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Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen

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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 (30 June 2025) | Viewed by 8669

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Prof. Dr. Joachim Erich Thiem

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Department of Chemistry, Faculty of Science, University of Hamburg, Martin- Luther-King-Platz 6, Hamburg, Germany
Interests: synthetic carbohydrate chemistry; preparative chemoenzymatic synthesis; carbohydrates as chemical feedstock

Special Issue Information

Dear Colleagues,

This Special Issue of Molecules is dedicated to Professor Dr. Hans Paulsen for his contributions to the field of glycoscience.

Hans Paulsen, born on May 20, 1922 in Altona, was drafted after graduating from high school and conducted labor and military service until 1945. He returned to Hamburg seriously ill and was only able to start studying chemistry in 1948. After completing his Diploma, he received his doctorate in 1955 as Dr. rer. nat. from the University of Hamburg in the research group of Prof. Kurt Heyns. In 1962, he completed his Habilitation at the Faculty of Mathematics and Natural Sciences with the thesis "Monosaccharides with Nitrogen in the Ring".

From 1953 onwards, he was employed as Scientific Assistant in Heyns' group for teaching, researching, and planning tasks in the construction of the university's new chemistry center. In 1968, the Privatdozent was appointed University Professor. He did not follow the offer to fill a chair at the University of Kiel, but instead took up the newly created Professorship for Natural Product Chemistry in Hamburg, a position he held from 1972 until his retirement in 1987.

Hans Paulsen's scientific work lies at the heart of carbohydrate chemistry. Joint publications with his academic teacher Kurt Heyns dealt with the platinum-catalyzed oxidation of saccharides. Individual topics relating to the chemistry of carbohydrates with nitrogen in the hemiacetal ring later gained particular attention because such derivatives turned out to be extremely potent glycosidase inhibitors. Other research areas dealt with acyloxonium rearrangements in carbohydrate chemistry; phosphorus-containing saccharides; carbohydrates with branched functional chains; aminoglycoside antibiotics; and oligosaccharide, glycolipid, and O- and N-glycoprotein syntheses. Early on, Hans Paulsen recognized the impact of nuclear magnetic resonance spectroscopy (NMR) for structural assignments in organic chemistry and particularly complex saccharides; he purposefully expanded this technology in Hamburg. This enabled him to make important contributions to the conformations of monosaccharide and later oligosaccharide derivatives, as well as to the understanding of the exo-anomeric effect.

Hans Paulsen's scientific work, with more than 500 publications, has received some of the most prestigious national and international awards, including the Emil Fischer Medal, the Haworth Memorial Medal, the Claude S. Hudson Award, the Heyrovsky Medal, the Biyvoet Medal, and the Riken Eminent Scientist Award. Hans Paulsen has served as a co-Editor and a member of the Editorial Boards of numerous international journals. As one of the chief reviewers at the German Research Foundation, he helped shape the field of organic chemistry in Germany for many years.

Remarkably, behind this enormous impact stands a modest and reserved personality. Never loud but always with convincing detailed knowledge, he charismatically encouraged many young scientists to write their own articles. His withdrawn private lifestyle always became somewhat transparent when he reported enthusiastically, knowledgeably, and humorously with beautiful pictures about history, architecture, countries, and their people from numerous trips to all parts of the world.

We will remember Hans Paulsen as a great scientist and highly valued colleague.

It is with pleasure that we address all his colleagues and friends and ask for contributions to this Commemorative Special Issue dedicated to honoring his achievements in glycoscience.

Prof. Dr. Joachim Erich Thiem
Guest Editor

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Keywords

synthesis, chemical, enzymatic
glycosylation
mono-, di-, tri-, oligosaccharides
carbohydrate-based
modified carbohydrates
glycoconjugates

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Published Papers (11 papers)

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Research

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23 pages, 3157 KB

Open AccessArticle

Synthesis and Characterization of Glyco-SAMs on Gold Nanoparticles: A Modular Approach Towards Glycan-Based Recognition Studies

by Sebastian Kopitzki and Joachim Thiem

Molecules 2025, 30(18), 3765; https://doi.org/10.3390/molecules30183765 - 16 Sep 2025

Viewed by 326

Abstract

Within recent years, the interest in tools to investigate carbohydrate-protein (CPI) and carbohydrate-carbohydrate interactions (CCI) has increased significantly. For the investigation of CPI and CCI, several techniques employing different linking methods are available. For mimicking the glycocalyx self-assembled monolayer (SAM) formation of carbohydrate derivatives on gold nanoparticles is most appropriate. In contrast to methods for glyco-SAM formation used previously to analyze CPI/CCI, the novel approach allows for a facile and rapid synthesis to link spacers and carbohydrate derivatives and enhances the binding event by controlling the amount and orientation of ligand. For immobilization on biorepulsive aminooxy functionalized gold nanoparticles by oxime coupling, diverse aldehyde-functionalized glycan structures of mono-, di-, and complex trisaccharides were synthesized, employing several facile steps including olefin metathesis. Effective immobilization and first binding studies are presented for the lectin concanavalin A. This novel and advantageous immobilization method is presently employed in various biomimetic studies of carbohydrates and carbohydrate-based array development for diagnostics and screening. Full article

(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)

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16 pages, 1358 KB

Open AccessArticle

Characterization of Human Recombinant β1,4-GalNAc-Transferase B4GALNT1 and Inhibition by Selected Compounds

by Iram Abidi, Alexander N. Kocev, Jonathan L. Babulic, Chantelle J. Capicciotti, Jagdeep Walia and Inka Brockhausen

Molecules 2025, 30(17), 3615; https://doi.org/10.3390/molecules30173615 - 4 Sep 2025

Viewed by 1016

Abstract

Gangliosides are essential for membrane functions, cell recognition, and maintenance of the nervous system. GM2 gangliosidosis is a group of rare genetic lysosomal storage diseases that includes Tay-Sachs disease (TSD), Sandhoff disease (SD), and AB variant. TSD and SD are characterized by deficient β-N-acetyl-hexosaminidase activity. This leads to decreased catabolism of β-N-acetyl-hexosamine-containing ganglioside GM2 in the lysosomes, damage to cells and tissues, and severe neurological symptoms. GM2 is a major ganglioside accumulating in TSD and SD, and is synthesized from GM3 by β1,4-N-acetylgalactosaminyltransferase 1 (B4GALNT1, GM2 synthase). Therapies under development for GM2 gangliosidosis include adeno-associated virus gene therapy, enzyme replacement, and substrate reduction therapy (SRT). The goal of this work was to express and purify human B4GALNT1, characterize its activity, and explore its structural features by protein modeling and substrate docking. We used a panel of synthetic compounds to study their potential inhibition of B4GALNT1 activity. This work can serve to develop SRT for GM2 gangliosidosis. Full article

(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)

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16 pages, 990 KB

Open AccessArticle

Bivalent Inhibitors of Mannose-Specific Bacterial Adhesion: A Xylose-Based Conformational Switch to Control Glycoligand Distance

by Sven Ole Jaeschke, Ingo vom Sondern and Thisbe K. Lindhorst

Molecules 2025, 30(15), 3074; https://doi.org/10.3390/molecules30153074 - 23 Jul 2025

Viewed by 406

Abstract

Functional glycomimetics is suited to study the parameters of carbohydrate recognition that forms the basis of glycobiology. It is particularly attractive when a glycoligand allows for the investigation of two different states, such as varying distance between multiple glycoligands. Here, a xylopyranoside was employed as a scaffold for the presentation of two mannoside units which are ligands of the bacterial lectin FimH. The chair conformation of the central xyloside can be switched between a ⁴C₁ and a ¹C₄ conformation whereby the two conjugated mannoside ligands are flipped from a di-equatorial into a di-axial position. Concomitantly, the distance between the two glycoligands changes and, as a consequence, so does the biological activity of the respective bivalent glycocluster, as shown in adhesion–inhibition assays with live bacteria. Molecular modeling was employed to correlate the inter-ligand distance with the structure of the formed glycocluster–FimH complex. Our study suggests that conformational switches can be employed and further advanced as smart molecular tools to study structural boundary conditions of carbohydrate recognition in a bottom-up approach. Full article

(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)

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14 pages, 2831 KB

Open AccessArticle

Cooperatively Catalyzed Activation of Thioglycosides with Iodine and Iron(III) Trifluoromethanesulfonate

by Ashley R. Dent, Aidan M. DeSpain and Alexei V. Demchenko

Molecules 2025, 30(15), 3058; https://doi.org/10.3390/molecules30153058 - 22 Jul 2025

Viewed by 1071

Abstract

Reported herein is a further expansion of the cooperatively catalyzed Koenigs–Knorr glycosylation reaction, known as “the 4K reaction”. It has been discovered that molecular iodine, along with a metal salt and an acid additive, can activate thioglycosides. Previous mechanistic studies showed the interaction of the anomeric sulfur with thiophilic iodine; this complex is stable until the halophilic metal salt and the acid additive are added. This new avenue has allowed for the investigation of halophilic promoters that would not activate thioglycosides without iodine. Presented herein is the recent discovery of iron(III) triflate as an efficient activator of thioglycosides via the 4K reaction pathway. Full article

(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)

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16 pages, 1765 KB

Open AccessArticle

Towards Understanding the Basis of Brucella Antigen–Antibody Specificity

by Amika Sood, David R. Bundle and Robert J. Woods

Molecules 2025, 30(14), 2906; https://doi.org/10.3390/molecules30142906 - 9 Jul 2025

Viewed by 540

Abstract

Brucellosis continues to be a significant global zoonotic infection, with diagnosis largely relying on the detection of antibodies against the Brucella O-polysaccharide (O-PS) A and M antigens. In this study, computational methods, including homology modeling, molecular docking, and molecular dynamics simulations, were applied to investigate the interaction of the four murine monoclonal antibodies (mAbs) YsT9.1, YsT9.2, Bm10, and Bm28 with hexasaccharide fragments of the A and M epitopes. Through stringent stability criteria, based on interaction energies and mobility of the antigens, high-affinity binding of A antigen with YsT9.1 antibody and M antigen with Bm10 antibody was predicted. In both the complexes hydrophobic interactions dominate the antigen–antibody binding. These findings align well with experimental epitope mapping, indicating YsT9.1’s preference for internal sequences of the A epitope and Bm10’s preference for internal elements of the M epitope. Interestingly, no stable complexes were identified for YsT9.2 or Bm28 interacting with A or M antigen. This study provides valuable insights into the mechanism of molecular recognition of Brucella O-antigens that can be applied for the development of improved diagnostics, synthetic glycomimetics, and improved vaccine strategies. Full article

(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)

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16 pages, 556 KB

Open AccessFeature PaperArticle

Synthesis of Azide-Labeled β-Lactosylceramide Analogs Containing Different Lipid Chains as Useful Glycosphingolipid Probes

by Basant Mohamed, Rajendra Rohokale, Xin Yan, Amany M. Ghanim, Nermine A. Osman, Hanan A. Abdel-Fattah and Zhongwu Guo

Molecules 2025, 30(13), 2667; https://doi.org/10.3390/molecules30132667 - 20 Jun 2025

Viewed by 1265

Abstract

β-Lactosylceramide (β-LacCer) is not only a key intermediate in the biosynthesis of complex glycosphingolipids (GSLs) but also an important regulator of many biological processes. To facilitate the investigation of β-LacCer and other GSLs, a series of β-LacCer analogs with an azido group at the 6-C-position of the D-galactose in lactose and varied forms of the ceramide moiety were synthesized from commercially available lactose in sixteen linear steps by a versatile and diversity-oriented strategy, which engaged lipid remodeling and glycan functionalization at the final stage. These azide-labeled β-LacCer analogs are flexible and universal platforms that are suitable for further functionalization with other molecular tags via straightforward and biocompatible click chemistry, thereby paving the way for their application to various biological studies. Full article

(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)

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17 pages, 824 KB

Open AccessArticle

Total Synthesis of Cardenolides Acospectoside A and Acovenoside B

by Benzhang Liu, Peng Xu and Biao Yu

Molecules 2025, 30(11), 2297; https://doi.org/10.3390/molecules30112297 - 23 May 2025

Viewed by 572

Abstract

Acospectoside A (1) and acovenoside B (2), two cytotoxic cardenolides extracted from the venomous South African bush Acokanthera oppositifolia, are distinguished by their unique structural motifs of the l-acovenose moiety at C-3 and a 1β-O-acetylated cardenolide aglycone. Here, we report the synthesis of these cardiac glycosides featuring delicate introductions of the 1-O-acetyl group under acid-catalyzed conditions, 14β-OH by Mukaiyama hydration, and a C17-butenolide moiety by Stille coupling. Full article

(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)

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14 pages, 896 KB

Open AccessArticle

Chemical and Enzymatic Synthesis of DisialylGb5 and Other Sialosides for Glycan Array Assembly and Evaluation of Siglec-Mediated Immune Checkpoint Inhibition

by Kuo-Shiang Liao, Yixuan Zhou, Cinya Chung, Chih-Chuan Kung, Chien-Tai Ren, Chung-Yi Wu, Yi-Wei Lou, Po-Kai Chuang, Balázs Imre, Yves S. Y. Hsieh and Chi-Huey Wong

Molecules 2025, 30(11), 2264; https://doi.org/10.3390/molecules30112264 - 22 May 2025

Cited by 1 | Viewed by 1172

Abstract

Aberrant glycosylation, especially sialylation, on cell surface is often associated with cancer progression and immunosuppression. Over-sialylation of stage-specific embryonic antigen-4 (SSEA-4) to generate disialylGb5 (DSGb5) was reported to trigger Siglec-7 recognition and suppress NK-mediated target killing. In this study, efficient chemo-enzymatic and programmable one-pot methods were explored for the synthesis of DSGb5 and related sialosides for assembly of glycan microarrays and evaluation of binding specificity toward Siglecs-7, 9, 10, and 15 associated with immune checkpoint inhibition. The result showed weak binding of DSGb5 to these Siglecs; however, a truncated glycolyl glycan was identified to bind Siglec-10 strongly with a dissociation constant of 50 nM and exhibited a significant inhibition of Siglec-10 interacting with breast cancer cells. Full article

(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)

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Review

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29 pages, 1256 KB

Open AccessReview

Hans Paulsen: Contributions to the Investigations of Glycoprotein Biosynthesis

by Inka Brockhausen

Molecules 2025, 30(18), 3735; https://doi.org/10.3390/molecules30183735 - 14 Sep 2025

Viewed by 285

Abstract

Hans Paulsen was one of the first scientists who believed that chemistry should be applied to biology and medicine. His interest in natural products and their roles solidified in the 1970s. He passed on his knowledge to hundreds of students and coworkers and advanced science with many national and international collaborators. No matter where he was, at home or travelling, he was always curious and keen to learn, from chemistry to enzymes, their roles in diseases, and the possible applications of synthetic compounds. His creative chemistry and synthesis of novel compounds made essential contributions to elucidating the mechanisms and pathways of glycoprotein biosynthesis. This review describes the biosynthetic pathways of the O- and N-glycans of glycoproteins and studies of novel substrates and inhibitors developed by Hans Paulsen’s group. Full article

(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)

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63 pages, 6750 KB

Open AccessReview

Synthesis and Immunogenicity of Pseudo-Oligosaccharides Structurally Related to Repeating Units of Capsular Phosphoglycans of Human Pathogens

by Elena A. Khatuntseva, Anastasia A. Kamneva, Dmitry V. Yashunsky and Nikolay E. Nifantiev

Molecules 2025, 30(15), 3068; https://doi.org/10.3390/molecules30153068 - 22 Jul 2025

Viewed by 716

Abstract

This review focuses on the synthesis of spacer-armed phosphooligosaccharides structurally related to the capsular phosphoglycans of pathogenic bacteria, including the Haemophilus influenzae serotypes a, b, c, and f, Neisseria meningitidis serogroups a and x, the Streptococcus pneumoniae serotypes 6a, 6b, 6c, 6f, 19a, and 19f, and the Campylobacter jejuni serotype HS:53, strain RM1221, in which the phosphodiester linkage is a structural component of a phosphoglycan backbone. Also, in this review, we summarize the current knowledge on the preparation and immunogenicity of neoglycoconjugates based on synthetic phosphooligosaccharides. The discussed data helps evaluate the prospects for the development of conjugate vaccines on the basis of synthetic phosphooligosaccharide antigens. Full article

(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)

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12 pages, 3918 KB

Open AccessReview

Sucrose-Based Macrocycles: An Update

by Sławomir Jarosz and Zbigniew Pakulski

Molecules 2025, 30(13), 2721; https://doi.org/10.3390/molecules30132721 - 24 Jun 2025

Viewed by 604

Abstract

Sucrose is by far the most abundant disaccharide found in nature, consisting of two simple hexose units: d-glucose and d-fructose. This exceptionally inexpensive and widely accessible raw material is produced in virtually limitless quantities. The vast majority is consumed in the food industry either in its native form—as commercial table sugar—or, to a lesser extent, as the basis for artificial sweeteners such as palatinose and sucralose. Beyond its dietary use, sucrose serves as a feedstock for the production of bioethanol, liquid crystals, biodegradable surfactants, and polymers. However, the application of this valuable and extremely cheap raw material (100% optical purity and eight stereogenic centers with precisely defined stereochemistry) in the synthesis of more sophisticated products remains surprisingly limited. In this short review, we focus on the strategic use of the sucrose scaffold in the design and synthesis of fine chemicals. Special attention will be paid to macrocyclic derivatives incorporating the sucrose backbone. These water-soluble structures show promise as molecular receptors within biological environments, offering unique advantages in terms of solubility, biocompatibility, and stereochemical precision. Full article

(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)

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