Synthesis and Evaluation of DNA Cross-linkers by Click Chemistry-Mediated Heterodimerization of Nor-Tomaymycins.

ABSTRACT: The covalent cross-linking of DNA duplex strands by small molecule drugs is a validated mechanism in anticancer therapy. The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) have been established as potent DNA binders that can achieve inter- and intrastrand DNA cross-links when dimerized, and have been used as cytotoxic payloads in multiple antibody-drug conjugates (ADCs). In this study, we explore the potential of click chemistry to obtain PBD heterodimers. The heterodimers D1-D4 were prepared by copper catalyzed or strain-promoted azide-alkyne cycloadditions (SPAACs) from the corresponding monomers M1 - M4 and MbA. The interactions of monomers and dimers with DNA were evaluated by DNA thermal denaturation analysis, a newly developed mass spectrometry-based method for the detection of single sta

SUBMITTER: Friederich J 

PROVIDER: S-EPMC12451421 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature