Novel heterocyclic NO-donors as potential anti-cancer agents

Abstract

A comparative study involving two sets of novel nitric oxide donating compounds was investigated. All target compounds were designed and prepared using traditional synthetic routes that were optimised to allow the efficient incorporation of either a furoxan core or a S-nitrosothiol group. In each synthetic sequence the NO was locked into a five-membered heterocyclic ring linked to an aromatic portion. This synthetic strategy provided the scope to generate a range of products with subtle substituent differences in order to help rationalise any variations seen, between individual compounds, in either the rate of NO release or biological profile. The chemical stability of all compounds was compared under a range of different conditions to ascertain the ease with which each heterocyclic ring breaks open, which is clearly a prerequisite for NO release. Having gained an appreciation of the stability and required handling conditions for each set of NO-donors, the compounds were evaluated for their ability to inhibit the proliferation of a panel of ovarian cancer cell lines. The results suggest that subtle chemical modifications to the structure of these NO-donors, in additional to changing the actual type of NO-donating species, can greatly influence their ability to release NO and act as cytotoxic agents.