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

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.