2024 Undergraduate Research Showcase

Mechanistic Studies of DNA-Protein Crosslink Formation Facilitated by Aziridinomitosenes with Varying Substitution Patterns

Document Type

Student Presentation

Presentation Date

4-19-2024

Faculty Sponsor

Dr. Don Warner

Abstract

Aziridinomitosenes (AZMs) are quinone-containing DNA alkylating agents, discovered as metabolites of the chemotherapeutic drug mitomycin C (MC). MC displays anti-tumor activity through the formation of DNA-interstrand crosslinks (ICLs), which inhibits DNA replication and results in cell death. Notably, prior to DNA binding, MC must undergo a bioreductive activation sequence that has been well studied and characterized. AZMs were historically known to produce DNA-monoalkylated adducts in the absence of reductive activation. However, we have previously shown that certain synthetic AZMs not only generate ICLs, but also DNA-protein crosslinks (DPCs) in the absence of exogenous reductants. Given that these were previously unreported adducts for AZMs, we proposed a nucleophilic activation/DNA modification sequence involving either of the C-6 or C-7 positions on the quinone ring (mitomycin numbering). To test this, we have synthesized analogs where C-6 and/or C-7 are blocked and then subjected them to a variety of DNA-binding experiments, including in vitro K-SDS assays to quantify the impact of AZM substitution on DPC formation. These experiments have demonstrated that AZMs unsubstituted at either the C-6 and/or C-7 positions form DPCs, while those blocked at both sites do not. These and related results will be presented and discussed in the context of the proposed mechanism.

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