TY - JOUR
T1 - Structure of a Covalent DNA Minor Groove Adduct with a Pyrrolobenzodiazepine Dimer
T2 - Evidence for Sequence-Specific Interstrand Crosslinking
AU - Jenkins, Terence C.
AU - Hurley, Laurence H.
AU - Neidle, Stephen
AU - Thurston, David E.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 1994/12/1
Y1 - 1994/12/1
N2 - 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-tetrahydro-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. However, ligand-induced distortion is confined to the Cyt7 and Ino8 residues on each strand. The Gua(N2)-Gua(N2) cross-link is stabilized by two directed H-bonds from the formed aminal residues to N3 acceptor atoms of adenine bases on the 3′-side of each covalently modified guanine. Evidence for sequence-specific cross-linking with DSB-120 is provided by extended modeling studies which suggest that recognition of the favored d(·GATC·) motif is dominated by van der Waals steric factors, although electrostatic and H-bonded interaction terms also play a key role. This conclusion supports recent covalent footprinting studies revealing that this PBD dimer shows a selectivity for embedded base sequences of the type 5′-(pu/py)GATC(py/pu).
AB - 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-tetrahydro-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. However, ligand-induced distortion is confined to the Cyt7 and Ino8 residues on each strand. The Gua(N2)-Gua(N2) cross-link is stabilized by two directed H-bonds from the formed aminal residues to N3 acceptor atoms of adenine bases on the 3′-side of each covalently modified guanine. Evidence for sequence-specific cross-linking with DSB-120 is provided by extended modeling studies which suggest that recognition of the favored d(·GATC·) motif is dominated by van der Waals steric factors, although electrostatic and H-bonded interaction terms also play a key role. This conclusion supports recent covalent footprinting studies revealing that this PBD dimer shows a selectivity for embedded base sequences of the type 5′-(pu/py)GATC(py/pu).
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U2 - 10.1021/jm00052a012
DO - 10.1021/jm00052a012
M3 - Article
C2 - 7799403
AN - SCOPUS:0028600121
VL - 37
SP - 4529
EP - 4537
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 26
ER -