Oxidative DNA Cleavage by the Antitumor Antibiotic Leinamycin and Simple 1,2-Dithiolan-3-one 1-Oxides:  Evidence for Thiol-Dependent Conversion of Molecular Oxygen to DNA-Cleaving Oxygen Radicals Mediated by Polysulfides

Mitra, Kaushik; Kim, Woongki; Daniels, and J. Scott; Gates, Kent S.

doi:10.1021/ja971359z

Cited by 94 publications

(91 citation statements)

References 25 publications

(39 reference statements)

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“…Our previous study revealed that leinamycin is able to produce reactive oxygen species (ROS) in addition to DNA alkylation with attack of the thiol on leinamycin [21,22]. In this reaction, ROS is generated from the persulfide through an initial reduction of molecular oxygen to superoxide radical, followed by disproportionation to hydrogen peroxide, leading to production of the hydroxyl radical via Fenton reaction chemistry [21].…”

Section: Introductionmentioning

confidence: 99%

“…In this reaction, ROS is generated from the persulfide through an initial reduction of molecular oxygen to superoxide radical, followed by disproportionation to hydrogen peroxide, leading to production of the hydroxyl radical via Fenton reaction chemistry [21]. The ability of leinamycin to produce ROS and unique types of DNA damage represents a new biochemical route that possesses strong cytotoxic activity against human cancer cells [21,22]. ROS is cytotoxic and intracellular generation of ROS can cause DNA strand cleavage and lead to cell death through general oxidative stress [23].…”

Section: Introductionmentioning

confidence: 99%

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Cellular Responses to the DNA Damaging Natural Compound Leinamycin

et al. 2013

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Leinamycin is a thiol dependent DNA alkylating agent which shows very potent activity against various human cancer cell lines (IC 50 values in the low nanomolar range). This natural compound forms guanine adducts (N7) in DNA which are converted into abasic sites and simultaneously generates Reactive Oxygen Species (ROS), to produce DNA strand breaks in human cancer cells. Our present study shows that leinamycin induces a group of DNA repair and transcription factor genes involved in DNA repair in a MDA-MB-231 human breast cancer cell line, which can mediate chemoresistance to leinamycin. In addition, N-acetylcysteine decreases leinamycin-mediated ROS production while increasing leinamycin mediated apoptotic cell death, without affecting the induction of repair genes. These data indicate that ROS is not a crucial player in leinamycin induced DNA damage and that a precursor of glutathione, N-acetylcysteine, can potentiate leinamycin mediated cytotoxicity by increasing the activation of leinamycin into its DNA reactive form.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cellular Responses to the DNA Damaging Natural Compound Leinamycin

et al. 2013

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“…[3][4][5][6] Initial attack of cellular thiols on leinamycin's 1,2-dithiolan-3-one 1-oxide "triggering unit" is believed to yield a key sulfenate intermediate (2) that undergoes intramolecular cyclization onto the neighboring carbonyl group. 7,8 The persulfide (3, RSS − ) ejected in this reaction causes oxidative stress, [9][10][11][12][13] while the resulting 1,2-oxathiolan-5-one derivative of leinamycin (4) undergoes further rearrangement to yield an episulfonium ion (5) that alkylates guanine residues in duplex DNA (Scheme 1). [8][9][10][11][12][13][14] The sulfenate ion (2) is proposed 7,8 to be a key intermediate in the thiol-triggered conversion of leinamycin to a DNA-alkylating episulfonium ion; however, to date, there is no experimental support for the existence of this entity.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 The persulfide (3, RSS − ) ejected in this reaction causes oxidative stress, [9][10][11][12][13] while the resulting 1,2-oxathiolan-5-one derivative of leinamycin (4) undergoes further rearrangement to yield an episulfonium ion (5) that alkylates guanine residues in duplex DNA (Scheme 1). [8][9][10][11][12][13][14] The sulfenate ion (2) is proposed 7,8 to be a key intermediate in the thiol-triggered conversion of leinamycin to a DNA-alkylating episulfonium ion; however, to date, there is no experimental support for the existence of this entity. In an effort to fill this gap in our knowledge, we set out to generate discrete sulfenate ions related to 2 and determine whether these intermediates are, in fact, competent to enter the leinamycin rearrangement reaction manifold.…”

Section: Introductionmentioning

confidence: 99%

Entering the leinamycin rearrangement via 2-(trimethylsilyl)ethyl sulfoxides

Keerthi

Gates

2007

Org. Biomol. Chem.

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Attack of cellular thiols on the antitumor natural product leinamycin is believed to generate a sulfenate intermediate that undergoes subsequent rearrangement to a DNA-alkylating episulfonium ion. Here, 2-(trimethylsilyl)ethyl sulfoxides were employed in a fluoride-triggered generation of sulfenate anions related to the putative leinamycin-sulfenate. The resulting sulfenates enter smoothly into a leinamycin-type rearrangement reaction to afford an episulfonium ion alkylating agent. The results provide evidence that the sulfenate ion is, indeed, a competent intermediate in the leinamycin rearrangement. Further, the molecules examined here may provide a foundation for the design of functional leinamycin analogues that bypass the unstable and synthetically challenging 1,2-dithiolan-3-one 1-oxide moiety found in the natural product.

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“…[1][2][3][4][5] Reaction of thiols with leinamycin leads to ejection of a persulfide intermediate (2) that generates cell-killing reactive oxygen species (Scheme 1). [6][7][8][9] In addition, the 1,2-oxathiolan-5-one derivative (3) formed in this reaction undergoes further rearrangement to an episulfonium ion (4) that efficiently alkylates guanine residues in duplex DNA. 6,10 The resulting 7-alkylguanine residues undergo rapid depurination to generate a burst of cytotoxic abasic sites in duplex DNA.…”

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confidence: 99%

Possible chemical mechanisms underlying the antitumor activity of S-deoxyleinamycin

Sivaramakrishnan

Gates

2008

Bioorganic & Medicinal Chemistry Letters

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Though less potent than the parent natural product leinamycin, S-deoxyleinamycin displays activity against human cancer cell lines that is comparable to many clinically-used agents. The results reported here suggest that the 1,2-dithiolan-3-one heterocycle found in S-deoxyleinamycin reacts with thiols to generate a persulfide intermediate (RSS − ) that could deliver biologically active polysulfides, hydrogen sulfide, and reactive oxygen species (O 2 • − , H 2 O 2 , and HO•) to the interior of cells.Leinamycin (1) is a structurally interesting natural product that displays impressive, nanomolar IC 50 -values against human cancer cell lines. 1-5 Reaction of thiols with leinamycin leads to ejection of a persulfide intermediate (2) that generates cell-killing reactive oxygen species (Scheme 1). [6][7][8][9] In addition, the 1,2-oxathiolan-5-one derivative (3) formed in this reaction undergoes further rearrangement to an episulfonium ion (4) that efficiently alkylates guanine residues in duplex DNA. 6,10 The resulting 7-alkylguanine residues undergo rapid depurination to generate a burst of cytotoxic abasic sites in duplex DNA. [11][12][13] The reaction with thiols may be central to the potent biological activity of leinamycin because cells contain millimolar concentrations of the thiol-containing tripeptide glutathione 14 that can trigger the release of cell killing reactive intermediates from this natural product.In light of the central role played by leinamycin's sulfoxide oxygen in the generation of cytotoxic reactive intermediates (Scheme 1), it is not surprising that S-deoxyleinamycin (5) is markedly less cytotoxic than leinamycin. For example, 5 displays an IC 50 value of 4 μM against HeLa S3 cells, whereas that for leinamycin is 27 nM. 3 Despite its diminished cytotoxicity relative to leinamycin, it is important to note that the activity of 5 is comparable to some clinically-used anticancer drugs. 15 Accordingly, studies of 5 have the potential to reveal new chemical processes by which organic molecules can elicit anticancer activity.Previous work has shown that 5 does not cause thiol-triggered DNA alkylation; 3 however, our previous experience with related sulfur heterocycles [16][17][18][19] led us to consider the possibility that reactions of thiols with the 1,2-dithiolan-3-one heterocycle in 5 might lead to the generation of superoxide radical (O 2 • − ). Under physiological conditions, superoxide radical decomposes to hydrogen peroxide and, ultimately, hydroxyl radical as shown in the (unbalanced) Eqns 4 -5, where M represents a transition metal such as iron or copper. 20 Intracellular production of *Corresponding author. Tel.: +1-573-882-6763; fax: +1-573-882-2754, e-mail gatesk@missouri.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in ...

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Oxidative DNA Cleavage by the Antitumor Antibiotic Leinamycin and Simple 1,2-Dithiolan-3-one 1-Oxides: Evidence for Thiol-Dependent Conversion of Molecular Oxygen to DNA-Cleaving Oxygen Radicals Mediated by Polysulfides

Cited by 94 publications

References 25 publications

Cellular Responses to the DNA Damaging Natural Compound Leinamycin

Cellular Responses to the DNA Damaging Natural Compound Leinamycin

Entering the leinamycin rearrangement via 2-(trimethylsilyl)ethyl sulfoxides

Possible chemical mechanisms underlying the antitumor activity of S-deoxyleinamycin

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