Abstract
DNA interstrand crosslinks (ICLs) are extremely cytotoxic lesions that block essential cellular processes, such as replication and transcription. Crosslinking agents are widely used in cancer chemotherapy and form an array of structurally diverse ICLs. Despite the clinical success of these agents, resistance of tumors to crosslinking agents, for example, through repair of these lesions by the cellular machinery remains a problem. We have previously reported the synthesis of site-specific ICLs mimicking those formed by nitrogen mustards to facilitate the studies of cellular responses to ICL formation. Here we extend these efforts and report the synthesis of structurally diverse major groove ICLs that induce severe, little or no distortion in the DNA. Our approach employs the incorporation of aldehyde precursors of different lengths into complementary strands and ICL formation using a double reductive amination with a variety of amines. Our studies provide insight into the structure and reactivity parameters of ICL formation by double reductive amination and yield a set of diverse ICLs that will be invaluable for exploring structure–activity relationships in ICL repair.
Highlights
DNA interstrand crosslinks (ICLs) are extremely cytotoxic lesions that covalently connect two complementary strands of a DNA duplex
We have previously reported that nitrogen mustards (NMs)-like ICLs can be synthesized by incorporation of two aldehyde precursors on complementary strands of DNA and crosslink formation using a double reductive amination reaction [17,22]
In the course of these studies, we noted that the efficiency of ICL formation is dependent upon the length of the ICL as well as the reactivity of the amine used in the reaction (Figure 1B)
Summary
DNA interstrand crosslinks (ICLs) are extremely cytotoxic lesions that covalently connect two complementary strands of a DNA duplex. As DNA strand separation is essential to cellular processes, such as transcription and replication, ICLs are highly cytotoxic [1,2,3]. Bifunctional electrophiles, such as cisplatin, nitrogen mustards (NMs) chloro ethyl nitroso ureas and mitomycin C, form ICLs and are a mainstay as frontline chemotherapeutic drugs [4]. ICLs are formed by endogenous bifunctional agents, such as malondialdehyde and formaldehyde [6,7,8], and such agents have likely been the evolutionary drivers for the cellular responses to ICL formation.
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