The azinomycins are two natural products derived from a strain of soil bacteria, Streptomyces griseofuscus. They were initially of interest for their potent cytotoxicity, possessing antibacterial and anticancer properties. In early studies the azinomycins were used in antitumor studies in mice, and azinomycin B was used in a clinical study in humans with several types of cancer with some success.
The azinomycins were soon discovered to be DNA-binding agents, and to be able to cross-link DNA. DNA cross-links are the most biologically significant type of DNA adduct, requiring repair by nucleotide excision repair and homologous recombination. Cross-links that are not repaired can lead directly to replication failure when the replication fork reaches the cross-link or indirectly through the introduction of double-stranded breaks.
Once the structures of the azinomycins were determined they became of interest as a synthetic challenge. The azinomycins bear an unusual aziridino[1,2-a]pyrrolidine ring, which is not found in any other natural product. Additionally, they bear a reactive epoxide. It is through the aziridine and the epoxide that the azinomycins can cross-link DNA. A total synthesis has been completed for azinomycin A, but azinomycin B has not yet been synthesized. This synthetic difficulty in addition to the instability of the molecules and their unreliable availability through culture has led to the exploration of azinomycin partial structures and analogs.
In this study a series of azinomycin partial structures that explore the effect of stereochemistry and lengthening the azinomycin backbone were studied. These molecules were examined for their site selectivity in DNA alkylation and their cytotoxicity against two commonly studied breast cancer cell lines. All partial structures are capable of alkylating DNA through the epoxide, although they lack the aziridine, and all possess moderate to significant cytotoxicity. The length of the backbone of the partial structures did not greatly affect sequence selectivity or cytotoxicity, but it was discovered that stereochemistry significantly modified the sequence selectivity of a set of truncated epoxyamides. The sequence selectivity of the natural stereochemistry epoxyamide and its enantiomer became a key focus of this work. The sequence selectivity of these two molecules over a wide variety of binding sites was examined and the basis for their selectivity at their favored sequences was elucidated using molecular modeling.