Cyclopropabenzaindoles (CBIs) are exquisitely potent cytotoxins which bind and alkylate in the minor
groove of DNA. They are not selective for cancer cells, so prodrugs are required. CBIs can be formed at
physiological pH by Winstein cyclisation of 1-chloromethyl-3-substituted-5-hydroxy-2,3-dihydrobenzo[
e]indoles (5-OH-seco-CBIs). Corresponding 5-NH2-seco-CBIs should also undergo Winstein cyclisation
similarly. A key triply orthogonally protected intermediate on the route to 5-NH2-seco-CBIs has been
synthesised, via selective monotrifluoroacetylation of naphthalene-1,3-diamine, Boc protection, electrophilic
iodination, selective allylation at the trifluoroacetamide and 5-exo radical ring-closure with
TEMPO. This intermediate has potential for introduction of peptide prodrug masking units (deactivating
the Winstein cyclisation and cytotoxicity), addition of diverse indole-amide side-chains (enhancing noncovalent
binding prior to alkylation) and use of different leaving groups (replacing the usual chlorine, allowing tuning of the rate of Winstein cyclisation). This key intermediate was elaborated into a simple model 5-NH2-seco-CBI with a dimethylaminoethoxyindole side-chain. Conversion to a bio-reactive entity and the bioactivity of this system were confirmed through DNA-melting studies (DTm = 13 �C) and cytotoxicity against LNCaP human prostate cancer cells (IC50 = 18 nM).