D-Galactose as a Vector for Prodrug Design

Abstract

D-galactose is a simple and natural compound that has mainly been exploited in prodrug strategies. Galactosyl prodrugs can be considered a good approach to reach different goals in clinical drug application, especially when traditional drugs are likely to fail therapeutically owing to reasons such as the lack of site specificity, toxicity, and chemical instability. Indeed, of paramount importance is their ability to increase the selectivity of the parent compound, a phenomenon that helps to reduce the incidence of adverse effects, while preserving intact the pharmacodynamic features of the parent drug. Study results have varied according to the type of linkage between the drug and the hydroxyl group exploited. By working with these parameters, researchers have been able not only to generate selective pharmacological targeting of brain, liver, and cancerous cells, but also to improve cellular permeability as well as the pharmacokinetic profile of parent drugs. This review describes the broad spectrum of possibilities for exploiting D-galactose as a vector for prodrug design and the synthetic strategies that allow its realization.

Glucose conjugation for the specific targeting and treatment of cancer

“…Thus, it seems that many sugars can be conjugated to anticancer agents to take advantage of GLUT-mediated cellular entry; the choice of which sugar to utilize may depend on the desired cleavage mechanism of the compound. For instance, D-galactose, the C4 epimer of glucose, has been reported to possess an equivalent affinity and uptake rate by GLUT-1 compared to glucose [86]. Galactose-conjugated drugs may be used to selectively target certain types of cancers known to highly express galactosidase enzymes, such as breast and colon cancers [87].…”

Prochelator strategies for site-selective activation of metal chelators

“…23 A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 6 The use of sugars as protecting groups has been reported in tumor-associated enzyme activation of prodrugs such as ADEPT and PMT. 37,38 In a different twist on this theme, our group has incorporated glucose and galactose moieties into 8-hydroxyquinoline (HQ) scaffold in order to obtain prochelators The proposed mechanism of action for glucose-appended HQ prochelators involves the active transport of these compounds into cancer cells, the hydrolysis triggered by cytosolic β-glucosidase and Cu 2+ complexation. 26,27 As for HQ galactoconjugates, we have proposed a different prochelator strategy based on ADEPT.…”

Galactose‐modified duocarmycin prodrugs as senolytics

“…Galactose modification has been frequently used to improve the pharmacokinetic properties or the delivery of existing drugs. In addition, galactose modification can be used to generate prodrugs that rely on E. coli β‐galactosidase for controlled activation (Melisi, Curcio, Luongo, Morelli, & Rimoli, 2011). When combined with antibody‐linked β‐galactosidase, this approach is known as antibody‐directed enzyme prodrug therapy (ADEPT) (Bagshawe, 2006; Tietze & Schmuck, 2011).…”