Enediynes model studies

Chen T, Greenberg MM. Model studies indicate that copper phenanthroline induces direct strand breaks via 3-elimination of the 2 -deoxyribonolactone intermediate observed in enediyne mediated DNA damage. Chem Soc. 1998 120 3815-3816. 

Since DNA is the predominant target of the natural enediynes, a natural extension of the photo-Bergman lies in the development of efficient enediyne-based photonucleases. Based on their model studies. Funk and WiUiams designed both a phenanthrene and pyrene enediyne 49, which by virtue of the aminoalkyl side-chains had affinity for DNA (Scheme 13). ... 

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. 

Scheme 7-41 Model enediyne studies of Nicolaou, Bergman and co-workers.

Nicolaou et al. were first to identify and study the features of the natural product essential for its activation through the design and synthesis of model systems based on 312 (Scheme 7-66) [250, 251]. These were traced retrosynthetically to tetrahydrophenanthridine (313) and were synthesized as summarized in Scheme 7-67. Highlights of this synthetic approach include (a) regiospecific functionalization of the tetrahydrophenanthridine ring (313 -+ 314 and 314 315) (b) palladium-catalyzed construction of the enediyne (316 -> 317) ... 

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