁻¹ and wheat arabinoxylan at 8.9 mg mL⁻¹, using Purolite-MpXyn10. Its derivative was also successfully applied in the hydrolysis of soluble xylan present in hydrothermal liquor, with 0.9 mg mL⁻¹ of XOS after 3 h at 50 °C. This derivative maintained more than 80% XOS yield after six cycles of the assay. The results obtained provide a basis for the application of immobilized MpXyn10 to produce XOS with high purity and other high-value-added products in the lignocellulosic biorefinery field. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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21 pages, 6651 KiB

Open AccessArticle

Comparative Study of the Solid-Liquid Interfacial Adsorption of Proteins in Their Native and Amyloid Forms

by Ágnes Ábrahám, Flavio Massignan, Gergő Gyulai, Miklós Katona, Nóra Taricska and Éva Kiss

Int. J. Mol. Sci. 2022, 23(21), 13219; https://doi.org/10.3390/ijms232113219 - 30 Oct 2022

Cited by 5 | Viewed by 1898

Abstract

The adhesive properties of amyloid fibers are thought to play a crucial role in various negative and positive aggregation processes, the study of which might help in their understanding and control. Amyloids have been prepared from two proteins, lysozyme and β-lactoglobulin, as well [...] Read more.

The adhesive properties of amyloid fibers are thought to play a crucial role in various negative and positive aggregation processes, the study of which might help in their understanding and control. Amyloids have been prepared from two proteins, lysozyme and β-lactoglobulin, as well as an Exendin-4 derivative miniprotein (E5). Thermal treatment was applied to form amyloids and their structure was verified by thioflavin T (ThT), 8-Anilino-1-naphthalenesulfonic acid (ANS) dye tests and electronic circular dichroism spectroscopy (ECD). Adsorption properties of the native and amyloid forms of the three proteins were investigated and compared using the mass-sensitive quartz crystal microbalance (QCM) technique. Due to the possible electrostatic and hydrophobic interactions, similar adsorbed amounts were found for the native or amyloid forms, while the structures of the adsorbed layers differed significantly. Native proteins formed smooth and dense adsorption layers. On the contrary, a viscoelastic, highly loose layer was formed in the presence of the amyloid forms, shown by increased motional resistance values determined by the QCM technique and also indicated by atomic force microscopy (AFM) and wettability measurements. The elongated structure and increased hydrophobicity of amyloids might contribute to this kind of aggregation. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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18 pages, 1538 KiB

Open AccessArticle

Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics

by Dominika Pindjakova, Eliska Pilarova, Karel Pauk, Hana Michnova, Jan Hosek, Pratibha Magar, Alois Cizek, Ales Imramovsky and Josef Jampilek

Int. J. Mol. Sci. 2022, 23(19), 11648; https://doi.org/10.3390/ijms231911648 - 1 Oct 2022

Cited by 6 | Viewed by 1874

Abstract

A series of eleven benzylated intermediates and eleven target compounds derived from salicylanilide were tested against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference strains and against three clinical isolates of methicillin-resistant S. aureus (MRSA) and three isolates of vancomycin-resistant [...] Read more.

A series of eleven benzylated intermediates and eleven target compounds derived from salicylanilide were tested against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference strains and against three clinical isolates of methicillin-resistant S. aureus (MRSA) and three isolates of vancomycin-resistant E. faecalis. In addition, the compounds were evaluated against Mycobacterium tuberculosis H37Ra and M. smegmatis ATCC 700084. The in vitro cytotoxicity of the compounds was assessed using the human monocytic leukemia cell line THP-1. The lipophilicity of the prepared compounds was experimentally determined and correlated with biological activity. The benzylated intermediates were found to be completely biologically inactive. Of the final eleven compounds, according to the number of amide groups in the molecule, eight are diamides, and three are triamides that were inactive. 5-Chloro-2-hydroxy-N-[(2S)- 4-(methylsulfanyl)-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (3e) and 5-chloro-2-hydroxy-N-[(2S)-(4-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino)pentan-2-yl)benzamide (3f) showed the broadest spectrum of activity against all tested species/isolates comparable to the used standards (ampicillin and isoniazid). Six diamides showed high antistaphylococcal activity with MICs ranging from 0.070 to 8.95 μM. Three diamides showed anti-enterococcal activity with MICs ranging from 4.66 to 35.8 μM, and the activities of 3f and 3e against M. tuberculosis and M. smegmatis were MICs of 18.7 and 35.8 μM, respectively. All the active compounds were microbicidal. It was observed that the connecting linker between the chlorsalicylic and 4-CF₃-anilide cores must be substituted with a bulky and/or lipophilic chain such as isopropyl, isobutyl, or thiabutyl chain. Anticancer activity on THP-1 cells IC₅₀ ranged from 1.4 to >10 µM and increased with increasing lipophilicity. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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15 pages, 2058 KiB

Open AccessArticle

Mixture Effects of Tryptophan Intestinal Microbial Metabolites on Aryl Hydrocarbon Receptor Activity

by Aneta Vrzalová, Petra Pečinková, Peter Illés, Soňa Gurská, Petr Džubák, Martin Szotkowski, Marián Hajdúch, Sridhar Mani and Zdeněk Dvořák

Int. J. Mol. Sci. 2022, 23(18), 10825; https://doi.org/10.3390/ijms231810825 - 16 Sep 2022

Cited by 9 | Viewed by 2265

Abstract

Aryl hydrocarbon receptor (AHR) plays pivotal roles in intestinal physiology and pathophysiology. Intestinal AHR is activated by numerous dietary, endogenous, and microbial ligands. Whereas the effects of individual compounds on AHR are mostly known, the effects of real physiological mixtures occurring in the [...] Read more.

Aryl hydrocarbon receptor (AHR) plays pivotal roles in intestinal physiology and pathophysiology. Intestinal AHR is activated by numerous dietary, endogenous, and microbial ligands. Whereas the effects of individual compounds on AHR are mostly known, the effects of real physiological mixtures occurring in the intestine have not been studied. Using reporter gene assays and RT-PCR, we evaluated the combinatorial effects (3520 combinations) of 11 microbial catabolites of tryptophan (MICTs) on AHR. We robustly (n = 30) determined the potencies and relative efficacies of single MICTs. Synergistic effects of MICT binary mixtures were observed between low- or medium-efficacy agonists, in particular for combinations of indole-3-propionate and indole-3-lactate. Combinations comprising highly efficacious agonists such as indole-3-pyruvate displayed rather antagonist effects, caused by saturation of the assay response. These synergistic effects were confirmed by RT-PCR as CYP1A1 mRNA expression. We also tested mimic multicomponent and binary mixtures of MICTs, prepared based on the metabolomic analyses of human feces and colonoscopy aspirates, respectively. In this case, AHR responsiveness did not correlate with type of diet or health status, and the indole concentrations in the mixtures were determinative of gross AHR activity. Future systematic research on the synergistic activation of AHR by microbial metabolites and other ligands is needed. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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20 pages, 3262 KiB

Open AccessArticle

Study of Biological Activities and ADMET-Related Properties of Novel Chlorinated N-arylcinnamamides

by Tomas Strharsky, Dominika Pindjakova, Jiri Kos, Lucia Vrablova, Hana Michnova, Jan Hosek, Nicol Strakova, Veronika Lelakova, Lenka Leva, Lenka Kavanova, Michal Oravec, Alois Cizek and Josef Jampilek

Int. J. Mol. Sci. 2022, 23(6), 3159; https://doi.org/10.3390/ijms23063159 - 15 Mar 2022

Cited by 7 | Viewed by 2806

Abstract

A series of eighteen 4-chlorocinnamanilides and eighteen 3,4-dichlorocinnamanilides were designed, prepared and characterized. All compounds were evaluated for their activity against gram-positive bacteria and against two mycobacterial strains. Viability on both cancer and primary mammalian cell lines was also assessed. The lipophilicity of [...] Read more.

A series of eighteen 4-chlorocinnamanilides and eighteen 3,4-dichlorocinnamanilides were designed, prepared and characterized. All compounds were evaluated for their activity against gram-positive bacteria and against two mycobacterial strains. Viability on both cancer and primary mammalian cell lines was also assessed. The lipophilicity of the compounds was experimentally determined and correlated together with other physicochemical properties of the prepared derivatives with biological activity. 3,4-Dichlorocinnamanilides showed a broader spectrum of action and higher antibacterial efficacy than 4-chlorocinnamanilides; however, all compounds were more effective or comparable to clinically used drugs (ampicillin, isoniazid, rifampicin). Of the thirty-six compounds, six derivatives showed submicromolar activity against Staphylococcus aureus and clinical isolates of methicillin-resistant S. aureus (MRSA). (2E)-N-[3,5-bis(trifluoromethyl)phenyl]- 3-(4-chlorophenyl)prop-2-enamide was the most potent in series 1. (2E)-N-[3,5-bis(Trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2E)-3-(3,4-dichlorophenyl)-N-[3-(trifluoromethyl)phenyl]prop-2-enamide, (2E)-3-(3,4-dichloro- phenyl)-N-[4-(trifluoromethyl)phenyl]prop-2-enamide and (2E)-3-(3,4-dichlorophenyl)- N-[4-(trifluoromethoxy)phenyl]prop-2-enamide were the most active in series 2 and in addition to activity against S. aureus and MRSA were highly active against Enterococcus faecalis and vancomycin-resistant E. faecalis isolates and against fast-growing Mycobacterium smegmatis and against slow-growing M. marinum, M. tuberculosis non-hazardous test models. In addition, the last three compounds of the above-mentioned showed insignificant cytotoxicity to primary porcine monocyte-derived macrophages. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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21 pages, 3303 KiB

Open AccessArticle

Towards Property Profiling: SYNTHESIS and SAR Probing of New Tetracyclic Diazaphenothiazine Analogues

by Anna Empel, Andrzej Bak, Violetta Kozik, Malgorzata Latocha, Alois Cizek, Josef Jampilek, Kinga Suwinska, Aleksander Sochanik and Andrzej Zieba

Int. J. Mol. Sci. 2021, 22(23), 12826; https://doi.org/10.3390/ijms222312826 - 26 Nov 2021

Cited by 9 | Viewed by 1964

Abstract

A series of new tertiary phenothiazine derivatives containing a quinoline and a pyridine fragment was synthesized by the reaction of 1-methyl-3-benzoylthio-4-butylthioquinolinium chloride with 3-aminopyridine derivatives bearing various substituents on the pyridine ring. The direction and mechanism of the cyclization reaction of intermediates with [...] Read more.

A series of new tertiary phenothiazine derivatives containing a quinoline and a pyridine fragment was synthesized by the reaction of 1-methyl-3-benzoylthio-4-butylthioquinolinium chloride with 3-aminopyridine derivatives bearing various substituents on the pyridine ring. The direction and mechanism of the cyclization reaction of intermediates with the structure of 1-methyl-4-(3-pyridyl)aminoquinolinium-3-thiolate was related to the substituents in the 2- and 4-pyridine position. The structures of the compounds were analyzed using ¹H, ¹³C NMR (COSY, HSQC, HMBC) and X-ray analysis, respectively. Moreover, the antiproliferative activity against tumor cells (A549, T47D, SNB-19) and a normal cell line (NHDF) was tested. The antibacterial screening of all the compounds was conducted against the reference and quality control strain Staphylococcus aureus ATCC 29213, three clinical isolates of methicillin-resistant S. aureus (MRSA). In silico computation of the intermolecular similarity was performed using principal component analysis (PCA) and hierarchical clustering analysis (HCA) on the pool of structure/property-related descriptors calculated for the novel tetracyclic diazaphenothiazine derivatives. The distance-oriented property evaluation was correlated with the experimental anticancer activities and empirical lipophilicity as well. The quantitative shape-based comparison was conducted using the CoMSA method in order to indicate the potentially valid steric, electronic and lipophilic properties. Finally, the numerical sampling of similarity-related activity landscape (SALI) provided a subtle picture of the SAR trends. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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14 pages, 3742 KiB

Open AccessArticle

Analysis of Cryopreservation Protocols and Their Harmful Effects on the Endothelial Integrity of Human Corneas

by Silvia Rodríguez-Fernández, Marcelino Álvarez-Portela, Esther Rendal-Vázquez, María Piñeiro-Ramil, Clara Sanjurjo-Rodríguez, Rocío Castro-Viñuelas, Jacinto Sánchez-Ibáñez, Isaac Fuentes-Boquete and Silvia Díaz-Prado

Int. J. Mol. Sci. 2021, 22(22), 12564; https://doi.org/10.3390/ijms222212564 - 22 Nov 2021

Cited by 10 | Viewed by 2576

Abstract

Corneal cryopreservation can partially solve the worldwide concern regarding donor cornea shortage for keratoplasties. In this study, human corneas were cryopreserved using two standard cryopreservation protocols that are employed in the Tissue Bank of the Teresa Herrera Hospital (Spain) to store corneas for [...] Read more.

Corneal cryopreservation can partially solve the worldwide concern regarding donor cornea shortage for keratoplasties. In this study, human corneas were cryopreserved using two standard cryopreservation protocols that are employed in the Tissue Bank of the Teresa Herrera Hospital (Spain) to store corneas for tectonic keratoplasties (TK protocol) and aortic valves (AV protocol), and two vitrification protocols, VS55 and DP6. Endothelial viability and general corneal state were evaluated to determine the protocol that provides the best results. The potential corneal cryopreservation protocol was studied in detail taking into consideration some cryopreservation-related variables and the endothelial integrity and stroma arrangement of the resulting cryopreserved corneas. TK corneas showed mostly viable endothelial cells, while the others showed few (AV) or none (DP6 and VS55). The corneal structure was well maintained in TK and AV corneas. TK corneas showed endothelial acellular areas surrounded by injured cells and a normal-like stromal fiber arrangement. Cryoprotectant solutions of the TK protocol presented an increasing osmolality and a physiological pH value. Cooling temperature rate of TK protocol was of 1 °C/min to −40 °C and 3 °C/min to −120 °C, and almost all of dimethyl sulfoxide left the tissue after washing. Future studies should be done changing cryopreservation-related variables of the TK protocol to store corneas of optical grade. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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36 pages, 53661 KiB

Open AccessArticle

Synthesis, In Silico Prediction and In Vitro Evaluation of Antimicrobial Activity, DFT Calculation and Theoretical Investigation of Novel Xanthines and Uracil Containing Imidazolone Derivatives

by Samar El-Kalyoubi, Fatimah Agili, Wael A. Zordok and Ashraf S. A. El-Sayed

Int. J. Mol. Sci. 2021, 22(20), 10979; https://doi.org/10.3390/ijms222010979 - 12 Oct 2021

Cited by 23 | Viewed by 2540

Abstract

Novel xanthine and imidazolone derivatives were synthesized based on oxazolone derivatives 2a-c as a key intermediate. The corresponding xanthine 3-5 and imidazolone derivatives 6-13 were obtained via reaction of oxazolone derivative 2a-c with 5,6-diaminouracils 1a-e under various conditions. Xanthine compounds 3-5 were obtained [...] Read more.

Novel xanthine and imidazolone derivatives were synthesized based on oxazolone derivatives 2a-c as a key intermediate. The corresponding xanthine 3-5 and imidazolone derivatives 6-13 were obtained via reaction of oxazolone derivative 2a-c with 5,6-diaminouracils 1a-e under various conditions. Xanthine compounds 3-5 were obtained by cyclocondensation of 5,6-diaminouracils 1a-c with different oxazolones in glacial acetic acid. Moreover, 5,6-diaminouracils 1a-e were reacted with oxazolones 2a-c in presence of drops of acetic acid under fused condition yielding the imidazolone derivatives 6-13. Furthermore, Schiff base of compounds 14-16 were obtained by condensing 5,6-diaminouracils 1a,b,e with 4-dimethylaminobenzaldehyde in acetic acid. The structural identity of the resulting compounds was resolved by IR, ¹H-, ¹³C-NMR and Mass spectral analyses. The novel synthesized compounds were screened for their antifungal and antibacterial activities. Compounds 3, 6, 13 and 16 displayed the highest activity against Escherichia coli as revealed from the IC₅₀ values (1.8–1.9 µg/mL). The compound 16 displayed a significant antifungal activity against Candia albicans (0.82 µg/mL), Aspergillus flavus (1.2 µg/mL) comparing to authentic antibiotics. From the TEM microgram, the compounds 3, 12, 13 and 16 exhibited a strong deformation to the cellular entities, by interfering with the cell membrane components, causing cytosol leakage, cellular shrinkage and irregularity to the cell shape. In addition, docking study for the most promising antimicrobial tested compounds depicted high binding affinity against acyl carrier protein domain from a fungal type I polyketide synthase (ACP), and Baumannii penicillin- binding protein (PBP). Moreover, compound 12 showed high drug- likeness, and excellent pharmacokinetics, which needs to be in focus for further antimicrobial drug development. The most promising antimicrobial compounds underwent theoretical investigation using DFT calculation. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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15 pages, 10374 KiB

Open AccessArticle

The Influence of UV Light on Photodegradation of Acetylsalicylic Acid

by Monica Daescu, Miruna Iota, Constantin Serbschi, Alina C. Ion and Mihaela Baibarac

Int. J. Mol. Sci. 2021, 22(8), 4046; https://doi.org/10.3390/ijms22084046 - 14 Apr 2021

Cited by 6 | Viewed by 3483

Abstract

Photodegradation of the aqueous solutions of acetylsalicylic acid, in the absence (ASA) and the presence of excipients (ASE), is demonstrated by the photoluminescence (PL). A shift of the PL bands from 342 and 338 nm to 358 and 361–397 nm for ASA and [...] Read more.

Photodegradation of the aqueous solutions of acetylsalicylic acid, in the absence (ASA) and the presence of excipients (ASE), is demonstrated by the photoluminescence (PL). A shift of the PL bands from 342 and 338 nm to 358 and 361–397 nm for ASA and ASE in solid state and as aqueous solutions was reported. By exposure of the solution of ASA 0.3 M to UV light, a decrease in the PL band intensity was highlighted. This behavior was revealed for ASA in the presence of phosphate buffer (PB) having the pH equal to 6.4, 7, and 8 or by the interaction with NaOH 0.3 M. A different behavior was reported in the case of ASE. In the presence of PB, an increase in the intensity of the PL band of ASE simultaneously with a change of the ratio between the intensities of the bands at 361–364 and 394–397 nm was highlighted. The differences between PL spectra of ASA and ASE have their origin in the presence of salicylic acid (SAL). The interaction of ASE with NaOH induces a shift of the PL band at 405–407 nm. Arguments for the reaction of ASA with NaOH are shown by Raman scattering and FTIR spectroscopy. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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15 pages, 2002 KiB

Open AccessArticle

Structure Driven Prediction of Chromatographic Retention Times: Applications to Pharmaceutical Analysis

by Roman Szucs, Roland Brown, Claudio Brunelli, James C. Heaton and Jasna Hradski

Int. J. Mol. Sci. 2021, 22(8), 3848; https://doi.org/10.3390/ijms22083848 - 8 Apr 2021

Cited by 12 | Viewed by 5788

Abstract

Pharmaceutical drug development relies heavily on the use of Reversed-Phase Liquid Chromatography methods. These methods are used to characterize active pharmaceutical ingredients and drug products by separating the main component from related substances such as process related impurities or main component degradation products. [...] Read more.

Pharmaceutical drug development relies heavily on the use of Reversed-Phase Liquid Chromatography methods. These methods are used to characterize active pharmaceutical ingredients and drug products by separating the main component from related substances such as process related impurities or main component degradation products. The results presented here indicate that retention models based on Quantitative Structure Retention Relationships can be used for de-risking methods used in pharmaceutical analysis and for the identification of optimal conditions for separation of known sample constituents from postulated/hypothetical components. The prediction of retention times for hypothetical components in established methods is highly valuable as these compounds are not usually readily available for analysis. Here we discuss the development and optimization of retention models, selection of the most relevant structural molecular descriptors, regression model building and validation. We also present a practical example applied to chromatographic method development and discuss the accuracy of these models on selection of optimal separation parameters. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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14 pages, 3775 KiB

Open AccessArticle

Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway

by Dandan Guo, Liming He, Yaoxin Gao, Chenxu Jin, Haizhen Lin, Li Zhang, Liting Wang, Ying Zhou, Jie Yao, Yixin Duan, Renzheng Yang, Wenwei Qiu and Wenzheng Jiang

Int. J. Mol. Sci. 2021, 22(8), 3807; https://doi.org/10.3390/ijms22083807 - 7 Apr 2021

Cited by 9 | Viewed by 2586

Abstract

Osteoarthritis (OA), a degenerative joint disorder, has been reported as the most common cause of disability worldwide. The production of inflammatory cytokines is the main factor in OA. Previous studies have been reported that obeticholic acid (OCA) and OCA derivatives inhibited the release [...] Read more.

Osteoarthritis (OA), a degenerative joint disorder, has been reported as the most common cause of disability worldwide. The production of inflammatory cytokines is the main factor in OA. Previous studies have been reported that obeticholic acid (OCA) and OCA derivatives inhibited the release of proinflammatory cytokines in acute liver failure, but they have not been studied in the progression of OA. In our study, we screened our small synthetic library of OCA derivatives and found T-2054 had anti-inflammatory properties. Meanwhile, the proliferation of RAW 264.7 cells and ATDC5 cells were not affected by T-2054. T-2054 treatment significantly relieved the release of NO, as well as mRNA and protein expression levels of inflammatory cytokines (IL-6, IL-8 and TNF-α) in LPS-induced RAW 264.7 cells. Moreover, T-2054 promoted extracellular matrix (ECM) synthesis in TNF-α-treated ATDC5 chondrocytes. Moreover, T-2054 could relieve the infiltration of inflammatory cells and degeneration of the cartilage matrix and decrease the levels of serum IL-6, IL-8 and TNF-α in DMM-induced C57BL/6 mice models. At the same time, T-2054 showed no obvious toxicity to mice. Mechanistically, T-2054 decreased the extent of p-p65 expression in LPS-induced RAW 264.7 cells and TNF-α-treated ATDC5 chondrocytes. In summary, we showed for the first time that T-2054 effectively reduced the release of inflammatory mediators, as well as promoted extracellular matrix (ECM) synthesis via the NF-κB-signaling pathway. Our findings support the potential use of T-2054 as an effective therapeutic agent for the treatment of OA. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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27 pages, 4162 KiB

Open AccessArticle

Synthesis and Hybrid SAR Property Modeling of Novel Cholinesterase Inhibitors

by Jiri Kos, Violetta Kozik, Dominika Pindjakova, Timotej Jankech, Adam Smolinski, Sarka Stepankova, Jan Hosek, Michal Oravec, Josef Jampilek and Andrzej Bak

Int. J. Mol. Sci. 2021, 22(7), 3444; https://doi.org/10.3390/ijms22073444 - 26 Mar 2021

Cited by 21 | Viewed by 2660

Abstract

A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl(3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC [...] Read more.

A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl(3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC₅₀ = 36.05 µM in the series, while benzyl{3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC₅₀ = 22.23 µM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure–activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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14 pages, 3810 KiB

Open AccessArticle

Altering the Sex Pheromone Cyclo(l-Pro-l-Pro) of the Diatom Seminavis robusta towards a Chemical Probe

by Eli Bonneure, Amber De Baets, Sam De Decker, Koen Van den Berge, Lieven Clement, Wim Vyverman and Sven Mangelinckx

Int. J. Mol. Sci. 2021, 22(3), 1037; https://doi.org/10.3390/ijms22031037 - 21 Jan 2021

Cited by 7 | Viewed by 3321

Abstract

As a major group of algae, diatoms are responsible for a substantial part of the primary production on the planet. Pennate diatoms have a predominantly benthic lifestyle and are the most species-rich diatom group, with members of the raphid clades being motile and [...] Read more.

As a major group of algae, diatoms are responsible for a substantial part of the primary production on the planet. Pennate diatoms have a predominantly benthic lifestyle and are the most species-rich diatom group, with members of the raphid clades being motile and generally having heterothallic sexual reproduction. It was recently shown that the model species Seminavis robusta uses multiple sexual cues during mating, including cyclo(l-Pro-l-Pro) as an attraction pheromone. Elaboration of the pheromone-detection system is a key aspect in elucidating pennate diatom life-cycle regulation that could yield novel fundamental insights into diatom speciation. This study reports the synthesis and bio-evaluation of seven novel pheromone analogs containing small structural alterations to the cyclo(l-Pro-l-Pro) pheromone. Toxicity, attraction, and interference assays were applied to assess their potential activity as a pheromone. Most of our analogs show a moderate-to-good bioactivity and low-to-no phytotoxicity. The pheromone activity of azide- and diazirine-containing analogs was unaffected and induced a similar mating behavior as the natural pheromone. These results demonstrate that the introduction of confined structural modifications can be used to develop a chemical probe based on the diazirine- and/or azide-containing analogs to study the pheromone-detection system of S. robusta. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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18 pages, 5237 KiB

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Antioxidant, Cytotoxic, Genotoxic, and DNA-Protective Potential of 2,3-Substituted Quinazolinones: Structure—Activity Relationship Study

by Jana Hricovíniová, Zuzana Hricovíniová and Katarína Kozics

Int. J. Mol. Sci. 2021, 22(2), 610; https://doi.org/10.3390/ijms22020610 - 9 Jan 2021

Cited by 12 | Viewed by 2261

Abstract

The evaluation of antioxidant compounds that counteract the mutagenic effects caused by the direct action of reactive oxygen species on DNA molecule is of considerable interest. Therefore, a series of 2,3-substituted quinazolinone derivatives (Q1–Q8) were investigated by different assays, and the relationship between [...] Read more.

The evaluation of antioxidant compounds that counteract the mutagenic effects caused by the direct action of reactive oxygen species on DNA molecule is of considerable interest. Therefore, a series of 2,3-substituted quinazolinone derivatives (Q1–Q8) were investigated by different assays, and the relationship between their biological properties and chemical structure was examined. Genotoxicity and the potential DNA-protective effects of Q1–Q8 were evaluated by comet assay and DNA topology assay. Antioxidant activity was examined by DPPH-radical-scavenging, reducing-power, and total antioxidant status (TAS) assays. The cytotoxic effect of compounds was assessed in human renal epithelial cells (TH-1) and renal carcinoma cells (Caki-1) by MTT assay. Analysis of the structure–activity relationship disclosed significant differences in the activity depending on the substitution pattern. Derivatives Q5–Q8, bearing electron-donating moieties, were the most potent members of this series. Compounds were not genotoxic and considerably decreased the levels of DNA lesions induced by oxidants (H₂O₂, Fe²⁺ ions). Furthermore, compounds exhibited higher cytotoxicity in Caki-1 compared to that in TH-1 cells. Substantial antioxidant effect and DNA-protectivity along with the absence of genotoxicity suggested that the studied quinazolinones might represent potential model structures for the development of pharmacologically active agents. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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14 pages, 1171 KiB

Open AccessArticle

Advantages and Pitfalls of Capillary Electrophoresis of Pharmaceutical Compounds and Their Enantiomers in Complex Samples: Comparison of Hydrodynamically Opened and Closed Systems

by Marián Masár, Jasna Hradski, Martin G. Schmid and Roman Szucs

Int. J. Mol. Sci. 2020, 21(18), 6852; https://doi.org/10.3390/ijms21186852 - 18 Sep 2020

Cited by 19 | Viewed by 3042

Abstract

Several research disciplines require fast, reliable and highly automated determination of pharmaceutically active compounds and their enantiomers in complex biological matrices. To address some of the challenges of Capillary Electrophoresis (CE), such as low concentration sensitivity and performance degradation linked to the adsorption [...] Read more.

Several research disciplines require fast, reliable and highly automated determination of pharmaceutically active compounds and their enantiomers in complex biological matrices. To address some of the challenges of Capillary Electrophoresis (CE), such as low concentration sensitivity and performance degradation linked to the adsorption and interference of matrix components, CE in a hydrodynamically closed system was evaluated using the model compounds Pindolol and Propranolol. Some established validation parameters such as repeatability of injection efficiency, resolution and sensitivity were used to assess its performance, and it was found to be broadly identical to that of hydrodynamically opened systems. While some reduction in separation efficiency was observed, this was mainly due to dispersion caused by injection and it had no impact on the ability to resolve enantiomers of model compounds even when spiked into complex biological matrix such as blood serum. An approximately 18- to 23-fold increase in concentration sensitivity due to the employment of wide bore capillaries was observed. This brings the sensitivity of CE to a level similar to that of liquid chromatography techniques. In addition to this benefit and unlike in hydrodynamically opened systems, suppression of electroosmotic flow, which is essential for hydrodynamically closed systems practically eliminates the matrix effects that are linked to protein adsorption. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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17 pages, 2261 KiB

Open AccessArticle

Ternary Cu(II) Complex with GHK Peptide and Cis-Urocanic Acid as a Potential Physiologically Functional Copper Chelate

by Karolina Bossak-Ahmad, Marta D. Wiśniewska, Wojciech Bal, Simon C. Drew and Tomasz Frączyk

Int. J. Mol. Sci. 2020, 21(17), 6190; https://doi.org/10.3390/ijms21176190 - 27 Aug 2020

Cited by 19 | Viewed by 5596

Abstract

The tripeptide NH₂–Gly–His–Lys–COOH (GHK), cis-urocanic acid (cis-UCA) and Cu(II) ions are physiological constituents of the human body and they co-occur (e.g., in the skin and the plasma). While GHK is known as Cu(II)-binding molecule, we found that urocanic [...] Read more.

The tripeptide NH₂–Gly–His–Lys–COOH (GHK), cis-urocanic acid (cis-UCA) and Cu(II) ions are physiological constituents of the human body and they co-occur (e.g., in the skin and the plasma). While GHK is known as Cu(II)-binding molecule, we found that urocanic acid also coordinates Cu(II) ions. Furthermore, both ligands create ternary Cu(II) complex being probably physiologically functional species. Regarding the natural concentrations of the studied molecules in some human tissues, together with the affinities reported here, we conclude that the ternary complex [GHK][Cu(II)][cis-urocanic acid] may be partly responsible for biological effects of GHK and urocanic acid described in the literature. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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15 pages, 4907 KiB

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Cationic Pillar[6]arene Induces Cell Apoptosis by Inhibiting Protein Tyrosine Phosphorylation Via Host–Guest Recognition

by Can-Peng Li, Yu-Xun Lu, Cheng-Ting Zi, Yu-Ting Zhao, Hui Zhao and Ya-Ping Zhang

Int. J. Mol. Sci. 2020, 21(14), 4979; https://doi.org/10.3390/ijms21144979 - 15 Jul 2020

Cited by 7 | Viewed by 3061

Abstract

We reported for the first time that cationic pillar[6]arene (cPA6) could tightly bind to peptide polymer (MW~20–50 kDa), an artificial substrate for tyrosine (Tyr) phosphorylation, and efficiently inhibit Tyr protein phosphorylation through host–guest recognition. We synthesized a nanocomposite of black phosphorus nanosheets loaded [...] Read more.

We reported for the first time that cationic pillar[6]arene (cPA6) could tightly bind to peptide polymer (MW~20–50 kDa), an artificial substrate for tyrosine (Tyr) phosphorylation, and efficiently inhibit Tyr protein phosphorylation through host–guest recognition. We synthesized a nanocomposite of black phosphorus nanosheets loaded with cPA6 (BPNS@cPA6) to explore the effect of cPA6 on cells. BPNS@cPA6 was able to enter HepG2 cells, induced apoptosis, and inhibited cell proliferation by reducing the level of Tyr phosphorylation. Furthermore, BPNS@cPA6 showed a stronger ability of inhibiting cell proliferation in tumor cells than in normal cells. Our results revealed the supramolecular modulation of enzymatic Tyr phosphorylation by the host–guest recognition of cPA6. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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Towards a New Biomarker for Diabetic Retinopathy: Exploring RBP3 Structure and Retinoids Binding for Functional Imaging of Eyes In Vivo

by Vineeta Kaushik, Luca Gessa, Nelam Kumar and Humberto Fernandes

Int. J. Mol. Sci. 2023, 24(5), 4408; https://doi.org/10.3390/ijms24054408 - 23 Feb 2023

Cited by 3 | Viewed by 5525

Abstract

Diabetic retinopathy (DR) is a severe disease with a growing number of afflicted patients, which places a heavy burden on society, both socially and financially. While there are treatments available, they are not always effective and are usually administered when the disease is [...] Read more.

Diabetic retinopathy (DR) is a severe disease with a growing number of afflicted patients, which places a heavy burden on society, both socially and financially. While there are treatments available, they are not always effective and are usually administered when the disease is already at a developed stage with visible clinical manifestation. However, homeostasis at a molecular level is disrupted before visible signs of the disease are evident. Thus, there has been a constant search for effective biomarkers that could signal the onset of DR. There is evidence that early detection and prompt disease control are effective in preventing or slowing DR progression. Here, we review some of the molecular changes that occur before clinical manifestations are observable. As a possible new biomarker, we focus on retinol binding protein 3 (RBP3). We argue that it displays unique features that make it a very good biomarker for non-invasive, early-stage DR detection. Linking chemistry to biological function and focusing on new developments in eye imaging and two-photon technology, we describe a new potential diagnostic tool that would allow rapid and effective quantification of RBP3 in the retina. Moreover, this tool would also be useful in the future to monitor therapeutic effectiveness if levels of RBP3 are elevated by DR treatments. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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24 pages, 4946 KiB

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Chemistry towards Biology—Instruct: Snapshot

by Miloš Hricovíni, Raymond J. Owens, Andrzej Bak, Violetta Kozik, Witold Musiał, Roberta Pierattelli, Magdaléna Májeková, Yoel Rodríguez, Robert Musioł, Aneta Slodek, Pavel Štarha, Karina Piętak, Dagmara Słota, Wioletta Florkiewicz, Agnieszka Sobczak-Kupiec and Josef Jampílek

Int. J. Mol. Sci. 2022, 23(23), 14815; https://doi.org/10.3390/ijms232314815 - 26 Nov 2022

Cited by 2 | Viewed by 2220

Abstract

The knowledge of interactions between different molecules is undoubtedly the driving force of all contemporary biomedical and biological sciences. Chemical biology/biological chemistry has become an important multidisciplinary bridge connecting the perspectives of chemistry and biology to the study of small molecules/peptidomimetics and their [...] Read more.

The knowledge of interactions between different molecules is undoubtedly the driving force of all contemporary biomedical and biological sciences. Chemical biology/biological chemistry has become an important multidisciplinary bridge connecting the perspectives of chemistry and biology to the study of small molecules/peptidomimetics and their interactions in biological systems. Advances in structural biology research, in particular linking atomic structure to molecular properties and cellular context, are essential for the sophisticated design of new medicines that exhibit a high degree of druggability and very importantly, druglikeness. The authors of this contribution are outstanding scientists in the field who provided a brief overview of their work, which is arranged from in silico investigation through the characterization of interactions of compounds with biomolecules to bioactive materials. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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16 pages, 594 KiB

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Evolutionary Overview of Molecular Interactions and Enzymatic Activities in the Yeast Cell Walls

by Renata Teparić, Mateja Lozančić and Vladimir Mrša

Int. J. Mol. Sci. 2020, 21(23), 8996; https://doi.org/10.3390/ijms21238996 - 26 Nov 2020

Cited by 14 | Viewed by 3304

Abstract

Fungal cell walls are composed of a polysaccharide network that serves as a scaffold in which different glycoproteins are embedded. Investigation of fungal cell walls, besides simple identification and characterization of the main cell wall building blocks, covers the pathways and regulations of [...] Read more.

Fungal cell walls are composed of a polysaccharide network that serves as a scaffold in which different glycoproteins are embedded. Investigation of fungal cell walls, besides simple identification and characterization of the main cell wall building blocks, covers the pathways and regulations of synthesis of each individual component of the wall and biochemical reactions by which they are cross-linked and remodeled in response to different growth phase and environmental signals. In this review, a survey of composition and organization of so far identified and characterized cell wall components of different yeast genera including Saccharomyces, Candida, Kluyveromyces, Yarrowia, and Schizosaccharomyces are presented with the focus on their cell wall proteomes. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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24 pages, 1674 KiB

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The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their Activity

by Kyung Chan Park, Mahendiran Dharmasivam and Des R. Richardson

Int. J. Mol. Sci. 2020, 21(18), 6805; https://doi.org/10.3390/ijms21186805 - 16 Sep 2020

Cited by 23 | Viewed by 4941

Abstract

The role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane [...] Read more.

The role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane surface or within extracellular vesicles. This process results in the regulation of key signaling pathways by the modulation of kinases, e.g., the epidermal growth factor receptor (EGFR). Considering their regulatory roles in cancer, therapeutics targeting various extracellular proteases have been discovered. These include the metal-binding agents di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which increase c-MET degradation by multiple mechanisms. Both the direct and indirect inhibition of protease expression and activity can be achieved through metal ion depletion. Considering direct mechanisms, chelators can bind zinc(II) that plays a catalytic role in enzyme activity. In terms of indirect mechanisms, Dp44mT and DpC potently suppress the expression of the kallikrein-related peptidase—a prostate-specific antigen—in prostate cancer cells. The mechanism of this activity involves promotion of the degradation of the androgen receptor. Additional suppressive mechanisms of Dp44mT and DpC on matrix metalloproteases (MMPs) relate to their ability to up-regulate the metastasis suppressors N-myc downstream regulated gene-1 (NDRG1) and NDRG2, which down-regulate MMPs that are crucial for cancer cell invasion. Full article

(This article belongs to the Special Issue Chemistry towards Biology)

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