Observation of a Single-Stranded DNA/Pyrrolobenzodiazepine Adduct

Rahman, K.M., James, C.H., Bui, T.T.T., Drake, A.F. and Thurston, D.E. (2011) Observation of a Single-Stranded DNA/Pyrrolobenzodiazepine Adduct. Journal of the American Chemical Society, 133 (48). pp. 19376-19385. 10.1021/ja205395r.

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DOI: 10.1021/ja205395r

Abstract

Pyrrolobenzodiazepine (PBD) antitumor agents have, to date, only been observed to bind to duplex DNA, apparently requiring a minor groove environment for covalent bond formation between their C11-position and the C2-NH2 functionality of a guanine base. Using an HPLC/MS assay we have now observed and isolated for the first time PBD adducts with single-stranded DNA fragments. Surprisingly, these adducts could only be formed through dissociation of duplex DNA adducts and not by direct interaction of PBDs with single-stranded DNA. They were sufficiently stable for characterization by MALDI-TOF-MS and remained intact after storing at -20 °C for at least 20 days, although the PBD became detached from the DNA within 7 days if stored at room temperature. Furthermore, addition of a complementary strand allowed the duplex adduct to reform. The relative stability of single-stranded PBD/DNA adducts despite a complete loss of minor groove structure was further confirmed by CD spectroscopic analysis. The CD signal induced by the presence of a PBD molecule in the single-stranded adducts remained prominent despite heating for 2 h at 50-60 °C, thus indicating their relatively robust nature.

Item Type:Article
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry
ID Code:2880
Journal or Publication Title:Journal of the American Chemical Society
Deposited By:Library Staff
Deposited On:01 Mar 2012 10:29
Last Modified:01 Mar 2012 10:29

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