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16 pages, 2893 KiB

Open AccessArticle

Cancer Vaccines Based on Fluorine-Modified KH-1 Elicit Robust Immune Response

by Yang Liu, Bohan Li, Xiujing Zheng, Decai Xiong and Xinshan Ye

Molecules 2023, 28(4), 1934; https://doi.org/10.3390/molecules28041934 - 17 Feb 2023

Cited by 2 | Viewed by 2157

Abstract

KH-1 is a tumor-associated carbohydrate antigen (TACA), which serves as a valuable target of antitumor vaccines for cancer immunotherapies. However, most TACAs are thymus-independent antigens (TD-Ag), and they tend to induce immunological tolerance, leading to their low immunogenicity. To overcome these problems, some [...] Read more.

KH-1 is a tumor-associated carbohydrate antigen (TACA), which serves as a valuable target of antitumor vaccines for cancer immunotherapies. However, most TACAs are thymus-independent antigens (TD-Ag), and they tend to induce immunological tolerance, leading to their low immunogenicity. To overcome these problems, some fluorinated derivatives of the KH-1 antigen were designed, synthesized, and conjugated to the carrier protein CRM197 to form glycoconjugates, which were used for immunological studies with Freund’s adjuvant. The results showed that fluorine-modified N-acyl KH-1 conjugates can induce higher titers of antibodies, especially IgG, which can recognize KH-1-positive cancer cells and can eliminate cancer cells through complement-dependent cytotoxicity (CDC). The trifluoro-modified KH-1-TF-CRM197 showed great potential as an anticancer vaccine candidate. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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14 pages, 2170 KiB

Open AccessArticle

Kukhtin–Ramirez-Reaction-Inspired Deprotection of Sulfamidates for the Synthesis of Amino Sugars

by Ting Li, Bingbing Xu, Dengxian Fu, Qian Wan and Jing Zeng

Molecules 2023, 28(1), 182; https://doi.org/10.3390/molecules28010182 - 25 Dec 2022

Viewed by 2474

Abstract

Herein, we present a mild strategy for deprotecting cyclic sulfamidates via the Kukhtin–Ramirez reaction to access amino sugars. The method features the removal of the sulfonic group of cyclic sulfamidates, which occurs through an N-H insertion reaction that implicates the Kukhtin–Ramirez adducts, followed [...] Read more.

Herein, we present a mild strategy for deprotecting cyclic sulfamidates via the Kukhtin–Ramirez reaction to access amino sugars. The method features the removal of the sulfonic group of cyclic sulfamidates, which occurs through an N-H insertion reaction that implicates the Kukhtin–Ramirez adducts, followed by a base-promoted reductive N-S bond cleavage. The mild reaction conditions of the protocol enable the formation of amino alcohols including analogs that bear multiple functional groups. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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13 pages, 1555 KiB

Open AccessCommunication

Stereoselective Synthesis of 2-Deoxythiosugars from Glycals

by Xueying You, Yifei Cai, Chenyu Xiao, Lijuan Ma, Yong Wei, Tianpeng Xie, Lei Chen and Hui Yao

Molecules 2022, 27(22), 7979; https://doi.org/10.3390/molecules27227979 - 17 Nov 2022

Cited by 6 | Viewed by 2109

Abstract

2-deoxythiosugars are more stable than 2-deoxysugars occurring broadly in bioactive natural products and pharmaceutical agents. An effective and direct methodology to stereoselectively synthesize α-2-deoxythioglycosides catalyzed by AgOTf has been developed. Various alkyl thiols and thiophenols were explored and the desired products were formed [...] Read more.

2-deoxythiosugars are more stable than 2-deoxysugars occurring broadly in bioactive natural products and pharmaceutical agents. An effective and direct methodology to stereoselectively synthesize α-2-deoxythioglycosides catalyzed by AgOTf has been developed. Various alkyl thiols and thiophenols were explored and the desired products were formed in good yields with excellent α-selectivity. This method was further applied to the syntheses of S-linked disaccharides and late-stage 2-deoxyglycosylation of estrogen, L-menthol, and zingerone thiols successfully. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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13 pages, 2369 KiB

Open AccessArticle

Design, Synthesis, and Bioassay of 2′-Modified Kanamycin A

by Ribai Yan, Xiaonan Li, Yuheng Liu and Xinshan Ye

Molecules 2022, 27(21), 7482; https://doi.org/10.3390/molecules27217482 - 2 Nov 2022

Cited by 1 | Viewed by 1827

Abstract

Chemical modification of old drugs is an important way to obtain new ones, and it has been widely used in developing new aminoglycoside antibiotics. However, many of the previous modifying strategies seem arbitrary for their lack of support from structural biological detail. In [...] Read more.

Chemical modification of old drugs is an important way to obtain new ones, and it has been widely used in developing new aminoglycoside antibiotics. However, many of the previous modifying strategies seem arbitrary for their lack of support from structural biological detail. In this paper, based on the structural information of aminoglycoside and its drug target, we firstly analyzed the reason that some 2′-N-acetylated products of aminoglycosides caused by aminoglycoside-modifying enzyme AAC(2′) can partially retain activity, and then we designed, synthesized, and evaluated a series of 2′-modified kanamycin A derivatives. Bioassay results showed our modifying strategy was feasible. Our study provided valuable structure–activity relationship information, which would help researchers to develop new aminoglycoside antibiotics more effectively. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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11 pages, 1382 KiB

Open AccessCommunication

Acid Catalyzed Stereocontrolled Ferrier-Type Glycosylation Assisted by Perfluorinated Solvent

by Zhiqiang Lu, Yanzhi Li, Shaohua Xiang, Mengke Zuo, Yangxing Sun, Xingxing Jiang, Rongkai Jiao, Yinghong Wang and Yuqin Fu

Molecules 2022, 27(21), 7234; https://doi.org/10.3390/molecules27217234 - 25 Oct 2022

Viewed by 1731

Abstract

Described herein is the first application of perfluorinated solvent in the stereoselective formation of O-/S-glycosidic linkages that occurs via a Ferrier rearrangement of acetylated glycals. In this system, the weak interactions between perfluoro-n-hexane and substrates could augment the [...] Read more.

Described herein is the first application of perfluorinated solvent in the stereoselective formation of O-/S-glycosidic linkages that occurs via a Ferrier rearrangement of acetylated glycals. In this system, the weak interactions between perfluoro-n-hexane and substrates could augment the reactivity and stereocontrol. The initiation of transformation requires only an extremely low loading of resin-H⁺ and the mild conditions enable the accommodation of a broad spectrum of glycal donors and acceptors. The ‘green’ feature of this chemistry is demonstrated by low toxicity and easy recovery of the medium, as well as operational simplicity in product isolation. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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16 pages, 2942 KiB

Open AccessArticle

Detailed Structural Analysis of the Immunoregulatory Polysaccharides from the Mycobacterium Bovis BCG

by Lan Luo, Xuemei Song, Xiao Chang, Sheng Huang, Yunxi Zhou, Shengmei Yang, Yan Zhu, Lanyan Zhang, Yongsheng Wu, Junyin Zhang, Zhipeng Zhou and Mingyi Wu

Molecules 2022, 27(17), 5691; https://doi.org/10.3390/molecules27175691 - 3 Sep 2022

Cited by 3 | Viewed by 2019

Abstract

Bacillus Calmette-Guérin polysaccharide and nucleic acid (BCG-PSN), extracted from Mycobacterium bovis, is an immunoregulatory medicine commonly used in clinic. However, the structural characteristics and potential pharmacological efficacy of the polysaccharides from BCG-PSN remain unclear. Herein, two polysaccharides (BCG-1 and BCG-2) were purified [...] Read more.

Bacillus Calmette-Guérin polysaccharide and nucleic acid (BCG-PSN), extracted from Mycobacterium bovis, is an immunoregulatory medicine commonly used in clinic. However, the structural characteristics and potential pharmacological efficacy of the polysaccharides from BCG-PSN remain unclear. Herein, two polysaccharides (BCG-1 and BCG-2) were purified and their structures were characterized. Monosaccharide composition analysis combined with methylation analysis and NMR data indicated that BCG-1 and BCG-2 were an α-D-(1→4)-mannan with (1→2)-linked branches, and an α-D-(1→4)-glucan with (1→6)-linked branches, respectively. Herein, the mannan from BCG-PSN was first reported. Bioactivity assays showed that BCG-1 and BCG-2 dose-dependently and potently increased the production of inflammatory mediators (NO, TNF-α, IL-6, IL-1β, and IL-10), as well as their mRNA expressions in RAW264.7 cells; both have similar or stronger effects compared with BCG-PSN injection. These data suggest that BCG-1 and BCG-2 are very likely the active ingredients of BCG-PSN. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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19 pages, 5233 KiB

Open AccessArticle

Hyaluronic Acid Oligosaccharide Derivatives Alleviate Lipopolysaccharide-Induced Inflammation in ATDC5 Cells by Multiple Mechanisms

by Hesuyuan Huang, Xuyang Ding, Dan Xing, Jianjing Lin, Zhongtang Li and Jianhao Lin

Molecules 2022, 27(17), 5619; https://doi.org/10.3390/molecules27175619 - 31 Aug 2022

Cited by 4 | Viewed by 2704

Abstract

High molecular weight hyaluronic acids (HMW-HAs) have been used for the palliative treatment of osteoarthritis (OA) for decades, but the pharmacological activity of HA fragments has not been fully explored due to the limited availability of structurally defined HA fragments. In this study, [...] Read more.

High molecular weight hyaluronic acids (HMW-HAs) have been used for the palliative treatment of osteoarthritis (OA) for decades, but the pharmacological activity of HA fragments has not been fully explored due to the limited availability of structurally defined HA fragments. In this study, we synthesized a series glycosides of oligosaccharides of HA (o-HAs), hereinafter collectively referred to as o-HA derivatives. Their effects on OA progression were examined in a chondrocyte inflammatory model established by the lipopolysaccharide (LPS)-challenged ATDC5 cells. Cell Counting Kit-8 (CCK-8) assays and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) showed that o-HA derivatives (≤100 μg/mL) exhibited no cytotoxicity and pro-inflammatory effects. We found that the o-HA and o-HA derivatives alleviated LPS-induced inflammation, apoptosis, autophagy and proliferation-inhibition of ATDC5 cells, similar to the activities of HMW-HAs. Moreover, Western blot analysis showed that different HA derivatives selectively reversed the effects of LPS on the expression of extracellular matrix (ECM)-related proteins (MMP13, COL2A1 and Aggrecan) in ATDC5 cells. Our study suggested that o-HA derivatives may alleviate LPS-induced chondrocyte injury by reducing the inflammatory response, maintaining cell proliferation, inhibiting apoptosis and autophagy, and decreasing ECM degradation, supporting a potential oligosaccharides-mediated therapy for OA. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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20 pages, 4040 KiB

Open AccessArticle

Critical Quality Control Methods for a Novel Anticoagulant Candidate LFG-Na by HPSEC-MALLS-RID and Bioactivity Assays

by Shunliang Zheng, Yi Wang, Jiashuo Wu, Siyao Wang, Huaifu Wei, Yongchun Zhang, Jianbo Zhou and Yue Shi

Molecules 2022, 27(14), 4522; https://doi.org/10.3390/molecules27144522 - 15 Jul 2022

Cited by 5 | Viewed by 1776

Abstract

A low molecular weight fucosylated glycosaminoglycan sodium (LFG-Na) is a novel anticoagulant candidate from the sea cucumber Holothuria fuscopunctata that selectively inhibits intrinsic tenase (iXase). The molecular weight, molecular weight distribution and bioactivities are the critical quality attributes of LFG-Na. The determination of [...] Read more.

A low molecular weight fucosylated glycosaminoglycan sodium (LFG-Na) is a novel anticoagulant candidate from the sea cucumber Holothuria fuscopunctata that selectively inhibits intrinsic tenase (iXase). The molecular weight, molecular weight distribution and bioactivities are the critical quality attributes of LFG-Na. The determination of these quality attributes of such an oligosaccharides mixture drug is challenging but critical for the quality control process to ensure its safety and efficacy in clinical use. Herein, the molecular weight and molecular weight distribution of LFG-Na were successfully determined using high performance size exclusion chromatography coupled with multi angle laser light scattering and refractive index detector (HPSEC-MALLS-RID). Comparing to the conventional method, HPSEC-MALLS-RID based on the refractive index increment (dn/dc) did not require the reference substances to establish the calibration curve. The acceptance criteria of LFG-Na were established, the weight-average molecular weight (

M_{w}

) should be 4000 to 6000 Da, the polydispersity (

M_{w}

/

M_{n}

) < 1.40, and the fraction with molecular weights of 1500 to 8000 Da should be no less than 80% of the total. HPSEC-MALLS-RID was also utilized for the determination of the starting material native fucosylated glycosaminoglycan (NFG) to choose a better manufacturing process. Furthermore, APTT assay was selected and the potency of anti-iXase, referring to the parallel line assay (PLA) method, was established to clarify the consistency of its biological activities. The results suggest that HPSEC-MALLS-RID and bioactivity assays are critical quality control methods for multi-component glycosaminoglycan LFG-Na. The methods also provide a feasible strategy to control the quality of other polysaccharide medicines. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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21 pages, 3506 KiB

Open AccessArticle

Synthesis, Biological Evaluation and Docking Studies of Ring-Opened Analogues of Ipomoeassin F

by Sarah O’Keefe, Pratiti Bhadra, Kwabena B. Duah, Guanghui Zong, Levise Tenay, Lauren Andrews, Hayden Schneider, Ashley Anderson, Zhijian Hu, Hazim S. Aljewari, Belinda S. Hall, Rachel E. Simmonds, Volkhard Helms, Stephen High and Wei Q. Shi

Molecules 2022, 27(14), 4419; https://doi.org/10.3390/molecules27144419 - 10 Jul 2022

Cited by 1 | Viewed by 3272

Abstract

The plant-derived macrocyclic resin glycoside ipomoeassin F (Ipom-F) binds to Sec61α and significantly disrupts multiple aspects of Sec61-mediated protein biogenesis at the endoplasmic reticulum, ultimately leading to cell death. However, extensive assessment of Ipom-F as a molecular tool and a therapeutic lead is [...] Read more.

The plant-derived macrocyclic resin glycoside ipomoeassin F (Ipom-F) binds to Sec61α and significantly disrupts multiple aspects of Sec61-mediated protein biogenesis at the endoplasmic reticulum, ultimately leading to cell death. However, extensive assessment of Ipom-F as a molecular tool and a therapeutic lead is hampered by its limited production scale, largely caused by intramolecular assembly of the macrocyclic ring. Here, using in vitro and/or in cellula biological assays to explore the first series of ring-opened analogues for the ipomoeassins, and indeed all resin glycosides, we provide clear evidence that macrocyclic integrity is not required for the cytotoxic inhibition of Sec61-dependent protein translocation by Ipom-F. Furthermore, our modeling suggests that open-chain analogues of Ipom-F can interact with multiple sites on the Sec61α subunit, most likely located at a previously identified binding site for mycolactone and/or the so-called lateral gate. Subsequent in silico-aided design led to the discovery of the stereochemically simplified analogue 3 as a potent, alternative lead compound that could be synthesized much more efficiently than Ipom-F and will accelerate future ipomoeassin research in chemical biology and drug discovery. Our work may also inspire further exploration of ring-opened analogues of other resin glycosides. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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13 pages, 3151 KiB

Open AccessArticle

High Expression Level of α2-3-Linked Sialic Acids on Salivary Glycoproteins of Breastfeeding Women May Help to Protect Them from Avian Influenza Virus Infection

by Li Ding, Yimin Cheng, Wei Guo, Siyue Sun, Xiangqin Chen, Tiantian Zhang, Hongwei Cheng, Jiayue Hao, Yunhua Lu, Xiurong Wang and Zheng Li

Molecules 2022, 27(13), 4285; https://doi.org/10.3390/molecules27134285 - 3 Jul 2022

Cited by 1 | Viewed by 2089

Abstract

Terminal sialic acids (Sia) on soluble glycoprotein of saliva play an important role in the clearance of influenza virus. The aim of this study is to investigate the alteration of sialylation on the salivary proteins of women during the lactation period and its [...] Read more.

Terminal sialic acids (Sia) on soluble glycoprotein of saliva play an important role in the clearance of influenza virus. The aim of this study is to investigate the alteration of sialylation on the salivary proteins of women during the lactation period and its effect on the saliva binding ability to virus. In total, 210 saliva samples from postpartum women with and without breastfeeding were collected, and the expression level of α2-3/6-linked Sia on the whole salivary proteins and specific glycoproteins of IgA and MUC5B from different groups were tested and verified using lectin microarray, blotting analysis and ELISA based method. The H1N1 vaccine and three strains of Avian influenza virus (AIV) were used for the saliva binding assay. Results showed that the variation in salivary expression level of α2-3-linked Sia was much more obvious than the α2-6-linked Sia, which was up-regulated significantly in the breastfeeding groups compared to the non-breastfeeding groups at the same postpartum stage. Furthermore, the binding abilities of salivary glycoproteins to AIV strains and H1N1 vaccine were increased in breastfeeding groups accordingly. This finding adds new evidence for the maternal benefit of breastfeeding and provides new thinking to protect postpartum women from AIV infection. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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14 pages, 4649 KiB

Open AccessArticle

Inhibition of Metastatic Hepatocarcinoma by Combined Chemotherapy with Silencing VEGF/VEGFR2 Genes through a GalNAc-Modified Integrated Therapeutic System

by Xunan Li, Xiang Wang, Nian Liu, Qiuyu Wang and Jing Hu

Molecules 2022, 27(7), 2082; https://doi.org/10.3390/molecules27072082 - 24 Mar 2022

Cited by 5 | Viewed by 2705

Abstract

Hepatocellular carcinoma (HCC) is a highly malignant tumor related to high mortality and is still lacking a satisfactory cure. Tumor metastasis is currently a major challenge of cancer treatment, which is highly related to angiogenesis. The vascular endothelial growth factor (VEGF)/VEGFR signaling pathway [...] Read more.

Hepatocellular carcinoma (HCC) is a highly malignant tumor related to high mortality and is still lacking a satisfactory cure. Tumor metastasis is currently a major challenge of cancer treatment, which is highly related to angiogenesis. The vascular endothelial growth factor (VEGF)/VEGFR signaling pathway is thus becoming an attractive therapeutic target. Moreover, chemotherapy combined with gene therapy shows great synergistic potential in cancer treatment with the promise of nanomaterials. In this work, a formulation containing 5-FU and siRNA against the VEGF/VEGFR signaling pathway into N-acetyl-galactosamine (GalNAc)-modified nanocarriers is established. The targeting ability, biocompatibility and pH-responsive degradation capacity ensure the efficient transport of therapeutics by the formulation of 5-FU/siRNA@GalNAc-pDMA to HCC cells. The nano-construct integrated with gene/chemotherapy exhibits significant anti-metastatic HCC activity against C5WN1 liver cancer cells with tumorigenicity and pulmonary metastasis in the C5WN1-induced tumor-bearing mouse model with a tumor inhibition rate of 96%, which is promising for future metastatic HCC treatment. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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Review

Jump to: Research

10 pages, 1930 KiB

Open AccessReview

Impact of N-Linked Glycosylation on Therapeutic Proteins

by Baoquan Chen, Wenqiang Liu, Yaohao Li, Bo Ma, Shiying Shang and Zhongping Tan

Molecules 2022, 27(24), 8859; https://doi.org/10.3390/molecules27248859 - 13 Dec 2022

Cited by 14 | Viewed by 4822

Abstract

Therapeutic proteins have unique advantages over small-molecule drugs in the treatment of various diseases, such as higher target specificity, stronger pharmacological efficacy and relatively low side effects. These advantages make them increasingly valued in drug development and clinical practice. However, although highly valued, [...] Read more.

Therapeutic proteins have unique advantages over small-molecule drugs in the treatment of various diseases, such as higher target specificity, stronger pharmacological efficacy and relatively low side effects. These advantages make them increasingly valued in drug development and clinical practice. However, although highly valued, the intrinsic limitations in their physical, chemical and pharmacological properties often restrict their wider applications. As one of the most important post-translational modifications, glycosylation has been shown to exert positive effects on many properties of proteins, including molecular stability, and pharmacodynamic and pharmacokinetic characteristics. Glycoengineering, which involves changing the glycosylation patterns of proteins, is therefore expected to be an effective means of overcoming the problems of therapeutic proteins. In this review, we summarize recent efforts and advances in the glycoengineering of erythropoietin and IgG monoclonal antibodies, with the goals of illustrating the importance of this strategy in improving the performance of therapeutic proteins and providing a brief overview of how glycoengineering is applied to protein-based drugs. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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19 pages, 2518 KiB

Open AccessReview

An Overview of Antitumour Activity of Polysaccharides

by Hongzhen Jin, Maohua Li, Feng Tian, Fan Yu and Wei Zhao

Molecules 2022, 27(22), 8083; https://doi.org/10.3390/molecules27228083 - 21 Nov 2022

Cited by 15 | Viewed by 3703

Abstract

Cancer incidence and mortality are rapidly increasing worldwide; therefore, effective therapies are required in the current scenario of increasing cancer cases. Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties, and they have become the focus of current [...] Read more.

Cancer incidence and mortality are rapidly increasing worldwide; therefore, effective therapies are required in the current scenario of increasing cancer cases. Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties, and they have become the focus of current antitumour drug research owing to their significant antitumour effects. In addition to the direct antitumour activity of some natural polysaccharides, their structures offer versatility in synthesizing multifunctional nanocomposites, which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues. This review aims to highlight recent advances in natural polysaccharides and polysaccharide-based nanomedicines for cancer therapy. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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15 pages, 1210 KiB

Open AccessReview

Recent Research and Application Prospect of Functional Oligosaccharides on Intestinal Disease Treatment

by Tong Xu, Ruijie Sun, Yuchen Zhang, Chen Zhang, Yujing Wang, Zhuo A. Wang and Yuguang Du

Molecules 2022, 27(21), 7622; https://doi.org/10.3390/molecules27217622 - 7 Nov 2022

Cited by 6 | Viewed by 3505

Abstract

The intestinal tract is an essential digestive organ of the human body, and damage to the intestinal barrier will lead to various diseases. Functional oligosaccharides are carbohydrates with a low degree of polymerization and exhibit beneficial effects on human intestinal health. Laboratory experiments [...] Read more.

The intestinal tract is an essential digestive organ of the human body, and damage to the intestinal barrier will lead to various diseases. Functional oligosaccharides are carbohydrates with a low degree of polymerization and exhibit beneficial effects on human intestinal health. Laboratory experiments and clinical studies indicate that functional oligosaccharides repair the damaged intestinal tract and maintain intestinal homeostasis by regulating intestinal barrier function, immune response, and intestinal microbial composition. Functional oligosaccharides treat intestinal disease such as inflammatory bowel disease (IBD) and colorectal cancer (CRC) and have excellent prospects for therapeutic application. Here, we present an overview of the recent research into the effects of functional oligosaccharides on intestinal health. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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25 pages, 6899 KiB

Open AccessReview

Recent Advances on Natural Aryl-C-glycoside Scaffolds: Structure, Bioactivities, and Synthesis—A Comprehensive Review

by Chen-Fu Liu

Molecules 2022, 27(21), 7439; https://doi.org/10.3390/molecules27217439 - 1 Nov 2022

Cited by 19 | Viewed by 4001

Abstract

Aryl-C-glycosides, of both synthetic and natural origin, are of great significance in medicinal chemistry owing to their unique structures and stability towards enzymatic and chemical hydrolysis as compared to O-glycosides. They are well-known antibiotics and potent enzyme inhibitors and possess [...] Read more.

Aryl-C-glycosides, of both synthetic and natural origin, are of great significance in medicinal chemistry owing to their unique structures and stability towards enzymatic and chemical hydrolysis as compared to O-glycosides. They are well-known antibiotics and potent enzyme inhibitors and possess a wide range of biological activities such as anticancer, antioxidant, antiviral, hypoglycemic effects, and so on. Currently, a number of aryl-C-glycoside drugs are on sale for the treatment of diabetes and related complications. This review summarizes the findings on aryl-C-glycoside scaffolds over the past 20 years, concerning new structures (over 200 molecules), their bioactivities—including anticancer, anti-inflammatory, antioxidant, antivirus, glycation inhibitory activities and other pharmacological effects—as well as their synthesis. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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13 pages, 1212 KiB

Open AccessReview

Not Just Anticoagulation—New and Old Applications of Heparin

by Lixuan Zang, Haomiao Zhu, Kun Wang, Yonghui Liu, Fan Yu and Wei Zhao

Molecules 2022, 27(20), 6968; https://doi.org/10.3390/molecules27206968 - 17 Oct 2022

Cited by 12 | Viewed by 6249

Abstract

In recent decades, heparin, as the most important anticoagulant drug, has been widely used in clinical settings to prevent and treat thrombosis in a variety of diseases. However, with in-depth research, the therapeutic potential of heparin is being explored beyond anticoagulation. To date, [...] Read more.

In recent decades, heparin, as the most important anticoagulant drug, has been widely used in clinical settings to prevent and treat thrombosis in a variety of diseases. However, with in-depth research, the therapeutic potential of heparin is being explored beyond anticoagulation. To date, heparin and its derivatives have been tested in the protection against and repair of inflammatory, antitumor, and cardiovascular diseases. It has also been explored as an antiangiogenic, preventive, and antiviral agent for atherosclerosis. This review focused on the new and old applications of heparin and discussed the potential mechanisms explaining the biological diversity of heparin. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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30 pages, 6804 KiB

Open AccessReview

Multivalent Pyrrolidine Iminosugars: Synthesis and Biological Relevance

by Yali Wang, Jian Xiao, Aiguo Meng and Chunyan Liu

Molecules 2022, 27(17), 5420; https://doi.org/10.3390/molecules27175420 - 24 Aug 2022

Cited by 3 | Viewed by 2440

Abstract

Recently, the strategy of multivalency has been widely employed to design glycosidase inhibitors, as glycomimetic clusters often induce marked enzyme inhibition relative to monovalent analogs. Polyhydroxylated pyrrolidines, one of the most studied classes of iminosugars, are an attractive moiety due to their potent [...] Read more.

Recently, the strategy of multivalency has been widely employed to design glycosidase inhibitors, as glycomimetic clusters often induce marked enzyme inhibition relative to monovalent analogs. Polyhydroxylated pyrrolidines, one of the most studied classes of iminosugars, are an attractive moiety due to their potent and specific inhibition of glycosidases and glycosyltransferases, which are associated with many crucial biological processes. The development of multivalent pyrrolidine derivatives as glycosidase inhibitors has resulted in several promising compounds that stand out. Herein, we comprehensively summarized the different synthetic approaches to the preparation of multivalent pyrrolidine clusters, from total synthesis of divalent iminosugars to complex architectures bearing twelve pyrrolidine motifs. Enzyme inhibitory properties and multivalent effects of these synthesized iminosugars were further discussed, especially for some less studied therapeutically relevant enzymes. We envision that this comprehensive review will help extend the applications of multivalent pyrrolidine iminosugars in future studies. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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20 pages, 4726 KiB

Open AccessReview

Rhamnose-Containing Compounds: Biosynthesis and Applications

by Siqiang Li, Fujia Chen, Yun Li, Lizhen Wang, Hongyan Li, Guofeng Gu and Enzhong Li

Molecules 2022, 27(16), 5315; https://doi.org/10.3390/molecules27165315 - 20 Aug 2022

Cited by 13 | Viewed by 4350

Abstract

Rhamnose-associated molecules are attracting attention because they are present in bacteria but not mammals, making them potentially useful as antibacterial agents. Additionally, they are also valuable for tumor immunotherapy. Thus, studies on the functions and biosynthetic pathways of rhamnose-containing compounds are in progress. [...] Read more.

Rhamnose-associated molecules are attracting attention because they are present in bacteria but not mammals, making them potentially useful as antibacterial agents. Additionally, they are also valuable for tumor immunotherapy. Thus, studies on the functions and biosynthetic pathways of rhamnose-containing compounds are in progress. In this paper, studies on the biosynthetic pathways of three rhamnose donors, i.e., deoxythymidinediphosphate-L-rhamnose (dTDP-Rha), uridine diphosphate-rhamnose (UDP-Rha), and guanosine diphosphate rhamnose (GDP-Rha), are firstly reviewed, together with the functions and crystal structures of those associated enzymes. Among them, dTDP-Rha is the most common rhamnose donor, and four enzymes, including glucose-1-phosphate thymidylyltransferase RmlA, dTDP-Glc-4,6-dehydratase RmlB, dTDP-4-keto-6-deoxy-Glc-3,5-epimerase RmlC, and dTDP-4-keto-Rha reductase RmlD, are involved in its biosynthesis. Secondly, several known rhamnosyltransferases from Geobacillus stearothermophilus, Saccharopolyspora spinosa, Mycobacterium tuberculosis, Pseudomonas aeruginosa, and Streptococcus pneumoniae are discussed. In these studies, however, the functions of rhamnosyltransferases were verified by employing gene knockout and radiolabeled substrates, which were almost impossible to obtain and characterize the products of enzymatic reactions. Finally, the application of rhamnose-containing compounds in disease treatments is briefly described. Full article

(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)

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