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

Bass, P. D.; Gubler, Daniel A.; Judd, Ted; Williams, Robert M.

doi:10.1021/cr3001059

Cited by 148 publications

(86 citation statements)

References 358 publications

(726 reference statements)

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“…Previous research has shown unambiguously that MC crosslinks DNA at CpG sequences, but that GpC sequences are not a target for DNA crosslinking . The CpG sequence‐specificity has also been observed for related mitomycinoid alkaloids …”

Section: Methodsmentioning

confidence: 92%

Sequence‐Dependent Diastereospecific and Diastereodivergent Crosslinking of DNA by Decarbamoylmitomycin C

Aguilar

Paz

Vargas

et al. 2018

Chemistry A European J

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Mitomycin C (MC), a potent antitumor drug, and decarbamoylmitomycin C (DMC), a derivative lacking the carbamoyl group, form highly cytotoxic DNA interstrand crosslinks. The major interstrand crosslink formed by DMC is the C1'' epimer of the major crosslink formed by MC. The molecular basis for the stereochemical configuration exhibited by DMC was investigated using biomimetic synthesis. The formation of DNA-DNA crosslinks by DMC is diastereospecific and diastereodivergent: Only the 1''S-diastereomer of the initially formed monoadduct can form crosslinks at GpC sequences, and only the 1''R-diastereomer of the monoadduct can form crosslinks at CpG sequences. We also show that CpG and GpC sequences react with divergent diastereoselectivity in the first alkylation step: 1"S stereochemistry is favored at GpC sequences and 1''R stereochemistry is favored at CpG sequences. Therefore, the first alkylation step results, at each sequence, in the selective formation of the diastereomer able to generate an interstrand DNA-DNA crosslink after the "second arm" alkylation. Examination of the known DNA adduct pattern obtained after treatment of cancer cell cultures with DMC indicates that the GpC sequence is the major target for the formation of DNA-DNA crosslinks in vivo by this drug.

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Section: Methodsmentioning

confidence: 92%

Sequence‐Dependent Diastereospecific and Diastereodivergent Crosslinking of DNA by Decarbamoylmitomycin C

Aguilar

Paz

Vargas

et al. 2018

Chemistry A European J

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“…66 Its mode of action is DNA alkylation and cross-linking. 67 Reductive activation 68 of mitomycin delivers the hydroquinone, which leads to methanol elimination and an aziridine ring-opening to give an extended quinone-methide electrophile. 69 This activated form binds to the minor groove of DNA and the N 2 of guanine (a good minor groove nucleophile with a propensity for attacking -electrophiles, see section 3.1), attacks the quinone-methide of activated mitomycin.…”

Section: Natural Products That Covalently Modify Nucleobasesmentioning

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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“…On this basis, we anticipated that we could access imine or aziridine containing PBDs using intramolecular 1,3-dipolar cycloadditions between azides and alkenes using alkenes derived from (S)-proline. Whilst we were interested in the possibility of producing an imine, we were more intrigued by the possibility of producing an aziridine due the known propensity [30] of aziridines to function as electrophiles and the potential biological activity that a novel system of this type might offer. We settled upon two approaches, as shown in Scheme 1.…”

Section: Synthesis and Reactivity Of The Pyrrolo-based Systemsmentioning

confidence: 99%

Intramolecular Azide to Alkene Cycloadditions for the Construction of Pyrrolobenzodiazepines and Azetidino-Benzodiazepines

et al. 2014

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Abstract:The coupling of proline-and azetidinone-substituted alkenes to 2-azidobenzoic and 2-azidobenzenesulfonic acid gives precursors that undergo intramolecular azide to alkene 1,3-dipolar cycloadditions to give imine-, triazoline-or aziridine-containing pyrrolo[1,4]benzodiazepines (PBDs), pyrrolo[1,2,5]benzothiadiazepines (PBTDs), and azetidino [1,4]benzodiazepines. The imines and aziridines are formed after loss of nitrogen from a triazoline cycloadduct. The PBDs are a potent class of antitumour antibiotics.

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

Cited by 148 publications

References 358 publications

Sequence‐Dependent Diastereospecific and Diastereodivergent Crosslinking of DNA by Decarbamoylmitomycin C

Sequence‐Dependent Diastereospecific and Diastereodivergent Crosslinking of DNA by Decarbamoylmitomycin C

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

Intramolecular Azide to Alkene Cycloadditions for the Construction of Pyrrolobenzodiazepines and Azetidino-Benzodiazepines

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