Enediynes antibiotic

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.)... 

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. 

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. 

The S3 unit is also to be found in compounds of natural origin [28, 32, 33]. A very simple one, isolated from an edible mushroom, exhibits both S2 and S3 moieties [34, 35]. 5-Methylthio-l,2,3-trithiane [28] is another example close to charatoxin, and the presence of an allylic trisulfide, and its role as a triggering device for their antitumour activity, in enediyne antibiotics [36,37], is truly astonishing. 

Ando T, Ishii M, Kajiura T, Kameyama T, Miwa K, Sugiura Y (1998) A New Non-Protein Enediyne Antibiotic N1999A2 Unique Enediyne Chromophore Similar to Neocarzinosta-tin and DNA Cleavage Feature. Tetrahedron Lett 39 6495... 

Fig. 12.13. Structures of some of the enediyne antibiotics. For details of the carbohydrate groups, see Dedon and Goldberg (1992)...

Double oxidation reactions of aminophenols (127) to the corresponding quinone-imines (128) using PIDA and PIFA were utilized for total synthesis of an enediyne antibiotic, ( )-dynemicin A (6), by Danishefsky and co-workers... 

Doyle, T.W. and Borders, D. B., Enediyne antitumor antibiotics, in Enediyne Antibiotics as Antitumor Agents, Borders, D. B. and Doyle, T. W., Eds., Marcel Dekker, New York, 1995, chap. 1. 

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