Biological and Medicinal Chemistry

Synthetic duocarmycins: structural evolution from SAR to prodrugs and ADCs - a searchable structure/function database

Authors

Abstract

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.

Content

Thumbnail image of Felber and Thorn-Seshold - The Duocarmycins v1.65.pdf

Supplementary material

Thumbnail image of Felber and Thorn-Seshold - The Duocarmycins - Poster v6.pdf
Felber & Thorn-Seshold - The Duocarmycins Poster - structural evolution from SAR to prodrugs and ADCs
This A0-size Poster gives a chemical structure overview of key developments of the duocarmycins, across the 200 most significant papers and compounds. These are organised by chronology, research aim, originating research group, and functional motifs. Every structure has a hyperlink to its paper DOI, and the accompanying CDX version can be mined for structures. The poster is vectorial, so can be printed at A0 or larger e.g. to hang in hallways. The aim was to test a new, helpful hybrid format that makes a large body of research quickly accessible in multiple ways that suit different purposes and audiences.
Thumbnail image of Felber and Thorn-Seshold - The Duocarmycins - Reference Library.ris
Felber & Thorn-Seshold - Synthetic duocarmycins: structural evolution from SAR to prodrugs and ADCs - Literature Citations (583 References)
A bibliographic RIS file that can be imported into all reference manager softwares (including e.g. Zotero), including the 583 publication and patent references covered in this Review
Thumbnail image of Felber and Thorn-Seshold - The Duocarmycins - SI v1.31.pdf
Felber & Thorn-Seshold - Synthetic duocarmycins: structural evolution from SAR to prodrugs and ADCs - Supporting Information
Workflow for the Systematic Literature Review (SLR) process used in this review; and bibliographies of the 583 major references covered, as organised by focus of research.

Supplementary weblinks

Thorn-Seshold research group webpage at the LMU Munich
A current version of the 200 Duocarmycins Poster will be curated and hosted at the Thorn-Seshold research group webpage