Solution structure of a 2:1 C2-(2-naphthyl) pyrrolo[2,1-c][1,4]benzodiazepine DNA adduct: molecular basis for unexpectedly high DNA helix stabilization.

Antonow, D., Barata, T.S., Jenkins, T.C., Parkinson, D.N., Howard, P.W., Thurston, D.E. and Zloh, M. (2008) Solution structure of a 2:1 C2-(2-naphthyl) pyrrolo[2,1-c][1,4]benzodiazepine DNA adduct: molecular basis for unexpectedly high DNA helix stabilization. Biochemistry, 47 (45). pp. 11818-11829. 10.1021/bi801225q.

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DOI: 10.1021/bi801225q

Abstract

The naturally occurring pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomers cuch as sibiromycin, anthramycin and tomaymycin form stable covalent adducts with duplex DNA at purine-guanine-purine sites. A correlative relationship betwwen DNA-binding affinity, as measured by enhanced thermal denaturation temperature of calf thymus DNA (Tm), and cytotoxicity is well documented for these naturally occurring compounds and a range of synthetic analogues with sibiromycin have the highest deltaTm value (16.3 degrees C), reflecting favorable hydrogen-bonding interactions between the molecule and DNA bases. We report here that, surprisingly, the structurally simple synthetic C2-(2-naphthyl)-substituted pyrrolo [2,1-c][1,4]benzodiazepine monomer (5) has a deltaTm value (15.8 degrees C) similar to that of sibiromycin and significantly higher than the values for either anthramycin (13.0 degrees C) or tomaymycin(2.6 degrees C). 5 also has similar cytotoxic potency to sibiromycin which is widely regarded as the most potent naturally occurring PBD monomer. To investigate this, we have used NMR in conjunction with molecular dynamics to study the 2:1 adduct formed between 5 and the DNA duplex d(AATCTTTAAAGATT)2. In contrast to the hydrogen-bonding interactions which predominate in the case of sibiromycin and anthramycin adducts, we have shown that the high binding affiity of 5 is due predominantly to hydrophobic (van der Waals) interactions. The high-resolution 2D NOESY, TOCSY and COSY data obtained have also allowed unequivocal determination of the orientation of the PBD molecule (A-ring toward 3-end of covalently bound strand), the stereochemistry at the C11 position of the PBD (C115) and the conformation of the C2-naphthyl ring which extends along the floor of the minor groove thus optimizing hydrophobic interactions with DNA. These results provide opportunities for future drug design in terms of extending planar hydrophobic groups at the C2 position of PBDs to maximize binding affinity.

Item Type:Article
Additional Information:Full text available 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:1271
Journal or Publication Title:Biochemistry
Deposited By:Library Staff
Deposited On:07 Jul 2009 10:45
Last Modified:21 Oct 2011 14:32

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