Recent advances on the one-pot synthesis to assemble size-controlled glycans and glycoconjugates and polysaccharides

Highlights

• Homogeneous glycans are important for the development of carbohydrate-based drugs.

• One-pot synthesis represents the fastest strategy for glycan assembly.

• One-pot synthesis of glycans and oligosaccharides by chemical and enzymatic methods were discussed.

• Provides representative synthetic examples in detail.

Abstract

Glycans and glycoconjugates in nature include macromolecules with important biological activities and widely distributed in all living organisms. These oligosaccharides and polysaccharides play important roles in a variety of normal physiological and pathological processes, such as cell metastasis, signal transduction, intercellular adhesion, inflammation, and immune response. However, the heterogeneity of naturally occurring glycans and glycoconjugates complicates detailed structure-activity relationship studies resulting in an incomplete understanding of their mechanisms of action and hindering further applications. Therefore, the synthesis of homogeneous, or nearly homogeneous, structurally defined glycans is of great significance for the development of carbohydrate-based drugs. One-pot synthesis represents the fastest strategy to assemble oligosaccharides and polysaccharides, although unfortunately, typically relies on random assembly. In this review, we examine the progress that has been made in the controlled one-pot synthesis of homogeneous or nearly homogeneous oligosaccharides and polysaccharides providing a broad spectrum of options to access size-controlled glycan products.

Introduction

Carbohydrates, the most abundant class of natural products, are polyhydroxyl aldehydes or polyhydroxyl ketones and their polycondensates and derivatives (Zhang & Ye, 2018). As one of the important class of biological macromolecules, polysaccharides are ubiquitously distributed in nature, present in all living organisms, including animals, plants and microbes (Liu, Willför, & Xu, 2015; Lovegrove et al., 2017; Qin et al., 2019). Moreover, carbohydrates are usually bound to lipids or proteins to form glycoconjugates such as glycolipids, glycoproteins and proteoglycans (Colombo, Pitirollo, & Lay, 2018; Lin, Qiao, Zhang, & Linhardt, 2020). These glycans and glycoconjugates play many critical roles, eliciting a myriad of key biological processes, involving viral and bacterial infection, cell signaling, cell proliferation and differentiation, angiogenesis and metastasis, immune-responses, and neurodegenerative diseases (Boltje, Buskas, & Boons, 2009; Ji, Li et al., 2020; Varki, 1993, 2017). For example, cell-surface glycans directly participate in a wide variety of biological recognition processes including cell adhesion, signaling, development, and the immune response (Dwek, 1996; Haltiwanger & Lowe, 2004; Jefferis, 2009; Macauley, Crocker, & Paulson, 2014; Nimmerjahn & Ravetch, 2008; Varki, 1993). SARS-CoV-2 infection has recently been reported to depend on cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2), suggesting that exogenous heparin presents potential therapeutic opportunities (Clausen et al., 2020; Kwon et al., 2020).

Polysaccharides generally have two properties associated with their homogeneity. Structural homogeneity refers to the presence of a single repeating unit while molecular weight homogeneity refers to a polydispersity index of 1.0. Most naturally occurring glycans are usually structurally heterogeneous coming from limited sources and with high-cost production. For example, animal-sourced heparin is a widely used polydisperse anticoagulant drug, complicating detailed structure activity relationship studies, thus, hampering its other therapeutic applications (Li & Wang, 2018; Zhang, Lin, Huang, & Linhardt, 2020). In addition, polysaccharides having different molecular weights can possess different physiological and pharmacological functions (Table 1). High molecular weight hyaluronic acid (HMW-HA) has been applied by inhalation to clinically treat inflammation, while low molecular weight hyaluronic acid (LMW-HA) exhibits proinflammatory characteristics (Li, Qiao et al., 2020; Li, Yao et al., 2020). Moreover, impurities are inevitably present due to the incorporation of other similar polysaccharides and bioactive entities such as viruses, prions or growth-modulating factors in animal tissues (Liu & Linhardt, 2014). A crisis resulted from the worldwide distribution of contaminated heparin in 2007 highlighted the importance of developing homogeneous heparin drug instead of a heterogeneous one from an animal source (Guerrini et al., 2010; Szajek et al., 2016). Consequently, efficiently preparing homogeneous, or nearly homogeneous, polysaccharides or structurally well-defined oligosaccharides is at the forefront of the new-generation carbohydrate-based drug development, resulting in reproducible biological properties as well as a safer and more secure supply chain (Fig. 1).