Thiol-Independent DNA Alkylation by Leinamycin

Breydo, Leonid; Hong, Zhou; Mitra, Kaushik; Gates, Kent S.

doi:10.1021/ja003309r

Cited by 51 publications

(42 citation statements)

References 21 publications

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“…80 As shown in Fig. 8, the natural product is activated by nucleophilic attack of a thiol 81 (although water activation is also possible) 82 , delivering a reactive dithioester and a sulfenic acid. The sulfenic acid then attacks the ester to form an oxathiolanone.…”

Section: Figmentioning

confidence: 99%

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

2016

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Developments in epigenomics, toxicology, and therapeutic nucleic acids all rely on a precise understanding of nucleic acid properties and chemical reactivity. In this review we discuss the properties and chemical reactivity of each nucleobase and attempt to provide some general principles for nucleic acid targeting or engineering. For adenine-thymine and guaninecytosine base pairs, we review recent quantum chemical estimates of their Watson-Crick interaction energy, - stacking energies, as well as the nuclear quantum effects on tautomerism. Reactions that target nucleobases have been crucial in the development of new sequencing technologies and we believe further developments in nucleic acid chemistry will be required to deconstruct the enormously complex transcriptome.

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Section: Figmentioning

confidence: 99%

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

2016

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“…Previous studies suggest that the 1, 2-dithiolan-3-one 1-oxide in leinamycin is the primary target of thiol attack as described in Figure 1 [6][7][8]. This reaction leads to the conversion of this heterocyle to a 1, 2-oxathiolan-5-one which undergoes a novel rearrangement reaction to produce a DNA attacking episulfonium ion [6][7][8]. This episulfonium ion associates noncovalently with the double stranded DNA and alkylates the N7 position of the guanine residue very efficiently [6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 97%

“…Leinamycin has shown to have potent anticancer activity in both in vivo and in vitro tumor models and is currently under consideration to be developed as an anticancer agent [5]. Previous studies suggest that the 1, 2-dithiolan-3-one 1-oxide in leinamycin is the primary target of thiol attack as described in Figure 1 [6][7][8]. This reaction leads to the conversion of this heterocyle to a 1, 2-oxathiolan-5-one which undergoes a novel rearrangement reaction to produce a DNA attacking episulfonium ion [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…This reaction leads to the conversion of this heterocyle to a 1, 2-oxathiolan-5-one which undergoes a novel rearrangement reaction to produce a DNA attacking episulfonium ion [6][7][8]. This episulfonium ion associates noncovalently with the double stranded DNA and alkylates the N7 position of the guanine residue very efficiently [6][7][8][9][10]. The guanine adduct is the only covalent DNA lesion which is formed by the reaction of thiol activated leinamycin with double stranded DNA.…”

Section: Introductionmentioning

confidence: 99%

“…For example, NAC attenuates cisplatin induced acute renal failure [29]. Leinamycin is a thiol dependent DNA damaging agent [6][7][8] and NAC is a thiol compound and precursor of reduced glutathione (GSH) [28]. Therefore, it is important to understand how NAC can modulate the cytotoxic effect of leinamycin in human cancer cells.…”

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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The Chemical Reactions of DNA Damage and Degradation

Gates

2006

Reviews of Reactive Intermediate Chemistry

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Thiol-Independent DNA Alkylation by Leinamycin

Cited by 51 publications

References 21 publications

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

Cellular Responses to the DNA Damaging Natural Compound Leinamycin

The Chemical Reactions of DNA Damage and Degradation

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