The design and synthesis of functional models of the ene-diyne toxins is the primary aim of this proposal. This will lead to the development of selective cytotoxic drugs based on novel mechanisms of antibiotic activity. The calicheamicins, esperimicins, and dynemycins are highly toxic species with elegant mechanisms of activation which were not anticipated before the natural structures were determined. With the mechanisms now well supported by in vitro studies, it is possible to design analogs which have all of the activation features, but will be readily available in quantity, can be tailored to avoid peripheral toxicity, and can have convenient tethers for conjugation with delivery agents such as antibodies. One model for calicheamicin has been demonstrated and will be elaborated in the current grant period. The key triggering step is de-blocking of the enol, and that operation can be designed to involve several different biological mechanisms, including disulfide exchange as established for the natural products. The result will be a simplified model for the """"""""warhead"""""""" or aglycone which can be triggered to produce high energy diradicals under physiological conditions. A second general triggering mechanism will be based on the same calicheamicin framework, but a different conformation adjustment, boat-chair cyclohexane. A similar set of physiologically compatible processes will be designed into the conformational trigger. A collaborative effort with the Medical Research Division of American Cyanamid will evaluate the new compounds as selective DNA cleavage agents and arrange attachment of the more active derivatives to delivery systems, including the monoclonal antibody conjugate now under study at Cyanamid with the natural product itself. An important aspect is the evaluation of various DNA delivery agents, following up on the results with netropsin in the previous grant period. The potency of the enediyne in DNA cleavage is very sensitive to positioning on the DNA and proper design of the delivery agents is a critical component.
|Semmelhack, M F; Wu, Lingyun; Pascal Jr, Robert A et al. (2003) Conformational control in activation of an enediyne. J Am Chem Soc 125:10496-7|
|Semmelhack, M F; Jiang, Y; Ho, D (2001) Synthesis of the amino sugar from C-1027. Org Lett 3:2403-6|