Reactions of the trisulfide moiety in calicheamicin

Ellestad, George A.; Hamann, Philip R.; Zein, Nada; Morton, George O.; Siegel, Marshall M.; Pastel, Michael J.; Borders, Donald B.; McGahren, William J.

doi:10.1016/s0040-4039(00)99395-x

Cited by 39 publications

(27 citation statements)

References 14 publications

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“…The fast kinetics during the first 5 min of the reaction might possibly indicate that supercoiled DNA is a better substrate for calicheamicinone binding than nicked DNA. More likely, it could reflect conversion of the drug to a less active form, whose action accounts for the slower terminal kinetics (15). Similar results were obtained at lower drug concentrations: rapid initial kinetics and a rather low percentage of linear molecules, even when all of the DNA was cut at the end of the experiment.…”

Section: Resultssupporting

confidence: 67%

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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Section: Resultssupporting

confidence: 67%

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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“…In support of the initiation reaction by nucleophilic attact, Ellestad et al first discovered an extensive array of sulfide exchange reactions with 18 in the presence of various thiols in organic medium [67]. These reactions were found to be highly solventdependent and during this work, the chemistry to convert 18 to derivatized disulfide calicheamicins was established [68].…”

mentioning

confidence: 92%

Understanding and Exploiting Natures Chemical Arsenal: The Past,Present and Future of Calicheamicin Research

Thorson

Sievers²,

Ahlert³

et al. 2000

CPD

158

136

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The enediyne antitumor antibiotics are appreciated for their novel molecular architecture, their remarkable biological activity and their fascinating mode of action and many have spawned considerable interest as anticancer agents in the pharmaceutical industry. Of equal importance to these astonishing properties, the enediynes also offer a distinct opportunity to study the unparalleled biosyntheses of their unique molecular scaffolds and what promises to be unprecedented modes of self-resistance to highly reactive natural products. Elucidation of these aspects should unveil novel mechanistic enzymology, and may provide access to the rational biosynthetic modification of enediyne structure for new drug leads, the construction of enediyne overproducing strains and eventually lead to an enediyne combinatorial biosynthesis program. This article strives to compile and present the critical research discoveries relevant to the clinically most promising enediyne, calicheamicin, from a historical perspective. Recent progress, particularly in the areas of biosynthesis, self-resistance, bio-engineering analogs and clinical studies are also highlighted.

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“…The aromatic hydrodisulfide anion may therefore be considered as the better leaving group, thus favoring path 2 over path 1 (scheme 1) (polarization of the sulfur atom will also stabilize the intermediate thiophosphonium ion 8). This type of intermediate has been reported in the desulfurization of calicheamicin γ I 1 [41]. However, to obtain 3, the reaction presumably proceeds via intermediate 7, assuming that the only sulfur that can be extruded is the central one, i.e.…”

Section: Loss Of 4 Amentioning

confidence: 63%

“…Nucleophile displacement at sulfur ultimately results in displacement of the thermodynamically more stable mercaptide, or hydrodisulfide, ion [30,31,40,41]. Although the pK a for phenylhydrodisulfide (PhSSH) has not been measured in solution, gas phase calculations [42] predict it to be lower than that of 4-methylbenzene thiol (6), in accord with the calculated relative acidities of polysulfanes (HS n H) in the gas phase [43].…”

Section: Loss Of 4 Amentioning

confidence: 98%

Desulfurization of aromatic polysulfides with triphenylphosphine

Zysman‐Colman¹,

Farrell²,

Harpp³

2004

Journal of Sulfur Chemistry

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The room temperature reaction of bis(4-methylbenzene) di-(3), tri-(4) and tetrasulfide (5) with triphenylphosphine has been followed by 1 H NMR. Mechanistic aspects of the cleavage of 3 and the desulfurization of 4 and 5, with concomitant formation of triphenylphosphine sulfide, are discussed. While tetrasulfide 5 is desulfurized over 10× faster than trisulfide 4, preliminary experiments indicate that 5 is not sufficiently reactive to efficiently transfer a sulfur atom to oligodeoxyribonucleotides.

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Reactions of the trisulfide moiety in calicheamicin

Cited by 39 publications

References 14 publications

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

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

Understanding and Exploiting Natures Chemical Arsenal: The Past,Present and Future of Calicheamicin Research

Desulfurization of aromatic polysulfides with triphenylphosphine

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