An aziridinomitosene, a compound related to the clinically used anticancer agent mitomycin C, has recently been shown to form DNA interstrand cross-links under non-reductive conditions. The occurrence of the cross-link is significant for two reasons. First, mitomycin C's antitumor activity is the result of the formation of rare interstrand DNA cross-links. Second, aziridinomitosenes were previously thought to be responsible solely for formation of less toxic DNA monoadducts. Several factors may facilitate this previously unobserved cytotoxic event, including the presence of two additional electrophilic sites located on the quinone ring at C-6 and C-7. Evidence suggests that the C-1 and C-10 electrophilic sites are key to crosslink formation, as is the case with mitomycin C, but the molecular structure of the cross-link is not known. The mechanism of DNA cross-linking by the synthetic aziridinomitosene is hypothesized to involve first monoalkylation of DNA at the C-1 aziridine site followed by a second event that activates the C-10 site for a second alkylation. The C-10 activation event is proposed to involve nucleophilic attack at the C-6 or C-7 atoms. This proposal aims to identify the molecular structure of the DNA-aziridinomitosene interstrand cross-link, determine the role of the four electrophilic sites, and investigate the physical properties required to induce cross-link formation. The proposed research involves three specific aims: 1) identify and prepare relevant mitosene analogs; 2) characterize mitosenes with respect to reduction potential, aziridine nitrogen pKa, and solvolytic stability; 3) conduct an in vitro assessment of DNA alkylation by mitosene derivatives. Upon completion of the studies, a thorough understanding of the significant structural features with respect to DNA alkylating ability will be understood. The information will serve to clarify existing literature observations and allow for future studies that exploit the most significant characteristics. ? ?
| Mallory, Chris M; Carfi, Ryan P; Moon, SangPhil et al. (2015) Modification of cellular DNA by synthetic aziridinomitosenes. Bioorg Med Chem 23:7378-85 |
