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In Vitro Studies with Methylproamine

A Potent New Radioprotector

¹ Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, Melbourne, Australia; ² School of Chemistry, University of Melbourne, Melbourne, Australia; ³ Chemistry Department, University of Auckland, Auckland, New Zealand; and ⁴ Centre de Biophysique Moleculaire, CNRS, Orleans, France

New analogues of the minor groove binding ligand Hoechst 33342 have been investigated in an attempt to improve radioprotective activity. The synthesis, DNA binding, and in vitro radioprotective properties of methylproamine, the most potent derivative, are reported. Experiments with V79 cells have shown that methylproamine is 100-fold more potent than the classical aminothiol radioprotector WR1065. The crystal structures of methylproamine and proamine complexes with the dodecamer d(CGCGAATTCGCG)₂ confirm that the new analogues also are minor groove binders. It is proposed that the DNA-bound methylproamine ligand acts as a reducing agent by an electron transfer mechanism, repairing transient radiation-induced oxidizing species on DNA.