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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 40157

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Prof. Dr. Ivo Piantanida

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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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Prof. Dr. René Csuk

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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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Prof. Dr. Claus Jacob

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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
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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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16 pages, 7066 KiB

Open AccessCommunication

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 - 6 Apr 2021

Cited by 11 | Viewed by 3740

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 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 pK_a values from a variety of theoretical methods indicated that the SMD_BONDI 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

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules)

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18 pages, 3481 KiB

Open AccessArticle

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 5 | Viewed by 3646

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, 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

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules)

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23 pages, 5437 KiB

Open AccessArticle

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 - 2 Oct 2020

Cited by 3 | Viewed by 2686

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 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

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules)

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17 pages, 3454 KiB

Open AccessArticle

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 9 | Viewed by 3182

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, 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

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules)

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17 pages, 3305 KiB

Open AccessArticle

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 - 7 Jul 2020

Cited by 7 | Viewed by 4785

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 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

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules)

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21 pages, 4547 KiB

Open AccessArticle

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 15 | Viewed by 3718

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 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 Tau^4RD, 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 Tau^4RD/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 Tau^4RD and of α-synuclein. Conclusions: This study describes the reciprocal influence that Tau^4RD and fatty acids exert on their conformational states, contributing to our understanding of fundamental aspects of Tau/lipid co-assembly. Full article

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules)

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18 pages, 3443 KiB

Open AccessArticle

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 - 7 May 2020

Cited by 10 | Viewed by 3412

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 (λ_max = 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 λ_max = 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

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules)

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15 pages, 2066 KiB

Open AccessArticle

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 2574

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.

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules)

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14 pages, 14093 KiB

Open AccessArticle

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 9 | Viewed by 4383

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 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

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules)

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14 pages, 6426 KiB

Open AccessArticle

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 10 | Viewed by 3588

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 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 (K_i = 5.6 µM) and carboxaldehyde-based derivative 15 (K_i = 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 K_i 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 (K_i = 5.2 ± 1.9 µM, k_inact/K_i = 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

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules)

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10 pages, 923 KiB

Open AccessFeature PaperArticle

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 2823

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 kinetic parameters: k_cat of (7.9 ± 0.2) × 10⁵ s⁻¹, and k_cat/K_m 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 K_Is 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

(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members (EBMs) of the Bioorganic Chemistry Section of Molecules)

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