Different DNA Binding and Damage Mode Between Anticancer Antibiotics Trioxacarcin A and LL-D49194α1

Overview

Journal JACS Au

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Sep 27

PMID 39328742

Authors

Ruo-Qin Gao

Xiao-Dong Hu

Qiang Zhou

Xian-Feng Hou

Chunyang Cao

Gong-Li Tang

Affiliations

Soon will be listed here.

Abstract

Trioxacarcin A (TXN) is a highly potent cytotoxic antibiotic with remarkable structural complexity. The crystal structure of TXN bound to double-stranded DNA (dsDNA) suggested that the TXN interaction might depend on positions of two sugar subunits on the minor and major grooves of dsDNA. LL-D49194α1 (LLD) is a TXN analogue bearing the same polycyclic polyketide scaffold with a distinct glycosylation pattern. Although LLD was in a phase I clinical trial, how LLD binds to dsDNA remains unclear. Here, we solved the solution structures at high resolutions of palindromic 2″-fluorine-labeled guanine-containing duplex d(AACCGGTT) and of its stable LLD and TXN covalently bound complexes. Combined with biochemical assays, we found that TXN-alkylated dsDNA would tend to keep DNA helix conformation, while LLD-alkylated dsDNA lost its stability more than TXN-alkylated dsDNA, leading to dsDNA denaturation. Thus, despite lower cytotoxicity in vitro, the differences of sugar substitutions in LLD caused greater DNA damage than TXN, thereby bringing about a completely new biological effect.

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