The high potency of the
tetrahydrofuran-containing
acetogenins (THF-ACGs) against a broad range of human
cancer cell lines has stimulated interest in structurally simpler mimetics. In this context, we have previously reported THF-
ACG mimetics in which the THF and
butenolide moieties of a mono-THF-
ACG were replaced with
carbohydrate and
thiophene residues, respectively. In the present study, towards the targeting of these
carbohydrate analogues to
prostate cancer (PCa), we synthesized
prodrugs in which a parent
thiophene or
butenolide congener was conjugated through a self-immolative linker to 2-[3-(1,3-dicarboxypropyl)ureido] pentanedioic
acid (DUPA), a highly specific
ligand for prostate-specific membrane
antigen (PSMA), which is overexpressed on prostate
tumors. Both
prodrugs were found to be more active against receptor positive LNCaP than receptor-negative PC-3 cells, with 2.5 and 12 times greater selectivity for the more potent
thiophene analog and the less active
butenolide congener, respectively. This selectivity for LNCaP over PC-3 contrasted with the behavior of the parent drugs, which showed similar or significantly higher activity for PC-3 compared to LNCaP. These data support the notion that higher activity of these DUPA-derived
prodrugs against LNCaP cells is connected to their binding to PSMA and suggest that the conjugation of PSMA
ligands to this family of
cytotoxic agents may be effective for targeting them to PCa.