Antibiotics, enediyne

The coupling reaction has widespread use in the construction of enediyne systems present in naturally occurring anticancer antibiotics[234]. The Pd-Cul catalyzed coupling reaction of the alkenyl bromides 323 and 326 with the... 

Beginning in the 1980s research directed toward the isolation of new drugs derived from natural sources identified a family of tumor inhibitory antibiotic substances characterized by novel struc tures containing a C C—C=C—C C unit as part of a nine or ten membered ring With one double bond and two triple bonds (-ene + di- + -yne) these com pounds soon became known as enediyne antibiotics The simplest member of the class is dynemian A most of the other enediynes have even more compli cated structures... 

Enediyne antibiotics (Section 9 4) A family of tumor inhibit mg substances that is characterized by the presence of a C=C—C=C—C = C unit as part of a nine or ten membered nng... 

In spite of the fact that few cycloalkynes occur naturally, they gained recent attention when it was discovered that some of them hold promise as anticancer drugs. (See the boxed essay Natural and Designed Enediyne Antibiotics following this section.)... 

Design and synthesis of analogs of dynemycin, antitumor antibiotic with an-thraquinone, 10-member enediyne, tetrahydropyridine, and oxirane fragments 99EJ01. 

The tightly bound chromophore could be extracted from the protein with methanol [186], and the major component of the extract was determined to have the enediyne structure 116 (Figure 11.21), related to chromophores of other chromoprotein antitumor agents such as neocarzinostatin. Additional minor components were extracted, variously containing an OH group instead of OMe attached to the enediyne core, with Cl instead of OMe when chloride was present in the buffer salt, or with OEt instead of OMe when ethanol was used for the extraction. Another byproduct was isolated in the form of structure 117, consistent with a facile cy-doaromatization reaction as observed for all other enediyne antibiotics. Surprisingly, 117 also displayed antibiotic and antitumor activity, perhaps due to alkylation of DNA or protein by the aziridine. The interpretation of these results was that 116 and the other enediyne byproducts were merely artifacts of the extraction procedure and that the true structure of the maduropeptin chromophore is the aziridine 118. 

Liu, W. and Shen, B. (2000) Genes for production of the enediyne antitumor antibiotic C-1027 in Streptomyces globisporus are clustered with the cagA gene that encodes the C-1027 apoprotein. Antimicrobial Agents and Chemotherapy, 44, 382. 

Zhang, J., Van Lanen, S.G., Ju, J. et al. (2008) A phosphopantetheinylatingpolyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis. Proceedings of the National Academy of Sciences of the United States of America, 105, 1460. 

Before the advent of enediyne antitumor antibiotics, there had been few examples of carbon radicals believed to mediate DNA cleavage. The simplest of all, the methyl radical has been shown to effect DNA cleavage under enzymatic as well as chemical conditions [24]. Oxidation of methylhydrazine by horseradish peroxidase or ferricyanide (Fig. 5) gave high yields of methyl radicals, which were shown to cleave DNA by purine ring alkylation. 

The feasibility of hydrogen abstraction at the peptidyl a-carbon hydrogen bond by 1,4-aryl diradicals has been determined by examining a model reaction, i.e. abstraction of deuterium from dideuterioglycine by aryl radicals. The results have biological implications for the reactivity of the enediyne anti-tumour antibiotics with proteins. The non-Arrhenius behaviour of hydrogen-abstraction reactions by radicals has been investigated. For a number of reactions studied the enthalpy of activation was found either to increase or to decrease as a function of temperature. 

Gemtuzumab ozogamicin (30 Mylotarg ) Calicheamicin (31) Enediyne-type antibiotic NP-derived Microbial Anticancer DNA-cleaving 319-331... 

To date, few carbohydrate interactions with DNA have involved interactions within the major groove. Among the classes of compounds known to exhibit DNA binding are enediyne antibiotics, anthracydines, pluramycins, indolocar-bazoles, and aureolic acids. Of the limited number of carbohydrates known for DNA binding, only a select few have displayed major groove contacts. These... 

It is noteworthy that Jones and Darby, who pioneered the enediyne rearrangement, now known as the Bergman rearrangement, and Nicolaou, who achieved the first total synthesis of the enediyne antibiotic calicheamicin 7 / were under the joint supervision of Profs. Franz Sondheimer and Peter Garratt. It might seem that all researchers in the enediyne field have been influenced by Sondheimer and Garratt. 

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