6-Thioguanosine Monophosphate Prodrugs Display Enhanced Performance against Thiopurine-Resistant Leukemia and Breast Cancer Cells

Abstract

Thiopurines are in widespread clinical use for the treatment of immunological disorders and certain cancers. However, treatment failure due to resistance or adverse drug reactions are common, asking for new therapeutic strategies. We investigated the potential of 6-thioguanosine monophosphate (6sGMP) prodrugs to overcome resistance to 6-thioguanine. We successfully developed synthetic routes toward diverse 6sGMP prodrugs, tested their proliferation inhibitory potential in different cell lines, and examined their mode of action. Our results show that 4-acetyloxybenzyl- and cycloSaligenyl-derivatized 6sGMP prodrugs are effective antiproliferative compounds in cells that are resistant to thiopurines. We find that resistance is related to the expression of salvage pathway enzyme HGPRT. Using TUC-seq DUAL, we demonstrate the intracellular conversion of 6sGMP prodrugs into bioactive 6sGTPs. Thus, our study offers a promising strategy for thiopurine therapy by using 6sGMP prodrugs, and it suggests TUC-seq DUAL as a simple and fast method to measure the success of thiopurine therapy.

Cytotoxicity of phosphoramidate, bis-amidate and cycloSal prodrug metabolites against tumour and normal cells

“…Again, this demonstrates that normal cells may have greater sensitivity to phosph(on) ate prodrug metabolites than tumour cell lines and should be considered when testing cycloSal prodrugs at higher concentrations. 20 The prodrug metabolite concentrations used in this study are within the reported concentration ranges used for phosphoramidate, bis-amidate and cycloSal prodrug compounds during in vitro evaluations. Furthermore, these concentrations are within the reported maximum plasma concentrations of several FDA approved anti-cancer agents.…”

“…15,16 The use of phosph(on)ate prodrugs is expanding, especially to non-nucleotide scaffolds, with compounds being evaluated at micro-molar concentrations during in vitro studies. [17][18][19][20] The metabolites liberated upon activation of the prodrug are rarely taken into account during the evaluation process and are often considered inert. Herein, the current generation of prodrugs, namely the phosphoramidate, bis-amidate and cycloSal prodrugs are evaluated for their potential toxicity.…”

Enantioselective copper-catalyzed B–H bond insertion reaction of α-diazo phosphonates to access chiral α-boryl phosphonates

“…For instance, they can act as active ingredients in drugs for the treatment of diseases and as ligands in metal catalytic reactions (Scheme 1a). [1][2][3][4][5][6][7] In the past few decades, various compounds containing phosphorus atoms and other non-phosphorus heteroatoms attached to the same chiral carbon atom have been reported, such as chiral a-hydroxy phosphonates, [8][9][10][11][12] chiral a-amino phos-phonates 13,14 and chiral a-silyl phosphonates. 15 However, the construction of chiral a-boryl phosphonates has not been reported (Scheme 1b).…”

Novel 7-Chloro-4-aminoquinoline-benzimidazole Hybrids as Inhibitors of Cancer Cells Growth: Synthesis, Antiproliferative Activity, in Silico ADME Predictions, and Docking

“…Cancer is a leading disease worldwide, and the projections indicate that the global incidence of cancer will continue to rise [ 1 , 2 ]. The conventional anti-cancer agents are losing their efficiency [ 3 ], highlighting the need to introduce new anti-cancer entities [ 4 , 5 , 6 ]. One strategy to address the issues with existing chemotherapeutics is molecular hybridization: a strategy that generates more efficient therapeutics by combining two (or more) pharmacophores or two (or more) entire drugs in a single hybrid molecule that addresses one or multiple targets [ 7 , 8 , 9 ].…”