Synthesis of the pyrimidine moiety of bleomycin

Umezawa, Yōji; Morishima, Hajime; Saito, Sei ichi; Takita, Tomohisa; Umezawa, Hamao; Kobayashi, Susumu; Otsuka, Masami; Narita, Masatoshi; Ohno, Masaji

doi:10.1021/ja00541a073

Cited by 46 publications

(14 citation statements)

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“…Pyrimidoblamic acid is ak ey subunit of the anticancer drug bleomycin A 2 .I ts modification would enable an improvement in or the simplification of bleomycina nalogues. Various total synthesis methods have been examined by Umezawa, [96] Hecht, [97] and Boger, [98] but there is often difficulty in controlling the stereochemistry of the tertiary carbon atom of the benzylic pyrimidine moiety Duerfeldt and Boger generate the pyrimidine core from an iEDDA reaction betweenas ubstituted electron-deficient triazine such as 78 ( Figure 25) and an amidine such as 79. [99] All the necessary stereochemistry is introduced before the cycloaddition.T his method also enables the late-stage functionalization of pyrimidoblamic acid, which allows analogues to be easily synthesized.…”

Section: Pyrimidoblamic Acidmentioning

confidence: 99%

Inverse‐Electron‐Demand Diels–Alder Reactions: Principles and Applications

Png

Zeng

et al. 2017

Chemistry An Asian Journal

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Inverse-electron-demand Diels-Alder (iEDDA) reactions are an intriguing class of cycloaddition reactions that have attracted increasing attention for their application in bioorthogonal chemistry, the total synthesis of natural products, and materials science. In many cases, the application of the iEDDA reaction has been demonstrated as an innovative approach to achieve target structures. The theoretical aspects of this class of reactions are of particular interest for scientists as a means to understand the various factors, such as steric strain and electron density of the attached groups, that govern the reaction and thus to elucidate the reaction mechanism. This review aims to summarize both theoretical investigations and application-driven research work on the iEDDA reaction. First, the historical aspects and the theoretical basis of the reaction, especially recent advances in time-dependent density functional theory (TD-DFT) calculations, as well as catalysis strategies will be highlighted and discussed. Second, the applications of this novel reaction in the context of materials science, bioorthogonal chemistry, and total synthesis of natural products will be elaborated with selected recent examples. The challenges and opportunities of the iEDDA reaction will be highlighted to give more insight into its potential applications in many other research areas.

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Section: Pyrimidoblamic Acidmentioning

confidence: 99%

Inverse‐Electron‐Demand Diels–Alder Reactions: Principles and Applications

Png

Zeng

et al. 2017

Chemistry An Asian Journal

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“…Bleomycins (BLMs) are the iron-based natural anti-tumour agents which show oxidative damage of DNA in cancer cells forming cytotoxic hydroxyl radicals. 27,28 Iron complexes with the metal in its +3 oxidation state are prone to reduction inside the cells by cellular reducing agents like glutathione (GSH). Iron(III) complexes having azide ligand are known to show significant DNA photocleavage activity.…”

Section: Introductionmentioning

confidence: 99%

Polypyridyl iron(II) complexes showing remarkable photocytotoxicity in visible light

et al. 2015

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Iron(II) complexes of polypyridyl ligands (B), viz. [Fe(B) 2 ]Cl 2 (1 and 2) of N, N, N-donor 2-(2-pyridyl)-1,10-phenanthroline (pyphen in 1) and 3-(pyridin-2-yl)dipyrido[3,2-a:2',3'-c]phenazine (pydppz in 2), are prepared and characterized. They are 1:2 electrolytes in aqueous DMF. The diamagnetic complexes exhibit metal to ligand charge transfer band near 570 nm in DMF. The complexes are avid binders to calf thymus DNA giving binding constant (K b ) values of ∼10 6 M −1 suggesting significant intercalative DNA binding of the complexes due to presence of planar phenanthroline bases. Complex 2 exhibits significant photocytotoxicity in immortalized human keratinocyte cells HaCaT and breast cancer cell line MCF-7 giving IC 50 values of 0.08 and 13 μM in visible light (400-700 nm). Complex 2 shows only minor dark toxicity in HaCaT cells but is non-toxic in dark in MCF-7 cancer cells. The light-induced cellular damage follows apoptotic pathway on generation of reactive oxygen species as evidenced from the dichlorofluorescein diacetate (DCFDA) assay.

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“…Iron is no doubt the preferred choice among the transition metals for its well known bio-essentiality and low dark toxicity. The interest in the chemistry of iron-based antitumor agents emerges from the chemotherapeutic activity of bleomycins (BLMs) that are iron containing naturally occurring drugs showing an oxidative damage of DNA forming cytotoxic hydroxyl radicals [27,28]. The complex can be designed such that its dark toxicity will remain nominal but suitable photosensitizers should be ligated to the metal to ensure the efficient PDT activity.…”

Section: Introductionmentioning

confidence: 99%