Mitomycin derivatives. 2. Derivatives of decarbamoylmitosane and decarbamoylmitosene

Kinoshita, Shukuo; Uzu, Keizo; Nakano, K.; Takahashi, Toshinaka

doi:10.1021/jm00284a006

Cited by 63 publications

(36 citation statements)

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“…MC was generously gifted by Professor Maria Tomasz. DMC was synthesized from MC by a published procedure . Phosphodiesterase I (snake venom diesterase (SVD), Crotalus adamanteus venom, E.C.…”

Section: Methodsmentioning

confidence: 99%

“…DMC was synthesized from MC by ap ublished procedure. [41] [12,23] Reproducibility Reactions under bifunctional conditions were repeated at least twice independently and average deviation from the mean value is represented with error bars on graphs or in brackets in tables. Autocatalytic activation reactions were only performed once as they were repeats of previous experiments.…”

Section: Methodsmentioning

confidence: 99%

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Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin C

Aguilar

Paz

Vargas

et al. 2018

Chemistry A European J

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Mitomycin C (MC), an antitumor drug, and decarbamoylmitomycin C (DMC), a derivative of MC, alkylate DNA and form deoxyguanosine monoadducts and interstrand crosslinks (ICLs). Interestingly, in mammalian culture cells, MC forms primarily deoxyguanosine adducts with a 1"-R stereochemistry at the guanine-mitosene bond (1"-α) whereas DMC forms mainly adducts with a 1"-S stereochemistry (1"-β). The molecular basis for the stereochemical configuration exhibited by DMC has been investigated using biomimetic synthesis. Here, we present the results of our studies on the monoalkylation of DNA by DMC. We show that the formation of 1"-β-deoxyguanosine adducts requires bifunctional reductive activation of DMC, and that monofunctional activation only produces 1"-α-adducts. The stereochemistry of the deoxyguanosine adducts formed is also dependent on the regioselectivity of DNA alkylation and on the overall DNA CG content. Additionally, we found that temperature plays a determinant role in the regioselectivity of duplex DNA alkylation by mitomycins: At 0 °C, both deoxyadenosine (dA) and deoxyguanosine (dG) alkylation occur whereas at 37 °C, mitomycins alkylate dG preferentially. The new reaction protocols developed in our laboratory to investigate DMC-DNA alkylation raise the possibility that oligonucleotides containing DMC 1"-β-deoxyguanosine adducts at a specific site may be synthesized by a biomimetic approach.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin C

Aguilar

Paz

Vargas

et al. 2018

Chemistry A European J

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“…Proof for the cross-link adduct as the critical cytotoxic lesion among the six MC adducts was provided by a study of 10-decarbamoyl mitomycin C ( 2; DMC), an artificial derivative obtained from MC by chemical removal of the 10-carbamoyl group [15]. DMC has long been regarded as an innocuous monofunctional MC derivative, incapable of causing ICLs, on account of lacking its carbamate alkylating center.…”

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confidence: 99%

Differential Toxicity of DNA Adducts of Mitomycin C

Bargonetti

Champeil

Tomasz

2010

Journal of Nucleic Acids

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The clinically used antitumor agent mitomycin C (MC) alkylates DNA upon reductive activation, forming six covalent DNA adducts in this process. This review focuses on differential biological effects of individual adducts in various mammalian cell cultures, observed in the authors' laboratories. Evidence is reviewed that various adducts are capable of inducing different cell death pathways in cancer cells.This evidence is derived from a parallel study of MC and its derivatives 2,7-diaminomitosene (2,7-DAM) which is the main metabolite of MC and forms two mono-adducts with DNA, and decarbamoyl mitomycin C (DMC), which alkylates and cross-links DNA, predominantly with a chirality opposite to that of the DNA adducts of MC. 2,7-DAM is not cytotoxic and does not activate the p53 pathway while MC and DMC are cytotoxic and able to activate the p53 pathway. DMC is more cytotoxic than MC and can also kill p53-deficient cells by inducing degradation of Checkpoint 1 protein, which is not seen with MC treatment of the p53-deficient cells. This difference in the cell death pathways activated by the MC and DMC is attributed to differential signaling by the DNA adducts of DMC. We hypothesize that the different chirality of the adduct-to-DNA linkage has a modulating influence on the choice of pathway.

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“…10-Decarbamoyl-MC was synthesized as described (10). Authentic samples of adduct 2 were prepared as described (8 were mixed in 0.015 M Tris HCl (pH 7.4) and hydrogenated by a published procedure (7).…”

mentioning

confidence: 99%

Reaction of DNA with chemically or enzymatically activated mitomycin C: isolation and structure of the major covalent adduct.

Tomasz¹,

Chowdary²,

Lipman³

et al. 1986

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

139

120

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The antitumor antibiotic mitomycin C is shown to form a covalent complex with calf thymus DNA under anaerobic conditions in the presence of either NADPH cytochrome c reductase/NADPH, xanthine oxidase/NADH, or the chemical reducing system H2/PtO2. Digestion of the complex with DNase I/snake venom diesterase/alkaline phosphatase yields a single mitomycin deoxyguanosine adduct as the major DNA alkylation product, identified as N2-(2",3,7"-diaminomitosen-l"a-yl) 2'-deoxyguanosine (Structure 2). Two minor adducts, 2-5% each of the total adduct pool, are isolated and identified as the 1"j8 stereoisomer of 2 (Structure 3), and 10"-decarbamoyl-2 (Structure 7). The same results were obtained with M13 DNA and poly(dG-dC) poly(dG-dC); however, in the latter case, a minor adduct apparently possessing two deoxyguanosine and one mitomycin unit is isolated. Digestion of the covalent mitomycin-calf thymus DNA complex with nuclease P1 yields four dinucleotide adducts, all of which consist of 2 linked at its 3' end to each of the four possible 5' nucleotides (A, T, G, and C). Upon treatment of each dinucleotide adduct with snake venom diesterase/alkaline phosphatase, 2 is released along with the corresponding free nucleoside. In apparent conflict with the present results, previous reports from another laboratory have indicated that modification of calf thymus DNA by mitomycin C under conditions identical to those described here result in the isolation of three mitomycin C mononucleotide adducts possessing linkages of the drug to N2 and 06 of guanine and N6 of adenine. Evidence is shown suggesting that the latter adducts are actually three of the above four dinucleotide derivatives of 2 obtained independently by us and, thus, all of them in fact possess an identical N2-mitosenylguanine adduct moiety. Model-building studies indicate an excellent fit of the guanine N2-linked drug molecule inside the minor groove of B-DNA with no appreciable distortion of the DNA structure.Mitomycin C (MC; Structure 1), a potent antibiotic and clinically used antitumor agent, is known to interact covalently with DNA in vivo and in vitro. This is manifested by the reversible melting behavior of MC-exposed DNA, attributed to formation of covalent crosslinks between the complementary strands (1) and by covalent association of the ultraviolet chromophore of MC to DNA (2). These processes require reduction of MC into a transiently activated form, which is thought to occur in cells and can be mimicked easily in vitro chemically or enzymatically (1). The cytotoxicity of MC is most likely a direct result of DNA alkylation, as indicated by the parallels in biological activity of MC with a number of known "DNA damaging agents": selective inhibition of DNA replication (1) and sister chromatid exchange (4), and cross-resistance or cross-hypersensitivity of bacterial (1, 5) and mammalian (6) cells to UV light and MC. The molecular nature of the covalent interactions between MC and DNA has remained elusive, mainly because of the difficulty of isolating low...

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Mitomycin derivatives. 2. Derivatives of decarbamoylmitosane and decarbamoylmitosene

Cited by 63 publications

References 0 publications

Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin C

Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin C

Differential Toxicity of DNA Adducts of Mitomycin C

Reaction of DNA with chemically or enzymatically activated mitomycin C: isolation and structure of the major covalent adduct.

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