Tirech, Mohammed; (2009) Design, Synthesis and Evaluation of Novel C2-Aryl Substituted Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) Dimers. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Synthetic introduction of an aryl substituent at the C2-position has dramatically enhanced the in vivo activity of pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) monomers. As dimerizing PBDs was known to enhance sequence selectivity and antitumour activity, the principal objective and work presented in this thesis focuses on developing new approaches to the synthesis of novel C2-aryl PBDs dimers via a new and improved methodology. During the course of the research project extensive method development was performed which resulted in the development and optimisation of an efficient, concise and versatile synthetic route which greatly reduced the number of synthetic steps of previously reported literature methods. Consequently, six novel C2-aryl PBD imine dimers, a deuterated DSB-120 analogue and a novel example of a PBD tetralactam C2-aryl dimer were successfully synthesized via this new and improved tetralactam route. The synthetic approach involved the use and development of model systems to optimise the critical C11-lactam reduction step of SEM-protected dilactams to generate the N10-C11 imine moiety, critical for biological activity of PBDs. In addition, the Suzuki cross-coupling reaction was used to introduce aryl substituents at the C2 position of PBD dimers. The use of such a versatile coupling reaction at a late stage in the synthesis has the potential to access a wide range of PBD dimer analogues in the future. The work also includes investigations into the Vilsmeier-Haack formylation of the tetralactam system and subsequent side chain elaboration through Wittig olefination chemistry. Five PBD dimers were evaluated for their in vitro cytotoxicity and were found to be highly potent exhibiting nano-molar and sub-nanomolar activity against the Human Chronic Myeloid Leukaemia cell line assay K562. Interestingly, the unsubstituted C2-aryl dimer 227 was the most potent exhibiting an IC50 value of 0.28 nM, closely followed by the para-methyl substituted compound 229 (IC50 = 0.38 nM). The more highly branched analogues were generally less cytotoxic with activity in the 10-30 nanomolar range. There results appear to indicate that steric volume is an important factor in determining the cytotoxicity of the compounds and the results support the hypothesis that a good fit within the minor groove of DNA is critical for potent biological activity.

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