PMID: 7799403Dec 23, 1994Paper

Structure of a covalent DNA minor groove adduct with a pyrrolobenzodiazepine dimer: evidence for sequence-specific interstrand cross-linking

Journal of Medicinal Chemistry
T C JenkinsD E Thurston

Abstract

The structure of the interstrand cross-linked adduct formed between a C8-C8'-linked pyrrolobenzodiazepine (PBD) dimer (DSB-120; 1,1'-(propane-1,3-diyldioxy)bis[(11aS)-7-methoxy-1,2,3,11a-t etrahydro-5H- pyrrolo[2,1-c][1,4]benzodiazepin-5-one]) and a self-complementary d(CICGATCICG)2 duplex has been determined from high-field 1D- and 2D-NMR data using a simulated annealing procedure. The refined structure supports earlier observations from solution NMR experiments and indicates that the covalently bound molecule spans six DNA base pairs in the minor groove, forming a symmetric cross-link between the spatially separated internal guanines and with active recognition of an embedded 5'-GATC bonding site. This result confirms that template-directed approaches are useful for the design of linked DNA-interactive PBD dimers with viable DNA cross-linking potential. Further, head-to-head connection of the PBD moieties results in an overall retention of 5'-GA bonding site preference for each alkylating PBD subunit. Structural analysis indicates that cross-link formation results in a localized perturbation of the DNA duplex, attributable in part to a mutual reduction in dynamic mobility or "covalent clamping" within the Gua4-Cyt7 base tract...Continue Reading

Citations

Oct 13, 2001·Bioorganic & Medicinal Chemistry Letters·S J GregsonD E Thurston
Apr 5, 2011·Expert Opinion on Investigational Drugs·John A Hartley
Jul 16, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Donglu ZhangS Cyrus Khojasteh
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Nov 20, 2016·Angewandte Chemie·Julia MantajDavid E Thurston
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Jun 20, 2019·Journal of Cellular Physiology·Sajad YaghoubiMeghdad Abdollahpour-Alitappeh
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