Duocarmycins as potent anticancer scaffolds: A8dvances in chemistry, structure–activity relationships, biological activity, prodrug design, and antibody-drug conjugate development

Duocarmycins constitute a class of highly potent DNA minor-groove alkylators first isolated from Streptomyces spp., capable of exerting cytotoxic effects at picomolar concentrations . Their mechanism of action involves sequence selective alkylation at AT-rich sites of DNA via activated cyclopropane electrophile. In spite of their exceptional potential, widespread clinical adoption has remained elusive, primarily owing to dose-limiting systemic toxicity and limited tumor selectivity. However, several prodrugs, and antibody-drug conjugates have been developed, which significantly expand the therapeutic potential of this class of compounds. This review critically summarizes the chemical and pharmacological evolution of duocarmycin-based analogues reported between 1978 and 2023. Databases including PubMed, Scopus, Web of Science, Google Scholar were used to collate literature and patent data using the keywords such as “Duocarmycin”, “CC-1065”, “DNA alkylating agents”, “prodrugs”, “antibody-drug conjugates”, and “Structure-activity Relationship”. Peer-reviewed articles and patents focusing on synthetic analogues, mechanistic insights, biological evaluation, and clinical progress were identified and critically assessed. Central to the discussion is a detailed structure–activity relationship (SAR) analysis of the principal alkylating pharmacophores including CPI, CBI, CI, CPyI, and CPzI analogues, highlighting the effect of structural modifications on DNA alkylation efficiency, cytotoxicity, and sequence selectivity. The review further discusses bifunctional alkylators and hybrid derivatives incorporating distamycin, bleomycin, polyamide and pyrrolobenzodiazepine motifs for sequence specificity and improved DNA recognition. In addition, recent advances in phenol-based and bioreductive prodrugs, as well as antibody-directed delivery systems, are comprehensively examined as strategies toreduce systemic toxicity and improve tumor selectivity. Overall, the studies provide valuable insights into therapeutic potential, limitations, and future development of duocarmycin-based anticancer agents.