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Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 34179

Special Issue Editors


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Guest Editor
Laboratory for Biomolecular Interactions and Spectroscopy, Head Division of Organic Chemistry and Biochemistry, Rudjer Boskovic Institute, 10000 Zagreb, Croatia
Interests: supramolecular and medicinal chemistry; design and synthesis of dyes; DNA/RNA recognition; small molecule/protein interactions; fluorescence spectroscopy and microscopy; circular dichroism; microcalorimetry methods (ITC; DSC); development of Raman probes for biomacromolecules
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Department of Organic Chemistry, Martin-Universitat Halle-Wittenberg, Halle, Germany
Interests: natural products; enzyme inhibition; cytotoxicity; antitumor active compounds; triterpenes
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Guest Editor
Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, D-66123 Saarbruecken, Germany
Interests: bioorganic chemistry; catalytic sensor/effector agents; epistemology; intracellular diagnostics; nanotechnology; natural products; reactive sulfur and selenium species; redox regulation via the cellular thiolstat
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue of Molecules is dedicated to recent advances in bioorganic chemistry research areas and comprises a diverse selection of exclusive papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section. It focuses on highlighting recent interesting investigations conducted in the laboratories of our section’s EBMs and represents our young section as an attractive open-access publishing platform for bioorganic chemistry research data

Prof. Ivo Piantanida
Prof. Dr. René Csuk
Prof. Dr. Claus Jacob
Guest Editors

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Published Papers (11 papers)

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Research

16 pages, 7066 KiB  
Communication
Ratiometric Near-Infrared Fluorescent Probes Based on Hemicyanine Dyes Bearing Dithioacetal and Formal Residues for pH Detection in Mitochondria
by Yunnan Yan, Yibin Zhang, Shuai Xia, Shulin Wan, Tara Vohs, Marina Tanasova, Rudy L. Luck and Haiying Liu
Molecules 2021, 26(7), 2088; https://doi.org/10.3390/molecules26072088 - 06 Apr 2021
Cited by 9 | Viewed by 3186
Abstract
Ratiometric near-infrared fluorescent probes (AH+ and BH+) have been prepared for pH determination in mitochondria by attaching dithioacetal and formal residues onto a hemicyanine dye. The reactive formyl group on probe BH+ allows for retention inside mitochondria as [...] Read more.
Ratiometric near-infrared fluorescent probes (AH+ and BH+) have been prepared for pH determination in mitochondria by attaching dithioacetal and formal residues onto a hemicyanine dye. The reactive formyl group on probe BH+ allows for retention inside mitochondria as it can react with a protein primary amine residue to form an imine under slightly basic pH 8.0. Probes AH+ and BH+ display ratiometric fluorescent responses to pH changes through the protonation and deprotonaton of a hydroxy group in hemicyanine dyes with experimentally determined pKa values of 6.85 and 6.49, respectively. Calculated pKa values from a variety of theoretical methods indicated that the SMDBONDI method of accounting for solvent and van der Waals radii plus including a water molecule located near the site of protonation produced the closest overall agreement with the experimental values at 7.33 and 6.14 for AH+ and BH+ respectively. Full article
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18 pages, 3481 KiB  
Article
The Regulation of Floral Colour Change in Pleroma raddianum (DC.) Gardner
by Fernanda Mendes Rezende, Mads Hartvig Clausen, Magdalena Rossi and Cláudia Maria Furlan
Molecules 2020, 25(20), 4664; https://doi.org/10.3390/molecules25204664 - 13 Oct 2020
Cited by 3 | Viewed by 3039
Abstract
Floral colour change is a widespread phenomenon in angiosperms, but poorly understood from the genetic and chemical point of view. This article investigates this phenomenon in Pleroma raddianum, a Brazilian endemic species whose flowers change from white to purple. To this end, [...] Read more.
Floral colour change is a widespread phenomenon in angiosperms, but poorly understood from the genetic and chemical point of view. This article investigates this phenomenon in Pleroma raddianum, a Brazilian endemic species whose flowers change from white to purple. To this end, flavonoid compounds and their biosynthetic gene expression were profiled. By using accurate techniques (Ultra Performance Liquid Chromatography-High-Resolution Mass Spectrometry (UPLC-HRMS)), thirty phenolic compounds were quantified. Five key genes of the flavonoid biosynthetic pathway were partially cloned, sequenced, and the mRNA levels were analysed (RT-qPCR) during flower development. Primary metabolism was also investigated by gas chromatography coupled to mass spectrometry (GC-EIMS), where carbohydrates and organic acids were identified. Collectively, the obtained results suggest that the flower colour change in P. raddianum is determined by petunidin and malvidin whose accumulation coincides with the transcriptional upregulation of early and late biosynthetic genes of the flavonoid pathway, mainly CHS and ANS, respectively. An alteration in sugars, organic acids and phenolic co-pigments is observed together with the colour change. Additionally, an increment in the content of Fe3+ ions in the petals, from the pink to purple stage, seemed to influence the saturation of the colour. Full article
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23 pages, 5437 KiB  
Article
Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors
by Maria Giulia Davighi, Francesca Clemente, Camilla Matassini, Amelia Morrone, Andrea Goti, Macarena Martínez-Bailén and Francesca Cardona
Molecules 2020, 25(19), 4526; https://doi.org/10.3390/molecules25194526 - 02 Oct 2020
Cited by 3 | Viewed by 2232
Abstract
Pharmacological chaperones (PCs) are small compounds able to rescue the activity of mutated lysosomal enzymes when used at subinhibitory concentrations. Nitrogen-containing glycomimetics such as aza- or iminosugars are known to behave as PCs for lysosomal storage disorders (LSDs). As part of our research [...] Read more.
Pharmacological chaperones (PCs) are small compounds able to rescue the activity of mutated lysosomal enzymes when used at subinhibitory concentrations. Nitrogen-containing glycomimetics such as aza- or iminosugars are known to behave as PCs for lysosomal storage disorders (LSDs). As part of our research into lysosomal sphingolipidoses inhibitors and looking in particular for new β-galactosidase inhibitors, we report the synthesis of a series of alkylated azasugars with a relative “all-cis” configuration at the hydroxy/amine-substituted stereocenters. The novel compounds were synthesized from a common carbohydrate-derived piperidinone intermediate 8, through reductive amination or alkylation of the derived alcohol. In addition, the reaction of ketone 8 with several lithium acetylides allowed the stereoselective synthesis of new azasugars alkylated at C-3. The activity of the new compounds towards lysosomal β-galactosidase was negligible, showing that the presence of an alkyl chain in this position is detrimental to inhibitory activity. Interestingly, 9, 10, and 12 behave as good inhibitors of lysosomal β-glucosidase (GCase) (IC50 = 12, 6.4, and 60 µM, respectively). When tested on cell lines bearing the Gaucher mutation, they did not impart any enzyme rescue. However, altogether, the data included in this work give interesting hints for the design of novel inhibitors. Full article
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17 pages, 3454 KiB  
Article
A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor
by Ángela-Patricia Hernández, Paula Díez, Pablo A. García, Martín Pérez-Andrés, Pablo Ortega, Pablo G. Jambrina, David Díez, María Ángeles Castro and Manuel Fuentes
Molecules 2020, 25(18), 4258; https://doi.org/10.3390/molecules25184258 - 17 Sep 2020
Cited by 7 | Viewed by 2682
Abstract
Natural products are the ideal basis for the design of novel efficient molecular entities. Podophyllotoxin, a naturally occurring cyclolignan, is an example of natural product which displays a high versatility from a biological activity point of view. Based on its unique chemical structure, [...] Read more.
Natural products are the ideal basis for the design of novel efficient molecular entities. Podophyllotoxin, a naturally occurring cyclolignan, is an example of natural product which displays a high versatility from a biological activity point of view. Based on its unique chemical structure, different derivatives have been synthesized presenting the original antitumoral properties associated with the compound, i.e., the tubulin polymerization inhibition and arising anti-topoisomerase II activity from structural modifications on the cyclolignan skeleton. In this report, we present a novel conjugate or hybrid which chemically combines both biological activities in one single molecule. Chemical design has been planned based in our lead compound, podophyllic aldehyde, as an inhibitor of tubulin polymerization, and in etoposide, an approved antitumoral drug targeting topoisomerase II. The cytotoxicity and selectivity of the novel synthetized hybrid has been evaluated in several cell lines of different solid tumors. In addition, these dual functional effects of the novel compound have been also evaluated by molecular docking approaches. Full article
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17 pages, 3305 KiB  
Article
Design, Synthesis and Biological Evaluation of Novel Anthraniloyl-AMP Mimics as PQS Biosynthesis Inhibitors Against Pseudomonas aeruginosa Resistance
by Shekh Sabir, Sujatha Subramoni, Theerthankar Das, David StC. Black, Scott A. Rice and Naresh Kumar
Molecules 2020, 25(13), 3103; https://doi.org/10.3390/molecules25133103 - 07 Jul 2020
Cited by 7 | Viewed by 4066
Abstract
The Pseudomonas quinolone system (PQS) is one of the three major interconnected quorum sensing signaling systems in Pseudomonas aeruginosa. The virulence factors PQS and HHQ activate the transcription regulator PqsR (MvfR), which controls several activities in bacteria, including biofilm formation and upregulation [...] Read more.
The Pseudomonas quinolone system (PQS) is one of the three major interconnected quorum sensing signaling systems in Pseudomonas aeruginosa. The virulence factors PQS and HHQ activate the transcription regulator PqsR (MvfR), which controls several activities in bacteria, including biofilm formation and upregulation of PQS biosynthesis. The enzyme anthraniloyl-CoA synthetase (PqsA) catalyzes the first and critical step in the biosynthesis of quinolones; therefore, it is an attractive target for the development of anti-virulence therapeutics against Pseudomonas resistance. Herein, we report the design and synthesis of novel triazole nucleoside-based anthraniloyl- adenosine monophosphate (AMP) mimics. These analogues had a major impact on the morphology of bacterial biofilms and caused significant reduction in bacterial aggregation and population density. However, the compounds showed only limited inhibition of PQS and did not exhibit any effect on pyocyanin production. Full article
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21 pages, 4547 KiB  
Article
Unsaturated Fatty Acid-Induced Conformational Transitions and Aggregation of the Repeat Domain of Tau
by Carlo Giorgio Barracchia, Roberto Tira, Francesca Parolini, Francesca Munari, Luigi Bubacco, Georgios A. Spyroulias, Mariapina D’Onofrio and Michael Assfalg
Molecules 2020, 25(11), 2716; https://doi.org/10.3390/molecules25112716 - 11 Jun 2020
Cited by 14 | Viewed by 3181
Abstract
Background: The intrinsically disordered, amyloidogenic protein Tau associates with diverse classes of molecules, including proteins, nucleic acids, and lipids. Mounting evidence suggests that fatty acid molecules could play a role in the dysfunction of this protein, however, their interaction with Tau remains poorly [...] Read more.
Background: The intrinsically disordered, amyloidogenic protein Tau associates with diverse classes of molecules, including proteins, nucleic acids, and lipids. Mounting evidence suggests that fatty acid molecules could play a role in the dysfunction of this protein, however, their interaction with Tau remains poorly characterized. Methods: In a bid to elucidate the association of Tau with unsaturated fatty acids at the sub-molecular level, we carried out a variety of solution NMR experiments in combination with circular dichroism and fluorescence measurements. Our study shows that Tau4RD, the highly basic four-repeat domain of Tau, associates strongly with arachidonic and oleic acid assemblies in a high lipid/protein ratio, perturbing their supramolecular states and itself undergoing time-dependent structural adaptation. The structural signatures of Tau4RD/fatty acid aggregates appear similar for arachidonic acid and oleic acid, however, they are distinct from those of another prototypical intrinsically disordered protein, α-synuclein, when bound to these lipids, revealing protein-specific conformational adaptations. Both fatty acid molecules are found to invariably promote the self-aggregation of Tau4RD and of α-synuclein. Conclusions: This study describes the reciprocal influence that Tau4RD and fatty acids exert on their conformational states, contributing to our understanding of fundamental aspects of Tau/lipid co-assembly. Full article
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18 pages, 3443 KiB  
Article
Flexibility and Preorganization of Fluorescent Nucleobase-Pyrene Conjugates Control DNA and RNA Recognition
by Željka Ban, Josipa Matić, Biserka Žinić, Anders Foller Füchtbauer, L. Marcus Wilhelmsson and Ivo Piantanida
Molecules 2020, 25(9), 2188; https://doi.org/10.3390/molecules25092188 - 07 May 2020
Cited by 10 | Viewed by 2919
Abstract
We synthesized a new amino acid-fluorescent nucleobase derivative (qAN1-AA) and from it two new fluorescent nucleobase–fluorophore (pyrene) conjugates, whereby only the analogue with the longer and more flexible linker (qAN1-pyr2) self-folded into intramolecularly stacked qAN1/pyrene conformation, yielding characteristic, 100 nm-red-shifted emission (λmax [...] Read more.
We synthesized a new amino acid-fluorescent nucleobase derivative (qAN1-AA) and from it two new fluorescent nucleobase–fluorophore (pyrene) conjugates, whereby only the analogue with the longer and more flexible linker (qAN1-pyr2) self-folded into intramolecularly stacked qAN1/pyrene conformation, yielding characteristic, 100 nm-red-shifted emission (λmax = 500 nm). On the contrary, the shorter and more rigid linker resulted in non-stacked conformation (qAN1-pyr1), characterized by the emission of free pyrene at λmax = 400 nm. Both fluorescent nucleobase–fluorophore (pyrene) conjugates strongly interacted with ds-DNA/RNA grooves with similar affinity but opposite fluorescence response (due to pre-organization), whereas the amino acid-fluorescent base derivative (qAN1-AA) was inactive. However, only intramolecularly self-folded qAN1-pyr2 showed strong fluorescence selectivity toward poly U (Watson–Crick complementary to qAN1 nucleobase) and poly A (reverse Hoogsteen complementary to qAN1 nucleobase), while an opposite emission change was observed for non-complementary poly G and poly C. Non-folded analogue (qAN1-pyr1) showed no ss-RNA selectivity, demonstrating the importance of nucleobase-fluorophore pre-organization. Full article
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15 pages, 2066 KiB  
Article
In the Mists of a Fungal Metabolite: An Unexpected Reaction of 2,4,5-Trimethoxyphenylglyoxylic Acid
by Immo Serbian, Anne Loesche, Sven Sommerwerk, Phil Liebing, Dieter Ströhl and René Csuk
Molecules 2020, 25(8), 1978; https://doi.org/10.3390/molecules25081978 - 23 Apr 2020
Viewed by 2216
Abstract
The reactions of phenylglyoxylic acids during the synthesis and biological evaluation of fungal metabolites led to the discovery of hitherto unknown compounds with a p-quinone methide (p-QM) structure. The formation of these p-QMs using 13C-labelled starting materials revealed [...] Read more.
The reactions of phenylglyoxylic acids during the synthesis and biological evaluation of fungal metabolites led to the discovery of hitherto unknown compounds with a p-quinone methide (p-QM) structure. The formation of these p-QMs using 13C-labelled starting materials revealed a key-step of this reaction being a retro-Friedel–Crafts alkylation. Full article
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14 pages, 14093 KiB  
Article
Comparison of Molecular Recognition of Trimethyllysine and Trimethylthialysine by Epigenetic Reader Proteins
by Jordi C. J. Hintzen, Jordi Poater, Kiran Kumar, Abbas H. K. Al Temimi, Bas J. G. E. Pieters, Robert S. Paton, F. Matthias Bickelhaupt and Jasmin Mecinović
Molecules 2020, 25(8), 1918; https://doi.org/10.3390/molecules25081918 - 21 Apr 2020
Cited by 7 | Viewed by 3792
Abstract
Gaining a fundamental insight into the biomolecular recognition of posttranslationally modified histones by epigenetic reader proteins is of crucial importance to understanding the regulation of the activity of human genes. Here, we seek to establish whether trimethylthialysine, a simple trimethyllysine analogue generated through [...] Read more.
Gaining a fundamental insight into the biomolecular recognition of posttranslationally modified histones by epigenetic reader proteins is of crucial importance to understanding the regulation of the activity of human genes. Here, we seek to establish whether trimethylthialysine, a simple trimethyllysine analogue generated through cysteine alkylation, is a good trimethyllysine mimic for studies on molecular recognition by reader proteins. Histone peptides bearing trimethylthialysine and trimethyllysine were examined for binding with five human reader proteins employing a combination of thermodynamic analyses, molecular dynamics simulations and quantum chemical analyses. Collectively, our experimental and computational findings reveal that trimethylthialysine and trimethyllysine exhibit very similar binding characteristics for the association with human reader proteins, thereby justifying the use of trimethylthialysine for studies aimed at dissecting the origin of biomolecular recognition in epigenetic processes that play important roles in human health and disease. Full article
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14 pages, 6426 KiB  
Article
Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome
by Kaja Rožman, Evan M. Alexander, Eva Ogorevc, Krištof Bozovičar, Izidor Sosič, Courtney C. Aldrich and Stanislav Gobec
Molecules 2020, 25(6), 1305; https://doi.org/10.3390/molecules25061305 - 12 Mar 2020
Cited by 8 | Viewed by 3104
Abstract
Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this [...] Read more.
Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this study, we present a series of 92 psoralen derivatives, of which 15 displayed inhibitory potency against the Mycobacterium tuberculosis proteasome in low micromolar concentrations. The best inhibitors, i.e., 8, 11, 13 and 15, exhibited a mixed type of inhibition and overall good inhibitory potency in biochemical assays. N-(cyanomethyl)acetamide 8 (Ki = 5.6 µM) and carboxaldehyde-based derivative 15 (Ki = 14.9 µM) were shown to be reversible inhibitors of the enzyme. On the other hand, pyrrolidine-2,5-dione esters 11 and 13 irreversibly inhibited the enzyme with Ki values of 4.2 µM and 1.1 µM, respectively. In addition, we showed that an established immunoproteasome inhibitor, PR-957, is a noncompetitive irreversible inhibitor of the mycobacterial proteasome (Ki = 5.2 ± 1.9 µM, kinact/Ki = 96 ± 41 M−1·s−1). These compounds represent interesting hit compounds for further optimization in the development of new drugs for the treatment of tuberculosis. Full article
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10 pages, 923 KiB  
Article
Sulfonamide Inhibition Studies of the β-Class Carbonic Anhydrase CAS3 from the Filamentous Ascomycete Sordaria macrospora
by Daniela Vullo, Ronny Lehneck, William A. Donald, Stefanie Pöggeler and Claudiu T. Supuran
Molecules 2020, 25(5), 1036; https://doi.org/10.3390/molecules25051036 - 25 Feb 2020
Cited by 5 | Viewed by 2405
Abstract
A new β-class carbonic anhydrase was cloned and purified from the filamentous ascomycete Sordaria macrospora, CAS3. This enzyme has a higher catalytic activity compared to the other two such enzymes from this fungus, CAS1 and CAS2, which were reported earlier, with the following [...] Read more.
A new β-class carbonic anhydrase was cloned and purified from the filamentous ascomycete Sordaria macrospora, CAS3. This enzyme has a higher catalytic activity compared to the other two such enzymes from this fungus, CAS1 and CAS2, which were reported earlier, with the following kinetic parameters: kcat of (7.9 ± 0.2) × 105 s−1, and kcat/Km of (9.5 ± 0.12) × 107 M−1∙s−1. An inhibition study with a panel of sulfonamides and one sulfamate was also performed. The most effective CAS3 inhibitors were benzolamide, brinzolamide, dichlorophnamide, methazolamide, acetazolamide, ethoxzolamide, sulfanilamide, methanilamide, and benzene-1,3-disulfonamide, with KIs in the range of 54–95 nM. CAS3 generally shows a higher affinity for this class of inhibitors compared to CAS1 and CAS2. As S. macrospora is a model organism for the study of fruiting body development in fungi, these data may be useful for developing antifungal compounds based on CA inhibition. Full article
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