Kinetic evidence for the formation of discrete 1,4-dehydrobenzene intermediates. Trapping by inter- and intramolecular hydrogen atom transfer and observation of high-temperature CIDNP

Lockhart, Thomas P.; Comita, Paul B.; Bergman, Robert G.

doi:10.1021/ja00404a018

Cited by 219 publications

(68 citation statements)

References 3 publications

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“…The enediyne function present within the core structure (Fig. 2, 1) undergoes coupling [Bergman reaction (29)] to the benzene diyl 2. Hydrogen atom abstraction occurs at both strands of the DNA duplex to provide the reduction product 3 and a DNA diradical that undergoes reaction with dioxygen, ultimately leading to double-strand breakage.…”

Section: General Features Of Glycoconjugate Ligands To Dnamentioning

confidence: 99%

Model of the interactions of calichemicin gamma 1 with a DNA fragment from pBR322.

Hawley

Kiessling²,

Schreiber³

1989

Proc. Natl. Acad. Sci. U.S.A.

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An analysis of the binding interactions of several DNA-drug complexes that utilize carbohydrates for DNA recognition has been undertaken. It is proposed that the carbohydrate residues function as general minor groove binding elements, and the stereochemistry of aglycone attachment sites is generally disposed to promote a right-handed helical geometry that is complementary to right-handed DNA. The constitution and stereochemistry of the DNA double-strand cleaving agent calichemicin yj is consistent with this analysis.Docking experiments with computer-generated models of this drug and a dodecamer duplex that was found to serve as a calichemicin cleavage site were performed to gain insight into the origin of the drug's sequence-selective binding and cutting properties. A model is presented that provides a molecular level understanding of the double-strand cleavage patterns that result from the action of calichemicin yV on DNA.

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Section: General Features Of Glycoconjugate Ligands To Dnamentioning

confidence: 99%

Model of the interactions of calichemicin gamma 1 with a DNA fragment from pBR322.

Hawley

Kiessling²,

Schreiber³

1989

Proc. Natl. Acad. Sci. U.S.A.

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“…Cleavage takes place at the 5'C and three nucleotides toward the 3' side of its complementary G residue. It has been proposed (5) that bioreductive activation of the trisulfide leads to formation of a thiolate species, which after a Michael addition to the adjacent trigonal carbon results in aromatization of the diyne-ene moiety by way of a Bergman reaction (7). The resulting biradical species is responsible for the DNA cleavage properties of the drug (Fig.…”

mentioning

confidence: 99%

The carbohydrate domain of calicheamicin gamma I1 determines its sequence specificity for DNA cleavage.

Drak

Iwasawa

Danishefsky

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

118

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We have investigated the DNA cleaving properties of calicheamicinone, the synthetic core aglycone of calicheamicin y', a natural product with extremely potent antitumor activity. Our experiments have shown that the synthetic analog binds and cleaves DNA, albeit without any sequence selectivity and with less efficiency than the natural compound. We propose that a key element in the sequence recognition process is the thiobenzoate ring present in the natural compound. We have demonstrated by one-dimensional NMR that there is direct hydrogen abstraction from DNA by calicheamicinone, with enhanced binding affinity contributed by the carbohydrate domain. The reduced efficiency of hydrogen abstraction from DNA by bound calicheamicinone, compared with the natural compound, implicates the carbohydrate moiety in positioning the drug for hydrogen abstraction.

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“…Diazene thermolysis produces both diyl 14 and its resonance form 15. Propagation analysis is pcrformcd as if thcse are separate diyls: exo cyclization to 16 is thc only reaction available for 14, while 15 undcrgocs a similar 1,7 exo closure at one radical site as well as a subphasc I cxo hcxcnyl closure for the alternate radical atom. In addition, cxo closure to the stabilizcd 18 precludes endo cyclization to the unstabilized cyclohexyl radical.…”

Section: Initiation;mentioning

confidence: 99%

Computer assisted analysis of reactions involving organic free radicals and diradicals

Laird¹,

Jorgensen²

1990

J. Chem. Inf. Comput. Sci.

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Recent extensions to the CAMEO program include a mechanistic model for free radical chain reactions. The controlling algorithm treats all reactions as a series of fundamental radical processes, i t . , abstractions, additions, and fragmentations. Chain propagating steps are mimicked by automatic resubmission of selected intermediates. Refinements for integration of biradical processing are described. Several prominent examples that demonstrate the synthetic utility of free radical reactions and the success of the CAMEO program in predicting complex sequences are presented.

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Kinetic evidence for the formation of discrete 1,4-dehydrobenzene intermediates. Trapping by inter- and intramolecular hydrogen atom transfer and observation of high-temperature CIDNP

Abstract: The observation of CIDNP, coupled with the reactivity exhibited by ~Z and the other two intermediates, implicate a biradical description of these molecules.

Cited by 219 publications

References 3 publications

Model of the interactions of calichemicin gamma 1 with a DNA fragment from pBR322.

Model of the interactions of calichemicin gamma 1 with a DNA fragment from pBR322.

The carbohydrate domain of calicheamicin gamma I1 determines its sequence specificity for DNA cleavage.

Computer assisted analysis of reactions involving organic free radicals and diradicals

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