Aziridinomitosenes (AZMs) are related to the clinically useful anti-cancer agent mitomycin C (MC). The search for compounds related to MC that display an increase in efficacy and a decrease in side-effects has led to the study and synthesis of numerous analogs, several of which have advanced to clinical trials. Reductively activated MC forms DNA interstrand cross-links (ICLs), which block DNA replication and protein synthesis and result in cell death. Several synthetic AZMs have been found to form, without prior activation, ICLs and DNA/protein cross-links (DPCLs). Although drug development is beyond the scope of the current proposal, AZM analogs capable of forming ICLs without prior reductive activation are intriguing drug candidates since literature reports have shown that there is a direct correlation between mitomycin toxicity and reduction potential. In addition, AZM-induced DPCLs may have increased therapeutic importance as a result of their ability to obstruct DNA-associated protein complexes and disrupt key biological processes. Since several chemotherapeutic agents have been reported to form DPCLs, including cisplatin and several nitrogen mustards, the ability of synthetic AZMs to form DPCLs is clearly worth future evaluation. Objective/Hypothesis/Aims. Evidence suggests that synthetic AZMs covalently modify DNA to form interstrand cross-links (ICLs) and DNA/protein cross-links (DPCLs). Given that these AZMs, unlike MC, do not require reductive activation prior to DNA binding, adduct formation by AZMs may be occurring via a novel mechanism. Since the primary structural difference between these and previously reported AZMs is the substitution pattern on the quinone ring, a hypothesis for activation is proposed to involve attack by a cellular nucleophile into the quinone ring. To test this hypothesis, the proposed research includes the following specific aims: 1) Identify and prepare relevant AZMs, 2) Characterize AZMs and reactive intermediates with respect to solvolytic stability and correlate with DNA-alkylating and cytotoxicity studies, 3) Conduct an in vitro assessment of DNA alkylation, including experiments that probe for the formation of ICLs and DPCLs, and 4) Investigate the cytotoxicity of AZM derivatives in cancer cell lines, including experiments that examine the mechanism of cell death upon exposure of cancer cells to AZMs. The projects described herein aim to gain a thorough understanding of the unique chemical and biological properties of AZMs that facilitate ICL and DPCL formation, which will ultimately provide a solid foundation for future research that may lead to more efficacious chemotherapy treatments.
Many of the most significant anticancer agents in use today exhibit their biological properties through the covalent modification of DNA. The aziridinomitosenes described within this proposal are novel DNA-modifying agents with as of yet undetermined therapeutic potential. The purpose of the described projects is to determine the manner in which these compounds manifest their potency in order to provide a solid foundation for future research leading to more efficacious chemotherapy treatments.
| Mallory, Chris M; Carfi, Ryan P; Moon, SangPhil et al. (2015) Modification of cellular DNA by synthetic aziridinomitosenes. Bioorg Med Chem 23:7378-85 |
