Design, synthesis and biophysical and biological evaluation of a series of pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugates.

Wells, G., Martin, C.R.H., Howard, P.W., Sands, Z.A., Laughton, C.A., Tiberghien, A.C., Woo, C.-K., Masterson, L., Stephenson, M.J., Hartley, J.A., Jenkins, T.C., Shnyder, S.D., Loadman, P.M., Waring, M.J. and Thurston, D.E. (2006) Design, synthesis and biophysical and biological evaluation of a series of pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugates. Journal of Medicinal Chemistry, 49 (18). pp. 5442-5461. 10.1021/jm051199z .

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DOI: 10.1021/jm051199z

Abstract

A novel series of methyl ester-terminated C8-linked pyrrolobenzodiazepine (PBD)-poly(N-methylpyrrole) conjugates (50a-f) has been synthesized and their DNA interaction evaluated by thermal denaturation, DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit to a polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) compared to the individual PBD and pyrrole components. 50a-f were found to bind mainly to identical DNA sequences but with apparent binding site widths increasing with molecular length and the majority of sites conforming to the consensus motif 5'-XGXWz (z = 3 ± 1; W = A or T; X = any base but preferably a purine). They also provided robust sequence-selective blockade of transcription at sites corresponding approximately to their DNA footprints. 50a-f were shown to have good cellular/nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed.

Item Type:Article
Additional Information:Full text available in print and electronically from the School of Pharmacy Library.
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry
ID Code:933
Journal or Publication Title:Journal of Medicinal Chemistry
Deposited By:Library Staff
Deposited On:20 May 2008 15:04
Last Modified:12 May 2011 12:59

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