Bird, Aisling Elizabeth; (2004) Design, synthesis & evaluation of potential N10 protected pyrrolo[2,1c][1,4]benzodiazepine prodrugs. Doctoral thesis (Ph.D.), University College London.

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Abstract

Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are low molecular weight molecules that recognise and bind to specific sequences of DNA, blocking transcription and in the case of dimers, replication. Previous SAR studies have shown that blocking the N10 position abolishes the ability of the PBD to bind covalently to guanine in the minor groove of DNA. This property of PBDs could be exploited in order to produce prodrugs capable of selectively targeting tumour cells. A number of different N10 protecting groups were investigated in order to synthesise a series of potential PBD prodrugs. PBD synthesis followed the approach originated by Fukuyama and co-workers in 1993, which relies on the use of N10 protecting groups to control the critical B-ring cyclisation step. Attachment of the prodrug compounds to the PBD core was successfully performed via a novel isocyanate intermediate which formed the desired carbamate. Oxidation of these compounds afforded the protected PBDs in good yield. Four N10 protected dimers, utilising the MOC, Psec, Ptec and Menpoc protecting groups, were successfully synthesised by the strategy described above. Three of these products have been evaluated at the National Cancer Institute in America. The Psec protected dimer was found to exhibit nanomolar activity across a panel of 60 human tumour cell lines. The compound has been referred to the NCI Biological Evaluation Committee for further investigation. In addition six PBD monomers protected with photolabile, O-nitrobenzyl based, protecting groups were also synthesised. Two of the compounds were functionalised so as to allow possible linkage to tumour-targeting antibodies.

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