Synthetic analogues of the DNA-alkylating cytotoxins of the duocarmycin class have been extensively investigated in the past 40 years, driven by their high potency, their unusual mechanism of bioactivity, and the beautiful modularity of their structure-activity relationship (SAR). This minireview analyses how the molecular designs of synthetic duocarmycins have evolved: from (1) early SAR studies, through to modern applications for directed cancer therapy as (2) prodrugs and (3) antibody-drug conjugates in late-stage clinical development. Analysing 583 primary research articles and patents from 1978-2022, we distill out a searchable A0-format "Minard map" poster of ca. 200 key structure/function-tuning steps tracing chemical developments across these three key areas. This structure-based overview showcases the ingenious approaches to tune and target bioactivity, that continue to drive development of the elegant and powerful duocarmycin platform.
Felber & Thorn-Seshold - The Duocarmycins Poster - structural evolution from SAR to prodrugs and ADCs
Felber & Thorn-Seshold - Synthetic duocarmycins: structural evolution from SAR to prodrugs and ADCs - Literature Citations (583 References)
Felber & Thorn-Seshold - Synthetic duocarmycins: structural evolution from SAR to prodrugs and ADCs - Supporting Information