Dynemicin

The novel intramolecular reaction of the alkenyl bromide with the terminal alkyne in 328, followed by intramolecular Diels-Alder reaction, afforded the highly strained dynemicin A structure 329 in one stepf237]. 

Learning By Modeling contains a model of dynemicin A which shows that the C=C—C=C—C=C unit can be incorporated into the molecule without much angle strain... 

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 structures containing a C=C—C=C—C=C unit as part of a nine- orten-membered ring. With one double bond and two triple bonds (-ene + di- + -yne), these compounds soon became known as enediyne antibiotics. The simplest member of the class is dynemicin A most of the other enediynes have even more complicated structures. 

Scheme 21. The Sonogashira coupling reaction in Nicolaou s dynemicin A model study.

Scheme 22. Schreiber s approach to dynemicin A system 86 by a tandem Sonogashira coupling/Diels-Alder reaction.

Lewis-acid-catalyzed Diels-Alder reaction of 3-phenylthio-2- quinolinones with silox-ydiene. Synthesis of the intermediate for dynemicin A core [97]... 

Several novel natural products with an intriguing system containing the cis-endiyne moiety have attracted considerable attention from chemists in recent years. Several derivatives with this characteristic skeleton have now been isolated neocarzinostatin,96 esperamicin,97 calicheamicin y. 9S and dynemicin Ai." The high antitumor activity of these compounds is based on an elegant... 

Wender PA, Zercher CK, Beckham S, Haubold EM (1993) A photochemically triggered DNA-cleaving agent - synthesis, mechanistic and DNA cleavage studies on a new analog of the antitumor antibiotic dynemicin. J Org Chem 58 5867-5869... 

In 2006 the preparation of simplified analogs of natural occurring enediynes, e.g. antitumor antibiotic dynemicin, was reported by Banfi and coworkers. They succeeded in synthesizing two different classes of such compounds where the embedded 10-membered enediyne system is fused either with a (3-lactam ring (lactenediynes) or with an epoxide. Biological tests on these molecules have demonstrated that some representatives are able to cleave the double strand of DNA even at very low concentrations [408]. 

The DNA-binding antibiotics, neocarzinostatin (NCS), dynemicin, calicheami-cin and esperamicin have all in common that they have an enediyne as a structural element, although they are otherwise very different (for a review see Nico-laou and Dai 1991). Their formulae are given in Fig. 12.13. 

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... 

Figure 2 Examples of polyketides. Polyketides demonstrate a broad range of biological activities, including antibiotic (oxytetracycline and erythromycin), antitumor (doxorubicin and dynemicin), antiparasitic (avermectin), and immunosuppressive (FK506). Monensin is used as a bovine feed supplement and an anticoccidial agent.

Scheme 4. Sonogashira reactions in the synthesis of 6-[2-(2,5-dimethoxyphenyl)ethyl]-4-ethylquinazoline 13, terbinafine 14 and dynemicin A IS.

Both BTI and DIB have been used in key-steps involving phenolic oxidation to quinone imines in the total synthesis of ( )-dynemicin A [12]. 

---