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Bioorganic Chemistry: Current and Future Perspectives

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Małgorzata Anna Marć

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Enrique Domínguez-Álvarez

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Claus Jacob

Molecules 2023, 28(16), 5959; https://doi.org/10.3390/molecules28165959 - 09 Aug 2023

Viewed by 321

Abstract

Bioorganic Chemistry is an emerging field developing at the interface between the traditional fields of Chemistry and Biochemistry [...] Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

Research

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Open AccessArticle

Deacetylated Sialic Acid Sensitizes Lung and Colon Cancers to Novel Cucurbitacin-Inspired Estrone Epidermal Growth Factor Receptor (EGFR) Inhibitor Analogs

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Rachel Willand-Charnley

Molecules 2023, 28(17), 6257; https://doi.org/10.3390/molecules28176257 - 26 Aug 2023

Viewed by 716

Abstract

Cancers utilize sugar residues such as sialic acids (Sia) to improve their ability to survive. Sia presents a variety of functional group alterations, including O-acetylation on the C6 hydroxylated tail. Previously, sialylation has been reported to suppress EGFR activation and increase cancer cell [...] Read more.

Cancers utilize sugar residues such as sialic acids (Sia) to improve their ability to survive. Sia presents a variety of functional group alterations, including O-acetylation on the C6 hydroxylated tail. Previously, sialylation has been reported to suppress EGFR activation and increase cancer cell sensitivity to Tyrosine Kinase Inhibitors (TKIs). In this study, we report on the effect of deacetylated Sia on the activity of three novel EGFR-targeting Cucurbitacin-inspired estrone analogs (CIEAs), MMA 294, MMA 321, and MMA 320, in lung and colon cancer cells. Acetylation was modulated by the removal of Sialate O-Acetyltransferase, also known as CAS1 Domain-containing protein (CASD1) gene via CRISPR-Cas9 gene editing. Using a variety of cell-based approaches including MTT cell viability assay, flow cytometry, immunofluorescence assay and in-cell ELISA we observed that deacetylated Sia-expressing knockout cells (1.24–6.49 μM) were highly sensitive to all CIEAs compared with the control cells (8.82–20.97 μM). Apoptosis and varied stage cell cycle arrest (G0/G1 and G2/M) were elucidated as mechanistic modes of action of the CIEAs. Further studies implicated overexpression of CIEAs’ cognate protein target, phosphorylated EGFR, in the chemosensitivity of the deacetylated Sia-expressing knockout cells. This observation correlated with significantly decreased levels of key downstream proteins (phosphorylated ERK and mTOR) of the EGFR pathway in knockout cells compared with controls when treated with CIEAs. Collectively, our findings indicate that Sia deacetylation renders lung and colon cancer cells susceptible to EGFR therapeutics and provide insights for future therapeutic interventions. Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

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Open AccessArticle

The Phthalic Selenoanhydride Decreases Rat Blood Pressure and Tension of Isolated Mesenteric, Femoral and Renal Arteries

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Enrique Domínguez-Álvarez

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Karol Ondrias

Molecules 2023, 28(12), 4826; https://doi.org/10.3390/molecules28124826 - 17 Jun 2023

Cited by 1 | Viewed by 484

Abstract

Phthalic selenoanhydride (R-Se) solved in physiological buffer releases various reactive selenium species including H₂Se. It is a potential compound for Se supplementation which exerts several biological effects, but its effect on the cardiovascular system is still unknown. Therefore, herein we aimed [...] Read more.

Phthalic selenoanhydride (R-Se) solved in physiological buffer releases various reactive selenium species including H₂Se. It is a potential compound for Se supplementation which exerts several biological effects, but its effect on the cardiovascular system is still unknown. Therefore, herein we aimed to study how R-Se affects rat hemodynamic parameters and vasoactive properties in isolated arteries. The right jugular vein of anesthetized Wistar male rats was cannulated for IV administration of R-Se. The arterial pulse waveform (APW) was detected by cannulation of the left carotid artery, enabling the evaluation of 35 parameters. R-Se (1–2 µmol kg⁻¹), but not phthalic anhydride or phthalic thioanhydride, transiently modulated most of the APW parameters including a decrease in systolic and diastolic blood pressure, heart rate, dP/dt_max relative level, or anacrotic/dicrotic notches, whereas systolic area, dP/dt_min delay, dP/dt_d delay, anacrotic notch relative level or its delay increased. R-Se (~10–100 µmol L⁻¹) significantly decreased the tension of precontracted mesenteric, femoral, and renal arteries, whereas it showed a moderate vasorelaxation effect on thoracic aorta isolated from normotensive Wistar rats. The results imply that R-Se acts on vascular smooth muscle cells, which might underlie the effects of R-Se on the rat hemodynamic parameters. Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

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Open AccessArticle

Multitargeting Histamine H₃ Receptor Ligands among Acetyl- and Propionyl-Phenoxyalkyl Derivatives

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Ewelina Honkisz-Orzechowska

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Agata Doroz-Płonka

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Anna Więckowska

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Holger Stark

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Katarzyna Kieć-Kononowicz

Molecules 2023, 28(5), 2349; https://doi.org/10.3390/molecules28052349 - 03 Mar 2023

Cited by 1 | Viewed by 909

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder, for which there is no effective cure. Current drugs only slow down the course of the disease, and, therefore, there is an urgent need to find effective therapies that not only treat, but also prevent it. [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder, for which there is no effective cure. Current drugs only slow down the course of the disease, and, therefore, there is an urgent need to find effective therapies that not only treat, but also prevent it. Acetylcholinesterase inhibitors (AChEIs), among others, have been used for years to treat AD. Histamine H₃ receptors (H₃Rs) antagonists/inverse agonists are indicated for CNS diseases. Combining AChEIs with H₃R antagonism in one structure could bring a beneficial therapeutic effect. The aim of this study was to find new multitargetting ligands. Thus, continuing our previous research, acetyl- and propionyl-phenoxy-pentyl(-hexyl) derivatives were designed. These compounds were tested for their affinity to human H₃Rs, as well as their ability to inhibit cholinesterases (acetyl- and butyrylcholinesterases) and, additionally, human monoamine oxidase B (MAO B). Furthermore, for the selected active compounds, their toxicity towards HepG2 or SH-SY5Y cells was evaluated. The results showed that compounds 16 (1-(4-((5-(azepan-1-yl)pentyl)oxy)phenyl)propan-1-one) and 17 (1-(4-((6-(azepan-1-yl)hexyl)oxy)phenyl)propan-1-one) are the most promising, with a high affinity for human H₃Rs (K_i: 30 nM and 42 nM, respectively), a good ability to inhibit cholinesterases (16: AChE IC₅₀ = 3.60 µM, BuChE IC₅₀ = 0.55 µM; 17: AChE IC₅₀ = 1.06 µM, BuChE IC₅₀ = 2.86 µM), and lack of cell toxicity up to 50 µM. Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

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Open AccessArticle

It Takes Two to Tango, Part II: Synthesis of A-Ring Functionalised Quinones Containing Two Redox-Active Centres with Antitumour Activities

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Joyce C. Oliveira

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Renato L. de Carvalho

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Eufrânio N. da Silva Júnior

Molecules 2023, 28(5), 2222; https://doi.org/10.3390/molecules28052222 - 27 Feb 2023

Cited by 1 | Viewed by 1335

Abstract

In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres (ortho-quinone/para-quinone or quinone/selenium-containing triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic [...] Read more.

In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres (ortho-quinone/para-quinone or quinone/selenium-containing triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic product was indicated, but not fully explored. Herein, we report the synthesis of 15 new quinone-based derivatives prepared from click chemistry reactions and their subsequent evaluation against nine cancer cell lines and the murine fibroblast line L929. Our strategy was based on the modification of the A-ring of para-naphthoquinones and subsequent conjugation with different ortho-quinoidal moieties. As anticipated, our study identified several compounds with IC₅₀ values below 0.5 µM in tumour cell lines. Some of the compounds described here also exhibited an excellent selectivity index and low cytotoxicity on L929, the control cell line. The antitumour evaluation of the compounds separately and in their conjugated form proved that the activity is strongly enhanced in the derivatives containing two redox centres. Thus, our study confirms the efficiency of using A-ring functionalized para-quinones coupled with ortho-quinones to obtain a diverse range of two redox centre compounds with potential applications against cancer cell lines. Here as well, it literally takes two for an efficient tango! Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

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Open AccessArticle

A Novel Hybridization LC-MS/MS Methodology for Quantification of siRNA in Plasma, CSF and Tissue Samples

by

Long Yuan

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Jean-François Dupuis

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Kevork Mekhssian

Molecules 2023, 28(4), 1618; https://doi.org/10.3390/molecules28041618 - 08 Feb 2023

Cited by 4 | Viewed by 2813

Abstract

Therapeutic oligonucleotides, such as antisense oligonucleotide (ASO) and small interfering RNA (siRNA), are a new class of therapeutics rapidly growing in drug discovery and development. A sensitive and reliable method to quantify oligonucleotides in biological samples is critical to study their pharmacokinetic and [...] Read more.

Therapeutic oligonucleotides, such as antisense oligonucleotide (ASO) and small interfering RNA (siRNA), are a new class of therapeutics rapidly growing in drug discovery and development. A sensitive and reliable method to quantify oligonucleotides in biological samples is critical to study their pharmacokinetic and pharmacodynamic properties. Hybridization LC-MS/MS was recently established as a highly sensitive and specific methodology for the quantification of single-stranded oligonucleotides, e.g., ASOs, in various biological matrices. However, there is no report of this methodology for the bioanalysis of double-stranded oligonucleotides (e.g., siRNA). In this work, we investigated hybridization LC-MS/MS methodology for the quantification of double-stranded oligonucleotides in biological samples using an siRNA compound, siRNA-01, as the test compound. The commonly used DNA capture probe and a new peptide nucleic acid (PNA) probe were compared for the hybridization extraction of siRNA-01 under different conditions. The PNA probe achieved better extraction recovery than the DNA probe, especially for high concentration samples, which may be due to its stronger hybridization affinity. The optimized hybridization method using the PNA probe was successfully qualified for the quantitation of siRNA-01 in monkey plasma, cerebrospinal fluid (CSF), and tissue homogenates over the range of 2.00–1000 ng/mL. This work is the first report of the hybridization LC-MS/MS methodology for the quantification of double-stranded oligonucleotides. The developed methodology will be applied to pharmacokinetic and toxicokinetic studies of siRNA-01. This novel methodology can also be used for the quantitative bioanalysis of other double-stranded oligonucleotides. Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

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Open AccessArticle

Selective Structural Derivatization of Flavonoid Acetamides Significantly Impacts Their Bioavailability and Antioxidant Properties

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Daniel Kasungi Isika

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Omowunmi A. Sadik

Molecules 2022, 27(23), 8133; https://doi.org/10.3390/molecules27238133 - 22 Nov 2022

Cited by 1 | Viewed by 937

Abstract

Flavonoids show abundant favorable physicochemical and drug related properties, leading to substantial biological applications which are limited by undesirable properties such as poor solubility, high polarity, low bioavailability, and enzymatic degradations. Chemical modification with bioisosteres can be used to address some of these [...] Read more.

Flavonoids show abundant favorable physicochemical and drug related properties, leading to substantial biological applications which are limited by undesirable properties such as poor solubility, high polarity, low bioavailability, and enzymatic degradations. Chemical modification with bioisosteres can be used to address some of these challenges. We report the synthesis and characterization of partial flavonoid acetamide derivatives from quercetin, apigenin and luteolin and the evaluation of their structure-activity relationships based on antioxidant, bioavailability, drug likeness, and toxicity properties. The sequential synthesis was achieved with 76.67–87.23% yield; the structures of the compounds were confirmed using ¹H & ¹³C NMR characterizations. The purity of each compound was determined by HPLC while the molecular weights were determined by mass spectrometry. The % bioavailability was determined using the dialysis tubing procedure and the values were in the range 15.97–38.12%. The antioxidant activity was determined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and expressed as the IC₅₀ values which were in the range 31.52–198.41 µM. The drug likeness and the toxicity properties of compounds 4, 5, 7, 11 and 15 were predicted using computational tools and showed satisfactory results. A structure-activity relationship evaluation reveals that hydroxyl and methylene groups attached on the 2-phenylchromen-4-one structure of the flavonoid play a colossal role in the overall antioxidant and bioavailability properties. The improved bioavailability and excellent drug relevance and toxicity properties present flavonoid acetamide derivatives as prospective drug candidates for further evaluations. Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

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Open AccessArticle

NMR Investigation of the Interaction of Three Non-Steroidal Anti-Inflammatory Drugs with Human Serum Albumin

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Federica Aiello

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Gloria Uccello-Barretta

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Claudio Picchi

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Samuele Nazzi

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Alessandra Recchimurzo

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Federica Balzano

Molecules 2022, 27(19), 6647; https://doi.org/10.3390/molecules27196647 - 06 Oct 2022

Cited by 4 | Viewed by 1058

Abstract

The understanding of the interaction between non-steroidal anti-inflammatory drugs and human serum albumin plays a fundamental role in the development of new drugs and new therapeutic strategies. Several studies have been performed, nevertheless, the interaction phenomena are still not fully understood. In this [...] Read more.

The understanding of the interaction between non-steroidal anti-inflammatory drugs and human serum albumin plays a fundamental role in the development of new drugs and new therapeutic strategies. Several studies have been performed, nevertheless, the interaction phenomena are still not fully understood. In this work, high-field solution Nuclear Magnetic Resonance (NMR) spectroscopy was applied to compare the strength of the interaction of diclofenac sodium salt, ketorolac tris salt and flurbiprofen sodium salt toward albumin. To this aim, mono- and bi-selective relaxation rate measurements were performed by applying selective π-pulses at the selected frequencies and by following magnetization recovery. On the basis of the dependence of relaxation parameters on albumin concentration, normalized affinity indexes were calculated for several protons of the drugs. Affinity indexes for diclofenac were about five-fold higher in comparison with ketorolac and flurbiprofen. Aromatic moieties of the three drugs and methine protons at the chiral centers of ketorolac and flurbiprofen were more involved in the interaction with albumin. In conclusion, NMR spectroscopy allows not only for the comparison of drug-to-protein affinities but also points out the nature of the drug sites that are more extensively involved in the interaction. Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

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Open AccessCommunication

Synthesis and Study of Dibenzo[b, f]oxepine Combined with Fluoroazobenzenes—New Photoswitches for Application in Biological Systems

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Molecules 2022, 27(18), 5836; https://doi.org/10.3390/molecules27185836 - 08 Sep 2022

Cited by 2 | Viewed by 1156

Abstract

Dibenzo[b, f]oxepine derivatives are an important scaffold in natural, medicinal chemistry, and these derivatives occur in several medicinally relevant plants. Two dibenzo[b, f]oxepines were selected and connected with appropriate fluorine azobenzenes. In the next step, the geometry of E [...] Read more.

Dibenzo[b, f]oxepine derivatives are an important scaffold in natural, medicinal chemistry, and these derivatives occur in several medicinally relevant plants. Two dibenzo[b, f]oxepines were selected and connected with appropriate fluorine azobenzenes. In the next step, the geometry of E/Z isomers was analyzed using density functional theory (DFT) calculations. Then the energies of the HOMO and LUMO orbitals were calculated for the E/Z isomers to determine the HOMO-LUMO gap. Next, modeling of the interaction between the obtained isomers of the compounds and the colchicine α and β-tubulin binding site was performed. The investigated isomers interact with the colchicine binding site in tubulin with a part of the dibenzo[b, f]oxepine or in a part of the azo switch, or both at the same time. Based on the UV-VIS spectra, it was found that in the case of compounds with an azo bond in the meta position, the absorption bands n→π* for both geometric isomers and their separation from π→π* are visible. These derivatives therefore have the potential to be used in photopharmacology. Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

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Open AccessArticle

Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione Core

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Giovanni Luca Beretta

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Paola Perego

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Sabrina Dallavalle

Molecules 2022, 27(9), 2791; https://doi.org/10.3390/molecules27092791 - 27 Apr 2022

Cited by 1 | Viewed by 1347

Abstract

G-quadruplexes are secondary structures originating from nucleic acid regions rich in guanines, which are well known for their involvement in gene transcription and regulation and DNA damage repair. In recent studies from our group, kynurenic acid (KYNA) derivative 1 was synthesized and found [...] Read more.

G-quadruplexes are secondary structures originating from nucleic acid regions rich in guanines, which are well known for their involvement in gene transcription and regulation and DNA damage repair. In recent studies from our group, kynurenic acid (KYNA) derivative 1 was synthesized and found to share the structural features typical of G-quadruplex binders. Herein, structural modifications were conducted on this scaffold in order to assist the binding with a G-quadruplex, by introducing charged hydrophilic groups. The antiproliferative activity of the new analogues was evaluated on an IGROV-1 human ovarian cancer cell line, and the most active compound, compound 9, was analyzed with NMR spectrometry in order to investigate its binding mode with DNA. The results indicated that a weak, non-specific interaction was set with duplex nucleotides; on the other hand, titration in the presence of a G-quadruplex from human telomere d(TTAGGGT)₄ showed a stable, although not strong, interaction at the 3′-end of the nucleotidic sequence, efficiently assisted by salt bridges between the quaternary nitrogen and the external phosphate groups. Overall, this work can be considered a platform for the development of a new class of potential G-quadruplex stabilizing molecules, confirming the crucial role of a planar system and the ability of charged nitrogen-containing groups to facilitate the binding to G-quadruplex grooves and loops. Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

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Open AccessArticle

Reactive Acrylamide-Modified DNA Traps for Accurate Cross-Linking with Cysteine Residues in DNA–Protein Complexes Using Mismatch Repair Protein MutS as a Model

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Molecules 2022, 27(8), 2438; https://doi.org/10.3390/molecules27082438 - 10 Apr 2022

Cited by 1 | Viewed by 1572

Abstract

Covalent protein capture (cross-linking) by reactive DNA derivatives makes it possible to investigate structural features by fixing complexes at different stages of DNA–protein recognition. The most common cross-linking methods are based on reactive groups that interact with native or engineered cysteine residues. Nonetheless, [...] Read more.

Covalent protein capture (cross-linking) by reactive DNA derivatives makes it possible to investigate structural features by fixing complexes at different stages of DNA–protein recognition. The most common cross-linking methods are based on reactive groups that interact with native or engineered cysteine residues. Nonetheless, high reactivity of most of such groups leads to preferential fixation of early-stage complexes or even non-selective cross-linking. We synthesised a set of DNA reagents carrying an acrylamide group attached to the C5 atom of a 2′-deoxyuridine moiety via various linkers and studied cross-linking with MutS as a model protein. MutS scans DNA for mismatches and damaged nucleobases and can form multiple non-specific complexes with DNA that may cause non-selective cross-linking. By varying the length of the linker between DNA and the acrylamide group and by changing the distance between the reactive nucleotide and a mismatch in the duplex, we showed that cross-linking occurs only if the distance between the acrylamide group and cysteine is optimal within the DNA–protein complex. Thus, acrylamide-modified DNA duplexes are excellent tools for studying DNA–protein interactions because of high selectivity of cysteine trapping. Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

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Review

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Open AccessReview

The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

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Molecules 2023, 28(4), 1973; https://doi.org/10.3390/molecules28041973 - 19 Feb 2023

Cited by 1 | Viewed by 1800

Abstract

In recent years, histone deacetylases (HDACs) have emerged as promising targets in the treatment of cancer. The approach is to inhibit HDACs with drugs known as HDAC inhibitors (HDACis). Such HDACis are broadly classified according to their chemical structure, e.g., hydroxamic acids, benzamides, [...] Read more.

In recent years, histone deacetylases (HDACs) have emerged as promising targets in the treatment of cancer. The approach is to inhibit HDACs with drugs known as HDAC inhibitors (HDACis). Such HDACis are broadly classified according to their chemical structure, e.g., hydroxamic acids, benzamides, thiols, short-chain fatty acids, and cyclic peptides. Fluorination plays an important role in the medicinal–chemical design of new active representatives. As a result of the introduction of fluorine into the chemical structure, parameters such as potency or selectivity towards isoforms of HDACs can be increased. However, the impact of fluorination cannot always be clearly deduced. Nevertheless, a change in lipophilicity and, hence, solubility, as well as permeability, can influence the potency. The selectivity towards certain HDACs isoforms can be explained by special interactions of fluorinated compounds with the structure of the slightly different enzymes. Another aspect is that for a more detailed investigation of newly synthesized fluorine-containing active compounds, fluorination is often used for the purpose of labeling. Aside from the isotope ¹⁹F, which can be detected by nuclear magnetic resonance spectroscopy, the positron emission tomography of ¹⁸F plays a major role. However, to our best knowledge, a survey of the general effects of fluorination on HDACis development is lacking in the literature to date. Therefore, the aim of this review is to highlight the introduction of fluorine in the course of chemical synthesis and the impact on biological activity, using selected examples of recently developed fluorinated HDACis. Full article

(This article belongs to the Special Issue Bioorganic Chemistry: Current and Future Perspectives)

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