DNA binders based on the integration of duocarmycins into minor groove-targeting polyamides have potent and selective anti-trypansosomal activity
4 affiliations
- 1School of Pharmacy, and School of Medicine, Pharmacy and Biomedical Sciences
- 2University of Portsmouth
- 3Norwich Medical School, University of East Anglia, Rosalind Franklin Road, Norwich, UK, NR4 7UQ
- 4School of Environment and Life Sciences
Abstract
Duocarmycins are attractive DNA alkylating agents due to their high potency; however, increasing their selectivity has always been a challenge. Here, we describe the integration of the duocarmycin subunits DSA and CI into minor groove-targeting polyamides, compounds that can ‘read’ DNA sequences. The synthesis of a CI analogue suitably substituted for solid phase synthesis using Fmoc-chemistry is described. The synthesis of the hybrid compounds is achieved using solid phase methods on chloro-trityl resin. The resulting hybrids display sequence-selective DNA alkylation, depending on the enantiomer and position of the duocarmycin unit as might be expected, except for the compounds with a central DSA alkylation subunit, which act more similarly to reversed analogues. The CI hybrids with a central unit are relatively unreactive with DNA and modelling studies suggest that the CI subunit is sub-optimally located for alkylation in these structures. Investigations against the parasite T. brucei, responsible for African trypanomiasis, highlight compounds with nanomolar potency and high selectivity (SI >300), showing that the integration of duocarmycins into the backbone of polyamides has promise for developing gene-targeting small molecule anti-parasitic agents.
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BibTeX
@misc{goddard2026binders,
title = {{DNA binders based on the integration of duocarmycins into minor groove-targeting polyamides have potent and selective anti-trypansosomal activity}},
author = {Zoë R. Goddard and Bethany R. Hood and Michael Brazzill and Deanne Hayward and Dietmar Steverding and Victoria Kamperi and Darren M. Gowers and Marco M. D. Cominetti and Michael J. Stephenson and Andrew M. Beekman and Maria O’Connell and David Rusling and Mark Searcey},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15009891/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009891/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - DNA binders based on the integration of duocarmycins into minor groove-targeting polyamides have potent and selective anti-trypansosomal activity
AU - Zoë R. Goddard
AU - Bethany R. Hood
AU - Michael Brazzill
AU - Deanne Hayward
AU - Dietmar Steverding
AU - Victoria Kamperi
AU - Darren M. Gowers
AU - Marco M. D. Cominetti
AU - Michael J. Stephenson
AU - Andrew M. Beekman
AU - Maria O’Connell
AU - David Rusling
AU - Mark Searcey
PY - 2026
DA - 2026/10/05
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009891/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009891/v1
AB - Duocarmycins are attractive DNA alkylating agents due to their high potency; however, increasing their selectivity has always been a challenge. Here, we describe the integration of the duocarmycin subunits DSA and CI into minor groove-targeting polyamides, compounds that can ‘read’ DNA sequences. The synthesis of a CI analogue suitably substituted for solid phase synthesis using Fmoc-chemistry is described. The synthesis of the hybrid compounds is achieved using solid phase methods on chloro-trityl resin. The resulting hybrids display sequence-selective DNA alkylation, depending on the enantiomer and position of the duocarmycin unit as might be expected, except for the compounds with a central DSA alkylation subunit, which act more similarly to reversed analogues. The CI hybrids with a central unit are relatively unreactive with DNA and modelling studies suggest that the CI subunit is sub-optimally located for alkylation in these structures. Investigations against the parasite T. brucei, responsible for African trypanomiasis, highlight compounds with nanomolar potency and high selectivity (SI >300), showing that the integration of duocarmycins into the backbone of polyamides has promise for developing gene-targeting small molecule anti-parasitic agents.
ER -