Alkylation and Crosslinking of DNA by the Unnatural Enantiomer of Mitomycin C: Mechanism of the DNA-Sequence Specificity of Mitomycins

Gargiulo, Dario; Musser, Stephen S.; Yang, Lijuan; Fukuyama, Tohru; Tomasz, Maria

doi:10.1021/ja00142a002

Cited by 33 publications

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“…This unusual situation is reminiscent of reports by Boger on the surprising cytotoxicity of ent -roseophillin, which was found to be 2–10 fold more potent than the naturally occurring roseophillin 47. While there are limited examples of natural products whose unnatural enantiomers demonstrate comparable biological potency (e.g., fredericamycin A,48 duocarmycin SA,49 CC-1065,50 and the cancer therapeutic mitomycin C51), we are not aware of compounds other than ent -roseophillin and ( R )-abyssinones III and IV 4´-OMe that are more active than their natural enantiomers. Also of interest was the fact that the ( S ) enantiomers were more cytotoxic than the unnatural ( R ) enantiomers (see Figure 3), while the ( R ) abyssinones were best able to downregulate the expression of MMP-2 (Figure 4).…”

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confidence: 75%

Concise Syntheses of the Abyssinones and Discovery of New Inhibitors of Prostate Cancer and MMP-2 Expression

Farmer

Biddle

Nibbs

et al. 2010

ACS Med. Chem. Lett.

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Hydrogen-bonding catalysis is an emerging field that facilitates rapid access to medicinally relevant enantioenriched small molecules. Here, we report the first asymmetric total syntheses of four members of the abyssinone class of natural products (I, II, III, and IV 4´-OMe) via quinine- or quinidine-derived thiourea-catalyzed intramolecular conjugate additions of β-keto ester alkylidenes. This concise strategy includes a tandem deprotection/decarboxylation final step that delivers all four natural products and their corresponding antipodes. A preliminary evaluation of all of these small molecules against a metastatic human prostate cancer cell line has identified that these compounds selectively and differentially inhibit cell growth and downregulate the expression of matrix metalloproteinase-2 (MMP-2) at non-toxic concentrations.

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confidence: 75%

Concise Syntheses of the Abyssinones and Discovery of New Inhibitors of Prostate Cancer and MMP-2 Expression

Farmer

Biddle

Nibbs

et al. 2010

ACS Med. Chem. Lett.

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“…This reactivity was attributed to common precovalent orientation of the two MM active forms relative to the target guanine in the minor groove, reinforcing the earlier proposal that, prior to covalent attachment, the 10′-carbamate group recognizes the CpG sequence by formation of a specific H-bond. [108] Further evidence for electronic effects transmitted through the base pairs was observed in that substituting fluorine for hydrogen at the 5-position of cytosine in CpG steps showed that the extent of cross-linking increased in the order 5-fluoro-C<C<5-methyl-C. [109] …”

Section: Biochemistrymentioning

confidence: 99%

Mitomycinoid Alkaloids: Mechanism of Action, Biosynthesis, Total Syntheses, and Synthetic Approaches

et al. 2013

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“…Poly(dG)·poly(dC), poly(dG-dC)·poly(dG-dC), and poly (dA-dT)·poly(dA-dT) were obtained from Pharmacia Biotech, Piscataway, NJ. All other materials were obtained as previously described …”

Section: Methodsmentioning

confidence: 99%

“…The percent yields of 2,7-DAM adducts 11 , 12 , and 13 designate the mole percent adducted guanine of total guanine nucleotide residues present in the oligonucleotide or DNA substrates. These yields were determined by HPLC of enzymatic digests of the adducted nucleic acids or oligonucleotides, based on HPLC peak area measurements of the appropriate components of the digests, as described in detail elsewhere …”

Section: Methodsmentioning

confidence: 99%

2,7-Diaminomitosene, a Monofunctional Mitomycin C Derivative, Alkylates DNA in the Major Groove. Structure and Base-Sequence Specificity of the DNA Adduct and Mechanism of the Alkylation

et al. 1996

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Reductive activation of the bifunctional alkylator and DNA cross-linking agent mitomycin C (MC) yields 2,7-diaminomitosene (2,7-DAM) as the major product of its activation both in cell-free systems and in vivo. 2,7-DAM lacks one of the alkylating functions of MC, the aziridine. We show that 2,7-DAM itself alkylates DNA monofunctionally upon reductive activation, to form a heat-labile adduct. A guanine-N7−2,7-DAM adduct was isolated from the drug−DNA complex upon heating. Nuclease digestion yielded this adduct both in the nucleoside (dG-2,7-DAM) and dinucleoside phosphate [d(GpG)-2,7-DAM] forms. The structures of all three forms were determined by LC−ESIMS and differential UV spectroscopy. The adduct is sequence-specific to guanines in (G) n tracts of DNA. A guanine-N7−2,7-DAM adduct in DNA was indirectly observed previously by Prakash et al. (Prakash, A. S.; Beall, H.; Ross, D.; Gibson, N. W. Biochemistry 1993, 32, 5518−5525). The results indicate that selective removal of the aziridine function of MC results in a switch from minor to major groove alkylation of DNA, and a switch of sequence specificity from guanines in CpG to guanines in (G) n tracts. They also show that the mitosene C-10 carbamate intrinsically reacts as an SN2 alkylating agent, specific to guanine-N7.

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Alkylation and Crosslinking of DNA by the Unnatural Enantiomer of Mitomycin C: Mechanism of the DNA-Sequence Specificity of Mitomycins

Cited by 33 publications

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Concise Syntheses of the Abyssinones and Discovery of New Inhibitors of Prostate Cancer and MMP-2 Expression

Concise Syntheses of the Abyssinones and Discovery of New Inhibitors of Prostate Cancer and MMP-2 Expression

Mitomycinoid Alkaloids: Mechanism of Action, Biosynthesis, Total Syntheses, and Synthetic Approaches

2,7-Diaminomitosene, a Monofunctional Mitomycin C Derivative, Alkylates DNA in the Major Groove. Structure and Base-Sequence Specificity of the DNA Adduct and Mechanism of the Alkylation

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