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Studies on DNA-Cleaving Agents: Computer Modeling Analysis of the Mechanism of Activation and Cleavage of Dynemicin- Oligonucleotide Complexes PAUL A

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Studies on DNA-Cleaving Agents: Computer Modeling Analysis of the Mechanism of Activation and Cleavage of Dynemicin- Oligonucleotide Complexes PAUL A Proc. Nati. Acad. Sci. USA Vol. 88, pp. 8835-8839, October 1991 Chemistry Studies on DNA-cleaving agents: Computer modeling analysis of the mechanism of activation and cleavage of dynemicin- oligonucleotide complexes PAUL A. WENDER*, ROBERT C. KELLYt, SUZANNE BECKHAM, AND BENJAMIN L. MILLER Department of Chemistry, Stanford University, Stanford, CA 94305 Communicated by John I. Brauman, July 15, 1991 (receivedfor review May 13, 1991) ABSTRACT Dynemicin A is a recently identified antitu- 506, version 2.1) with the AM1 Hamiltonian (7).] Abstraction mor antibiotic. Upon activation, dynemicin is reported to cause ofproximate deoxyribosyl hydrogens by this diradical would double-stranded cleavage of DNA, putatively through the initiate oxidative cleavage on opposing DNA strands. Con- intermediacy of a diradical. Computer modeling of this acti- version of diradical 4 to the alternative ene-diyne structure 7 vation and cleavage process is described herein as part of an is not observed. effort to establish a structural hypothesis for this mechanistic Semiempirical (8) and molecular mechanics (9) studies on sequence and for the design of simple analogues. Intercalation dynemicin itself have provided valuable information in sup- complexes of duplex dodecamers [d(CGCGAATTCGCG)J2 port of the above mechanism. Thus far, however, computa- and [d(GC)6]2 with both enantiomers of dynemicin and of all tional methods have not been used to evaluate the role of related mechanistic intermediates are evaluated. Examination DNA in the mode of action ofdynemicin, although they have of these structures shows that cycloaromatization of dynemicin been applied to calicheamicin (10) and neocarzinostatin (11), to a diradical intermediate results in the rotation of the yielding models that are consistent with known DNA cleav- diradical-forming subunit with respect to the intercalation age patterns. We describe herein computer modeling studies plane that is of an opposite sense for the two dynemicin designed to delineate at the molecular level the interaction of enantiomers. In addition, the activation of the (2S) enantiomer dynemicin and dynemicin-derived intermediates with oligo- of dynemicin occurs by a less restricted approach trajectory nucleotides selected to emulate native DNA. These studies than (2R) enantiomer. In all complexes, the address several fundamental issues that are crucial to the the corresponding development ofa structural hypothesis for the mode ofaction 5'-3' strand is at least 1 A closer than the 3'-5' strand to the of dynemicin and its analogues, including (i) the mechanistic diyl intermediate. As a result, complexes are produced in which fate ofthe two possible enantiomers of dynemicin [structures the diyl moiety is aligned along [(2S)J or across [(2R)] the minor 1-(2R) or 1-(2S)], a point of much interest since the absolute groove, leading to different predictions for the selectivity of stereochemistry of dynemicin is as yet unknown, (ii) the radical-initiated, oxidative lesion of DNA. Molecular dynamics effect of nucleophile size and approach trajectory in the simulations are found to support these predictions, including activation step and the dynamics of this activation process, the 3-base-pair offset cleavage reported for dynemicin. (iii) the influence of oligonucleotide sequence and length on dynemicin intercalation and activation, and (iv) the relation- The cleavage of DNA is a key process in the transfer of ship of intercalation sites to cleavage sites. The answers to genetic information, the mode of action of certain chemo- these questions provide a structural basis for evaluating therapeutic agents, and the function of reagents designed for mechanistic proposals, for predicting DNA cleavage pat- DNA modification and structure determination. DNA cleav- terns, and for designing new cleaving agents based on the age can be effected with a variety of agents ranging from the dynemicin lead. simple hydroxyl radical to relatively complex restriction enzymes. Within the past 5 years, the antitumor antibiotics calicheamicin (1), esperamicin (2), and neocarzinostatin (3) METHODS have emerged as a new structural and mechanistic class of A DNA octamer corresponding to [d(CGAATTCG)L2 and DNA-cleaving agents that are proposed to operate through dodecamers corresponding to [d(CGCGAATTCGCG)]2 and the inducible generation ofan arenyl or indenyl diradical. The [d(GC)62 were constructed in B-DNA form by using the most recently identified member of this class is dynemicin A program MACROMODEL (versions 2.0 and 3.0; W. C. Still, (structure 1 in Scheme I), a compound that exhibits potent Columbia University) running on a MicroVax 3900 and Evans cytotoxicity and in vivo antitumor activity (4, 5). Dynemicin and Sutherland PS340 system. All sequences were minimized has been shown to interact with the minor groove of DNA to a gradient of <0.100 kJ/mol per A under the AMBER force and, upon activation, to cause double-strand breaks 3 base field (12) before intercalation experiments were begun. Both pairs (bp) apart (6). Examination of the structure of dynemi- enantiomers corresponding to dynemicin A 1, the putative cin suggests that it could be activated for DNA cleavage quinone methide intermediate 2, the proposed quinone me- through reduction of its anthraquinone subunit, resulting in thide addition product 3, and a surrogate for the cyclized, heterolysis of the adjacent epoxide ring. Addition of a nu- diradical intermediate 5 were minimized to a gradient of cleophile to, or protonation of, the resultant anthraquinone <0.200 kJ/mol per A by using the MM2 force field (13, 14). methide (structure 2 in Scheme I) would provide an activated A surrogate for diradical intermediate 4 was necessary be- derivative 3 which, in the absence ofthe constraints imposed cause current molecular mechanics force fields are not pa- by the original epoxide ring, would undergo facile cycloar- rameterized for diradicals; the pyrazine ring was chosen as a omatization to diradical 4 (Scheme I). [Heats of formation surrogate because of its geometric similarity to the putative were determined by using the AMPAC program (QCPE no. diradical species. As the current parameter set available in The publication costs of this article were defrayed in part by page charge *To whom reprint requests should be addressed. payment. This article must therefore be hereby marked "advertisement" tSenior Scientist on leave from the Upjohn Company, Kalamazoo, in accordance with 18 U.S.C. §1734 solely to indicate this fact. MI 49001. 8835 Downloaded by guest on October 2, 2021 8836 Chemistry: Wender et al. Proc. Natl. Acad. Sci. USA 88 (1991) 25 24 0 OH 0 HN O,-89.261 wlroH OH 0 HN OH '- - OCH3 - -89.261 kcaVmol -125.574 kcaVrmol OH 0 OH OH OH OH 2 NOHB C 3 N N 0 0 0 OH OH OH HN OH OH OH HNHOP OH OH OH HNHO OH - NN E CH3 -, N N OCH3 p H H > H -147.107 kcaVmol -131.156 kcaVmol OH OH OH OHOH OH OH OH OH 3 4 5 0 0 OH OH HNHO OH OH OHHNHO OH NCOCHH 3 H I H -1 55.887 kcaVmol -255.815 kcal/mol OH OH OH OH OH OH 7 6 Scheme I AMBER did not extend to acetylenes, it was necessary to H-N-N angle. The H-lone pair-N angle was obtained from introduce standard parameters from MM2 into AMBER. In the this value, and the measured N-H distance by triangulation, case of stretching interactions, this was done by multiplying where the N-lone pair distance was set to 0.600 A, the value the MM2 constant by a proportionality factor; with other given in the MM2 force field (13, 14). parameters it was possible to use them without modification, Molecular dynamics simulations were carried out by using or to use values for available substructures in AMBER which the minimized complexes of 5-(2R) and 5-(2S) with [d(CGC- had force constants in MM2 identical to those of acetylenes. GAATTCGCG)h2 as starting structures. Bonds to hydrogen The resulting modified AMBER force field gave structures that were constrained with the SHAKE algorithm (16), and the were identical to those obtained with MM2 and, for dyne- thermal stability of each system was maintained by coupling micin A itself, produced a structure consistent with the x-ray to a 300 K external bath (17). Following a 15-ps preequili- crystallographic structure (5). (Copies of the modified pa- bration, the complexes were observed for 30 ps. A timestep rameters used in these calculations are available from the of 1 fs was used during both the preequilibration and obser- authors upon request.) vation periods, and the nonbonded interaction array was Initial intercalation spaces in the duplex oligonucleotides updated every 0.5 ps. were formed by docking only the anthraquinone portion of dynemicin into position between base pairs and minimizing for 1000 iterations under AMBER. The intercalator was then RESULTS removed, and the molecule of interest was placed into the Because of the absence of DNA cleavage data at the outset gap. The entire structure was then minimized to a gradient of ofthis study, G+C- and A+T-rich oligonucleotide sequences <0.200 kJ/mol per A by using the modified force field. were selected to explore two generic intercalation sites. Structures used to study the effect of nucleophile size on Sequence selection around these sites was guided by sym- DNA structure and strain energy were generated by adding metry considerations (to simplify calculations) and/or by the a hydrogen at C8 of 2 in the minimized complex, rearranging availability of solid state (18) or solution phase (19-24) the bond orders to give an unminimized form of 3, and structural information (for calibration). Sequence length was carrying out a substructure minimization on C8 to permit that initially set at 8 bp to minimize computational time. How- atom to pyramidalize. This yielded a complex designed to ever, an early finding of this study was that the intercalation mimic the conditions that would exist immediately after complexes ofthe resultant duplex octamers exhibit disrupted addition of a nucleophile.
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