Ab Initio Studies of the Reaction of Hydrogen Transfer from DNA to the Calicheamicinone Diradical

Molecular Medicine 7(12): 797–802, 2001 © 2001 The Picower Institute Press Original Articles Ab Initio Studies of the Reaction of Hydrogen Transfer from DNA to the Calicheamicinone Diradical Anne-Marie Sapse,1,2 Robert Rothchild,1 Rohtash Kumar,3 and J. William Lown3 1 City University of New York, John Jay College and Graduate Center Rockefeller University, New York, NY, USA 3 Department of Chemistry, University of Alberta, Edmonton, Alberta, CA 2 Accepted November 27, 2001 Abstract Background: The biological activity of enediyne chemotherapeutic (anti-cancer) agents is attributed to their ability to cleave duplex DNA. Part of the reaction of cleavage is the abstraction of hydrogens from the deoxyribose moiety of DNA by the biradical formed via a Bergman rearrangement. Methods: The mechanism of the reaction of abstraction of two hydrogen atoms from two deoxyribophosphate molecules by the calicheamicinone biradical is studied with ab initio calculations at Hartree-Fock and post-Hartree-Fock level. The Titan program is used to perform the calculations. Results: It is found that the reactions are exothermic and thus thermodynamically reasonable. Conclusions: The mechanism of DNA cleavage by the enediyne-containing drugs is likely to proceed by the abstraction of the hydrogens from deoxyribose by the biradical formed by the drug. Further studies should determine in which way the modification of the drug’s structure would make this reaction even more exothermic and, thus, more likely to occur. Introduction lead compounds. They are of interest, not only because of their unusual structures, but also because of their novel mode of action (2–6). Typically, they are composed of three functional units: a) an enediyne which is a part of a 10-membered ring, b) a trigger mechanism which, through a chemical reaction, leads to a reactive enediyne and c) a moiety which is responsible for the molecular recognition of DNA. The biological activity of these compounds is attributed to their ability to cleave duplex DNA irreversibly, by the cyclization of the enediynes to afford aromatic compounds through the intermediacy of 1,4-dehydrobenzene biradicals, obtained via a Bergman rearrangement, as shown in Scheme 1. In general, DNA cleavage occurs in four phases: Modern strategies for the treatment of cancer using cytotoxic chemicals are generally based on the concept of prodrug activation, where the injected drug is a conjugate, acted upon by enzymes in the body in order to release the active form of the drug. Provided that the prodrugs can be delivered selectively to the tumor cells, for example by monoclonal antibodies, toxic effects during transport within the body would be minimized. On the other hand, if the activation of the drug would only be possible in tumor cells, a delivery device would be unnecessary. Still another similar concept relies on so-called ADEPT strategy (antibody dependent enzyme-mediated prodrug therapy) (1). The later requires that the prodrug is activated by an enzyme which has been delivered selectively to tumor cells by antibodies. In order to implement such strategies, suitable prodrugs have to be available which can be furnished with the various trigger devices. In this regard, several recently developed potent antitumor antibodies containing (Z)enediynes or related systems, represent promising Address correspondence and reprint requests to: Anne-Marie Sapse, John Jay College, 445 W 59th St. NY, NY, 10019, USA. Phone: (212) 237-8949; fax: (212) 935-3594; e-mail: . 1. Recognizing and binding to DNA by a specific structural feature covalently bonded or complexed to the enediyne. 2. Activation of the enediyne towards a Bergman rearrangement. 3. Bergman cyclization to give 1,4-dehydroarene biradicals. 4. Abstraction of hydrogen from DNA by the 1,4dehydroarene biradicals thereby inflicting permanent damage to the genetic material. 798 Molecular Medicine, Volume 7, Number 12, December 2001 Recently, the Janda group (12) proposed an alternative mechanism for the enediyne cyclization. They designed and synthesized a catalytic antibody that accelerates the Bergman cyclization of an enediynol substrate. Enediynol reacts to form a quinone by an oxidative route in aqueous buffer either in the presence, or absence, of a catalytic antibody. The proposed mechanism suggests that, at least in the presence of oxygen, it may be quinone formation rather than diradical formation that accounts for the DNA-cleaving ability of enediynes. However, Hamann and Wang (13) have carefully evaluated the “quinone” mechanism proposed by Janda et al. (12) and strongly support the conventional mechanism consisting of hydrogen transfer from the deoxyribose moiety of DNA to the calicheamicin diradical resulting from the Bergman cycloaromatization product. The mechanism of this reaction has been proposed by Ellestad et al. (14), and it is shown in Scheme 2. The diradical 1 becomes the monoradical 4 or 5, according to Path 1 or Path 2, by abstracting a hydrogen from compound 2. The deoxyribose monoradicals thus obtained (compounds 3 . . Scheme 1. A number of theoretical studies have tried to determine the structure of some of these compounds as well as their mode of action. They comprise PRDDO studies of calicheamicin and esperamicin enediyne moieties (7), density functional studies (8) and solvated molecular dynamics simulations (9). Our group applied ab initio and semi-empirical methods to the study of calicheamicinone and its undergoing the Bergman rearrangement (10,11). Esperamicin A1, calicheamicin 1 and other enediynes such as dynamicin A and Neocarzinostatin chromophore are shown in Rothchild et al. (10). O O S S NHCO2CH3 NHCO2CH3 H H HO HO . . OH OH . H 1 4 O O S S NHCO2CH3 NHCO2CH3 H H HO HO . H OH OH H H 5 6 Path I OPO3-2 H C O C O OH O OPO3-2 O2 O OH -2 OPO3-2 -2 OPO3 H O OPO3 7 2 CH2 H H OH Path II 8 C H 5' H abstraction O CH2 4' H abstraction . OH 9 CH2 H O H OH 3 . H H H . -2 OPO3 2 H O O2 . O O OH Scheme 2. A-M. Sapse et al.: Hydrogen Transfer: DNA to Calicheamicinone Diradical 799 Table l. The optimized energies of the molecules shown in Scheme 2. (au) Molecule Energy HF/6-31G* Calicheamicinone diradical (1) Deoxyribose phosphate (2) Deoxyribose phosphate monoradical (3) Calichaemicinone monoradical (4) Calicheamicinone monoradical (5) Calicheamicinone (6) Deoxyribose phosphate monoradical (7) Peroxydeoxyribose phosphate Monoradical (8) (R) (S) Peroxydeoxyribose phosphate Monoradical (9) (R) (S) O2 M3 1478.62907 M1 1478.51701 LMP2/6-31G*//HF/6-31G* M3 1481.81614 M1 1481.72662 M1 1060.58816 M2 1059.95348 1479.28075 1479. 28211 M1 1479.93989 M2 1059.95809 M1 1062.53345 M2 1061.89308 1482.48727 1482.48919 M1 1483.15674 M2 1061.90023 1209.59728 1209.59603 1211.88951 1211.88841 1209.59800 1209.60854 M3 149.59826 1211.89089 1211.90442 M3 14 (...truncated)