Sialyltransferase Inhibitors for the Treatment of Cancer Metastasis: Current Challenges and Future Perspectives

Abstract

Potent, cell-permeable, and subtype-selective sialyltransferase inhibitors represent an attractive family of substances that can potentially be used for the clinical treatment of cancer metastasis. These substances operate by specifically inhibiting sialyltransferase-mediated hypersialylation of cell surface glycoproteins or glycolipids, which then blocks the sialic acid recognition pathway and leads to deterioration of cell motility and invasion. A vast amount of evidence for the in vitro and in vivo effects of sialyltransferase inhibition or knockdown on tumor progression and tumor cell metastasis or colonization has been accumulated over the past decades. In this regard, this review comprehensively discusses the results of studies that have led to the recent discovery and development of sialyltransferase inhibitors, their potential biomedical applications in the treatment of cancer metastasis, and their current limitations and future opportunities.

Keywords: cancer metastasis; drug design and development; hypersialylation; sialyltransferase; sialyltransferase inhibitors.

Figure 1

Illustration of the sialic acid metabolic pathway in cells and the pathobiological interactions of sialic acid residues on the cell surface.

Figure 2

Overview of sialic acid metabolism in cancer cells and sialyltransferase-mediated hypersialylation of glycoproteins or glycolipids at the cell surface. The cartoon shows that alteration of sialylation on cell surfaces not only enhances tumor progression and invasion, but also facilitates angiogenesis and metastasis in the metastatic cascade.

Figure 3

Chemical structures of 5a’-carbaoligosaccharides as acceptor mimics 1–4.

Figure 4

Structures of fluorinated mucin core 2 branched oligosaccharides 5–9.

Figure 5

Proposed mechanism of sialyltransferase-catalyzed reactions.

Figure 6

Structures of aromatic phosphoramidate CMP derivatives (R)-10 and (S)-10.

Figure 7

Structures of recently reported CMP-Neu5Ac transition state analogues [119,130,131].

Figure 8

Structures of bisubstrate analogues 51–55.

Figure 9

Chemical structure of 56.

Figure 10

Structure of non-natural sugar triazole nucleotide 57 discovered from MS-based HTS.

Figure 11

Structures of cell-permeable fluorine-substituted sialic acid analogues 58 and 59.

Figure 12

Structure of soyasaponin I.

Figure 13

The structures of the spirocyclic drimanes, stachybotrydial 68–70.

Figure 14

The core structures of flavonoid derivatives.

Figure 15

Structures of ginsenosides 80–83.

Figure 16

The structure of AL10.

Figure 17

Chemical structures of two second-generation lithocholic acid-based inhibitors.

Figure 18

Structures of thioether and sulfonic acid derivatives 111–115.