The dynemicins

Biosynthetic studies indieate that dynemicin A (4) is biosynthesized from two heptaketide chains, which form the bicyclie enediyne core and the anthraquinone moiety, respectively 

It is also possible that epoxide opening is initiated by electron push from the nitrogen atom rather than the phenol, and this will be discussed in a later section. In either case, epoxide opening is the trigger for cycloaromatization, diradical formation and DNA damage [118-120]. 

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During a synthesis of quinone imine precursors to the Dynemicins, Myers and co-workers100 encountered problems with the lability of the dimethyl acetal function in 56,1 [Scheme 1.56] whilst removing the robust phenolic methyl group using sodium ethanethiolate in hot DMF, However prior conversion of the free hydroxy function in the substrate to the magnesium salt 56.2 by reaction with ethylmagnesium bromide afforded protection for the dimethylacetal under the strenuous conditions of nucleophilic demethylation. 

These novel, extremely potent antibiotics all possessed one very unusual chemical structural feature an enediyne fragment within a ring. The first discovered was neocarzinostatin (NSC), which was found to be composed of a protein (NSC apoprotein) and the neocarzinostatin chromophore 30 in a 1 1 complex. The biological activity is associated with the NSC chromophore. However, it took until the discovery of the calichaemicin " 31 and esperamicin 32 families in 1987 to really gamer the broad attention of chemists. Other enediyne antibiotics include the dynemicin family, the kedarcidin chromophore, namenamicin, the C-1027 chromophore,and uncialamycin. " ... 

Finally, the dynemicin A analog lacking the heterocyclic nitrogen 96 was designed by Maier et al. In this case the triggering device is the quinone upon its reduction, the hydroquinone 97 was expected to undergo... 

Nicolaou, K.C. Dai, W.-M. Wendebom. S.V. Smith. A.L. Torisawa, Y. Maligres, P. Hwang, C.-K. Enediyne compounds equipped with acid-, base, and photo-sensitive triggering devices. Chemical simulation of the dynemicin A reaction cascade. Angew. Chem., Int. Ed. Engl. 1991. 30. 1032-1036. 

Scheme 7-71 Chemistry of dynemicin A model systems. Triggering the dynemicin cascade with base or acid (Nicolaou et al.).

Scheme 7-74 Photoinduced simulation of the dynemicin A cascade. Evidence for a quinone methide intermediate (Nicolaou et al.). NBn, o-nitrobenzyl.

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.

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... 

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