Design, synthesis and evaluation of pyrrolo[2,1-c][1,4]benzodiazepines containing endo/exo unsaturation.

The work presented in this thesis focused on developing new approaches to the synthesis of pyrrolo[2,1-c][1,4]benzodiazepines (PBDs). These compounds are generating interest because of their potential use as anti-tumour or disease-related gene targeting agents. According to SAR studies, PBDs containing endolexo unsaturation in the pyrrolo C-ring are required for maximum biological potency, and thus PBDs of such type have been selected as target molecules. Three novel PBD monomers (ZC-14, ZC-96 and ZC-99), four novel PBD dimers (ZC-204, ZC-207, ZC-209 and ZC-211) and one natural product (porothramycin B) have been successfully synthesized. The synthetic approach involves application of palladium mediated coupling reactions, including Heck, Suzuki and Stille reactions, to introduce various side chains at the C2-position of the PBD C-ring. Use of such versatile coupling reactions at a late stage in the synthesis has the potential to provide access to a wide range of analogues in the future. Extensive method development work has been carried out during the research programme and the yields of several initially low-yielding reactions have been significantly improved. The work includes protection of reactive sites in key intermediates and an investigation of an alternative N 10-amino protecting group. All novel PBDs displayed potent activity in initial in vitro cytotoxicity assays performed by the NCI. Both PBD monomers and dimers exhibited GI50 values of less than 10 nM in the majority of cell lines. The cytotoxicity of these molecules was also evaluated in the K562 cell line at UCL. Dimers generally showed enhanced activity compared with their corresponding monomers in this test. In the DNA cross-linking efficiency assay for novel PBD dimers, ZC-204 gave extremely low XL50 values, ZC-207 and ZC-211 also exhibited significant activity, however, ZC- 209 showed only moderate cross-linking efficiency