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The Pyrrolobenzodiazepine Dimer SJG-136 Forms Sequence-Dependent Intrastrand DNA Cross-Links and Monoalkylated Adducts in Addition to Interstrand Cross-Links

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Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, U.K., Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, U.K., and Spirogen Ltd., The School of Pharmacy, University of London WC1N 1AX, U.K.
†Gene Targeted Drug Design Research Group, University of London.
‡University of Bath.
§Spirogen Ltd., University of London.
Cite this: J. Am. Chem. Soc. 2009, 131, 38, 13756–13766
Publication Date (Web):September 2, 2009
https://doi.org/10.1021/ja902986x
Copyright © 2009 American Chemical Society

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    Abstract

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    SJG-136 (1) is a sequence-selective DNA-interactive agent that is about to enter phase II clinical trials. Using a HPLC/MS-based methodology developed to evaluate the binding of DNA-interactive agents to oligonucleotides of varying length and sequence, we have demonstrated that, in addition to the previously known interstrand cross-link at Pu-GATC-Py sequences, 1 can form a longer interstrand cross-link at Pu-GAATC-Py sequences, an intrastrand cross-link at both shorter Pu-GATG-Py and longer Pu-GAATG-Py sequences, and, in addition, monoalkylated adducts at suitable PBD binding sites where neither intra- or interstrand cross-links are feasible because of the unavailability of two appropriately positioned guanines. Crucially, we have demonstrated a preference for the extended intrastrand cross-link with Pu-GAATG-Py, which forms more rapidly than the other cross-links (rank order: Pu-GAATG-Py > Pu-GATC-Py ≫ Pu-GATG-Py and Pu-GAATC-Py). However, thermal denaturation studies suggest that the originally reported Pu-GATC-Py interstrand cross-link is more stable, consistent with the covalent joining of both strands of the duplex and a lower overall distortion of the helix according to modeling studies. These observations impact on the proposed mechanism of action of SJG-136 (1) both in vitro and in vivo, the repair of its adducts and mechanism of resistance in cells, and potentially on the type of pharmacodynamic assay used in clinical trials.

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    HPLC, CD, UV and MS data, and molecular models of interstrand and intrastrand adducts. This material is available free of charge via the Internet at http://pubs.acs.org.

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