Folic acid conjugates of a bleomycin mimic for selective targeting of folate receptor positive cancer cells

Arjan Geersing,Marianne G Rots,Gerard Roelfes,Reinder H De Vries,Gerrit Jansen

doi:10.1016/j.bmcl.2019.05.047

Abstract

A major challenge in the application of cytotoxic anti-cancer drugs is their general lack of selectivity, which often leads to systematic toxicity due to their inability to discriminate between malignant and healthy cells. A particularly promising target for selective targeting are the folate receptors (FR) that are often over-expressed on cancer cells. Here, we report on a conjugate of the pentadentate nitrogen ligand N4Py to folic acid, via a cleavable disulphide linker, which shows selective cytotoxicity against folate receptor expressing cancer cells.

Highlights

The bleomycins (BLMs) are a group of antitumor antibiotics that have long been used for the treatment of various tumors such as squamous cell carcinomas,[1] testicular carcinomas,[2] malignant lymphomas[3] and ovarian cancer.[4]
Even though some folate-conjugated metal complexes have been used as tracer molecules for diagnostic purposes,[20,35,36,37,38,39,40,41,42,43,44] to the best of our knowledge, no folate conjugated metal complexes have been reported as cytotoxic agents
We report on a bleomycin mimic, the pentadentate ligand N4Py, conjugated to folic acid (FA) via a redox sensitive cleavable linker, N4Py-S-S-FA, which shows good activity and is selective towards to folate receptor (FR)(+) cells

Summary

Introduction

The bleomycins (BLMs) are a group of antitumor antibiotics that have long been used for the treatment of various tumors such as squamous cell carcinomas,[1] testicular carcinomas,[2] malignant lymphomas[3] and ovarian cancer.[4]. The stability and in situ formation of the iron complexes of both conjugates were tested in tris-HCl buffer (pH 8.5) in presence of two equivalents of Fe(ClO4)[2] and 5 mM of glutathione (GSH), since cellular levels of GSH are in the range of 1–10 mM.[51,52] Analysis by LC-MS showed that 5 min after addition of GSH, a large amount of N4Py-S-SFA was already converted to the corresponding cleavage products

Results

Conclusion