The radical-
cations formed on one-electron oxidation of
indole-3-acetic acid (IAA) and its ring-substituted derivatives rapidly fragment, eliminating
carbon dioxide from the sidechain and forming a
carbon-centred
free radical (3-indolylmethyl or skatolyl, or analogues). This radical is reactive towards
DNA and possibly other targets in
anoxia, but in oxic or hypoxic cells rapidly adds
oxygen to form a
peroxyl radical. Subsequent products include 3-methylene-2-oxindole or analogues, reactive towards cellular nucleophiles such as
thiols and
DNA. The one-electron oxidation of indole-3-acetic
acids is efficiently achieved by
horseradish peroxidase (HRP), not requiring added
hydrogen peroxide cofactor. The combination of IAA and HRP is cytotoxic towards mammalian cells, including human tumour cells. Unexpectedly, some
halogen-substituted derivatives of IAA are very cytotoxic with HRP even though they are more difficult to oxidize. IAA is tolerated by humans in high doses and HRP is a robust
enzyme meeting many of the requirements for targeting to tumours by coupling to
antibodies or
polymers, or by gene transfection. It is suggested that the
indole acetic acids merit further evaluation as potential
prodrugs for use in
cancer therapy based on targeted delivery of HRP to tumours.