Chemistry of the 2,5-Didehydropyridine Biradical:  Computational, Kinetic, and Trapping Studies toward Drug Design

Hoffner, Johannes; Schottelius, Marc J.; Feichtinger, Derek; Chen, Peter

doi:10.1021/ja9730223

Cited by 138 publications

(184 citation statements)

References 35 publications

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“…In addition, the difference in RE p [Eq. (2)] is smaller than NICS would indicate. This disagreement may originate from s effects which certainly influence the NICS value.…”

Section: Discussionmentioning

confidence: 82%

“…Unfortunately, toxic side effects of enediyne-carrying drugs are severe so that an understanding of the factors governing the generation of these biradicals is essential for further drug development. [1] Chen and coworkers [2] have taken promising steps toward greater selectivity by modifications in the enediyne precursors. This type of approach requires a detailed knowledge of the reaction mechanism in order to engineer p-benzyne derivatives with the desired properties.…”

Section: Introductionmentioning

confidence: 99%

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A Valence Bond Study of the Bergman Cyclization: Geometric Features, Resonance Energy, and Nucleus-Independent Chemical Shift (NICS) Values

et al. 2000

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The Bergman cyclization of (Z)-hex-3-ene-1,5-diynes (1, enediynes), which produces pharmacologically important DNA-cleaving biradicals (1,4-benzyne, 2), was studied by using Hartree-Fock (HF) and density-functional theory (DFT) based valence bond (VB) methods (VB-HF and VB-DFT, respectively). We found that only three VB configurations are needed to arrive at results not too far from complete active space [CASSCF(6 x 6)] computations, while the quality of VB-DTF utilizing the same three configurations improves upon CASSCF(6 x 6) analogous to CASPT2. The dominant VB configuration in 1 contributes little to 2, while the most important biradical configuration in 2 plays a negligible role in 1. The avoided crossing of the energy curves of these two configurations along the reaction coordinate leads to the transition state (TS). As a consequence of the shape and position of the crossing section, the changes in geometry and in the electronic wavefunction along the reaction coordinate are non-synchronous; the TS is geometrically approximately 80% product-like and electronically approximately 70% reactant-like. While the pi resonance in the TS is very small, it is large (64.4 kcal mol(-1)) for 2 (cf. benzene=61.5 kcal mol(-1)). As a consequence, substituents operating on the sigma electrons should be much more effective in changing the Bergman reaction cyclization barrier. Furthermore, additional sigma resonance in 2 results in unusually high values for the nucleus-independent chemical shift (NICS, a direct measure for aromaticity). Similarly, the high NICS value of the TS is due mostly to sigma resonance to which the NICS procedure is relatively sensitive.

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“…In addition, the difference in RE p [Eq. (2)] is smaller than NICS would indicate. This disagreement may originate from s effects which certainly influence the NICS value.…”

Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

A Valence Bond Study of the Bergman Cyclization: Geometric Features, Resonance Energy, and Nucleus-Independent Chemical Shift (NICS) Values

et al. 2000

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“…These compounds, however, are also destructive to healthy cells. An understanding of the factors that control the selectivity of aryl monoradicals and biradicals in H-atom abstraction reactions could aid the development of drugs that are more selective and, thus, less cytotoxic [10]. Here, we report the results for the first of a series of gas-phase studies on the selectivity of aryl radicals in H-atom abstraction reactions.…”

mentioning

confidence: 99%

Quantitative determination of the selectivities of five different phenyl radicals in hydrogen atom abstraction from ethanol

Jing

Guler

Nash

et al. 2004

J. Am. Soc. Mass Spectrom.

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An experimental method is described for obtaining quantitative selectivity information for H-atom abstraction by organic radicals from different sites of a substrate in the gas phase. The method is used to determine the selectivities of five different phenyl radicals toward the three different types of hydrogen atoms in ethanol. This experimental method involves studying the reactivities and selectivities of derivatives of the radicals that contain a chemically inert, charged group (distonic ions), which allows them to be manipulated in a Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometer. A large number of studies suggest that the action of some potential anti-tumor antibiotics is based on H-atom abstraction by aromatic, ,-biradical intermediates from a sugar moiety in DNA (which ultimately leads to cell death) [1][2][3][4][5][6][7][8][9]. These compounds, however, are also destructive to healthy cells. An understanding of the factors that control the selectivity of aryl monoradicals and biradicals in H-atom abstraction reactions could aid the development of drugs that are more selective and, thus, less cytotoxic [10]. Here, we report the results for the first of a series of gas-phase studies on the selectivity of aryl radicals in H-atom abstraction reactions.An examination of H-versus D-atom abstraction from a partially labeled substrate by a phenyl radical yields semi-quantitative information about the selectivity of the radical. The difficulty, however, is that the selectivity observed in such reactions does not exactly correspond to the selectivity that is observed for the same site in an unlabeled compound. If a kinetic isotope effect (KIE) exists, the presence of a heavy isotope can affect the relative abundances of the products. That is, D-atom abstraction is likely to be slower, relative to H-atom abstraction, from the same site in the same molecule. Thus, in order to use the results obtained from selectivity studies of reactions of deuterium labeled compounds to understand the selectivities of the reactions of unlabeled analogs, it is necessary to develop a method that accounts for any potential KIE.Dunlop and Tully have previously reported a method for obtaining site-specific rate constants for H-atom abstraction by HO⅐ from 2-propanol in the gas phase by using a laser photolysis/laser-induced fluorescence technique [11]. However, this approach is based on the assumption that the KIE measured for HO⅐ for abstraction of a primary (methyl) H-/D-atom from ethane, or neopentane, represents the relative reactivity of HO⅐ toward CH 3 -and CD 3 -groups in 2-propanol. Herein, we report an approach that can be used to obtain quantitative selectivity information for radicals in H-atom abstraction reactions that involve partially deuterium-labeled substrates without the assumption made by Dunlop and Tully, and the application of this method for the determination of the selectivities of five substituted phenyl radicals toward the three different types of hydrogen atoms in ethanol. Our method is ...

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“…We conclude that the singlet biradical 4-S has a sufficiently long lifetime to abstract hydrogen atoms from DNA, which requires an activation enthalpy of less than 12 kcal mol À1 . [62] Its S-T splitting (DHA C H T U N G T R E N N U N G (S-T) = 2.7 kcal mol À1 , model 6) is similar to that of p-benzyne [38] (see also Supporting Information).…”

mentioning

confidence: 73%

“…, Table 2) are considerably larger than the barrier for hydrogen abstraction from DNA (estimated to be 12 kcal mol À1 [62] ). 4) The docking investigation leads to an inhibition constant of 6.7 10 À10 mol and a complexation energy of À12.5 kcal mol .…”

mentioning

confidence: 91%

The Reactivity of Calicheamicin γ₁^I in the Minor Groove of DNA: The Decisive Role of the Environment

Kraka

Tuttle

2007

Chemistry A European J

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Triggering and Bergman cyclization of calicheamicin gamma(1) (I) outside and inside the minor groove of the duplex 9mer-B-DNA sequence d(CACTCCTGG).d(CCAGGAGTG) were investigated by using density functional theory and molecular mechanics (DFT and MM) descriptions in which the ligand is completely described at the DFT and the receptor at the MM level. The calculated docking energy of calicheamicin gamma(1) (I) (-12.5 kcal mol(-1)) is close to the measured value of -9.7 kcal mol(-1) and the site specificity is in line with experimental observations. Calicheamicin is triggered in the minor groove in such a way that out of a cyclohexenone by Michael addition an E rather than a Z form of a cyclohexanone is formed, which in turn adopts a chair rather than a twistboat form. Decisive for the stereochemistry of the Michael addition is the orientation of the carbamate substituent at the headgroup of calicheamicin. Triggered calicheamicin can undergo the Bergman cyclization at body temperature only if present in its E chair form (activation enthalpy 16.4 kcal mol(-1)). An intermediate biradical is formed (docking energy -13.6 kcal mol(-1)), which has a sufficient lifetime to abstract two hydrogen atoms. Hydrogen abstraction is a two- rather than one-step process and involves the C5(H5') atom first and then the T22(H4') atom in line with experimental observations. The decisive role of using a DFT rather than an MM description for the ligand is documented.

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Chemistry of the 2,5-Didehydropyridine Biradical: Computational, Kinetic, and Trapping Studies toward Drug Design

Cited by 138 publications

References 35 publications

A Valence Bond Study of the Bergman Cyclization: Geometric Features, Resonance Energy, and Nucleus-Independent Chemical Shift (NICS) Values

A Valence Bond Study of the Bergman Cyclization: Geometric Features, Resonance Energy, and Nucleus-Independent Chemical Shift (NICS) Values

Quantitative determination of the selectivities of five different phenyl radicals in hydrogen atom abstraction from ethanol

The Reactivity of Calicheamicin γ₁^I in the Minor Groove of DNA: The Decisive Role of the Environment

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Chemistry of the 2,5-Didehydropyridine Biradical: Computational, Kinetic, and Trapping Studies toward Drug Design

Cited by 138 publications

References 35 publications

A Valence Bond Study of the Bergman Cyclization: Geometric Features, Resonance Energy, and Nucleus-Independent Chemical Shift (NICS) Values

A Valence Bond Study of the Bergman Cyclization: Geometric Features, Resonance Energy, and Nucleus-Independent Chemical Shift (NICS) Values

Quantitative determination of the selectivities of five different phenyl radicals in hydrogen atom abstraction from ethanol

The Reactivity of Calicheamicin γ1I in the Minor Groove of DNA: The Decisive Role of the Environment

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Product

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The Reactivity of Calicheamicin γ₁^I in the Minor Groove of DNA: The Decisive Role of the Environment