ABSTRACT

E-selectin on the vascular endothelium. Dissemination is also thought to be aided by the binding of sLe structures on cancer cells to selectins (P and L) expressed on platelets (Fuster et al., 2003; Magnani, 2004). Changes in sLe levels depends on the altered expression of a variety of a-(2→3)-STs (Brown et al., 2003).PolySia (linear homopolymer of a-(2→8)-linked Sia of up to 50 residues) provides a unique type of modification of the neural cell adhesion molecule (NCAM), and is expressed in a variety of cancers, predominantly of neuroectodermal origin (Roth et al., 1988; Daniel et al., 2000). PolySia has also been noted in malignancies of small-cell lung cancer (SCLC) and two reports have shown that the level of polySia expression was greater in SCLC than in carcinoid tumors (Scheidegger et al., 1994; Krug et al., 2004).Clearly, cell sialylation and the activities of various STs facilitate and enhance the metastatic potential of a variety of cancers. Therefore, specific inhibition of cancer cell surface sialylation should in principle inhibit metastasis and could potentially lead to novel anticancer agents. Two main approaches toward developing small molecular inhibitors of cancer cell sialylation have been described. The first approach relies on the fact that synthetic carbohydrate precursors of sLe can act as substrates for glycosyltransferases, including the a-(2→3)-STs involved in sLe biosynthesis, resulting in the diversion of sLe biosynthesis from endogenous glycans (Delannoy et al., 1996; Fuster et al., 2003). This leads to a reduction in sLe expression on cancer cells, resulting in decreased interactions with selectins, increased susceptibility to leukocyte-mediated lysis and a reduction in experimental pulmonary metastasis of colon adenocarcinoma (Fuster et al., 2003). Significant effort has also been made toward the development of glycomimetic inhibitors of selectins, particularly E-selectin, as potential antimetastasis agents. The development of glycomimetic inhibitors of selectin-mediated interactions will be discussed later in this chapter.In an alternative approach a number of groups have developed inhibitors that directly target key proteins of the sialylation pathway (Fig. 12.2). The majority of these inhibitors have been donor substrate (CMP-Neu5Ac) analogs or transition state mimetics. In the following section, we will discuss the development of these CMPNeu5Ac analogs and transition state mimetics that specifically target STs and the CST.