Diazopeptide chemistry

Potterton, Michael Andrew (1997). Diazopeptide chemistry. PhD thesis The Open University.

Abstract

The decomposition of diazopeptides in buffer-acid solutions (formate, acetate and phosphate) arc general-acid-catalysed, but the catalysis for these reactions is attenuated at high buffer-acid concentrations and non-linear second-order plots are observed. This behaviour is evident for both glycyl and non-glycyl diazopeptides, which decompose via different mechanisms i.e. A-2 and A-SE2 mechanisms, respectively. Hence, an explanation for this unusual kinetic behaviour, based on a change in the rate-limiting step with increasing [HA] must be excluded. Further, unlike glycyl diazopeptides, non-glycyl diazopeptides decompose to give products whose structure and yield is independent of the acid-catalyst. Thus, the acid-catalysis and non-linear kinetics observed can neither relate to product forming steps. The only plausible mechanistic explanation for this behaviour must, therefore, relate to the existence of a competing nucleophilic addition pathway of the buffer-acid across the diazo group to form azo-ester compounds. Good evidence was also found via kinetic and product studies, for the occurrence of similar reactions of diazopeptides with amines to form analogous triazene compounds. Such diazopeptide addition reactions may be biologically significant, as the compounds formed may have the potential to act as more stabilised, transportable forms of the cytotoxic diazonium ion. This study also includes the synthesis and spectroscopic characterisation of novel triazene-peptide compounds and metal-triazene-peptide complexes.

The above mechanisms for the decomposition of non-glycyl diazopeptides (where elimination, substitution and neighbouring group reactions arise) are supported by product studies involving spectroscopic analyses and the synthesis of novel, authentic compounds: The formation of cyclic products i.e. epoxides and lactams, from the acidcatalysed decompositions of N-(2-diazo-3-hydroxybutanoyl)glycine ethyl ester (2.1) and N-(2-diazo-3-carbamoylpropanoyl) glycine benzyl ester (4.1), respectively, are reported. Ring-Strained compounds are highly reactive especially towards nucleophiles, and therefore, could possibly be cytotoxic, acting as stabilised alkylating agents. Epoxide alkyl-oxygen bond fission to generate an alkylating agent, and stability for absorption intact from the gastric tract, are two fundamental requirements for the carcinogenic activity of epoxides. Hence, kinetic and product studies for epoxides cis(4.10), (4.14) and cis(4.15), derived via the nitrosation of a-amino threonyl and seryl residues, were carried out for reactions in dilute acidic and basic solutions and in aqueous morpholine. Further, independent studies have shown that epoxide (4.14) is mutagenic by Ames Test.

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