The goal of this revised renewal project is to develop transition-metal carbene complex-based approaches to polycyclic systems. It is noted that this methodology will allow for the rapid construction of a variety of polycyclic frameworks, many of which are found in biologically active natural products and that many of the ring systems accessible with this methodology are not readily accessible with existing methodology. The principal investigator states that current efforts are focused on the further expansion of this methodology as well as on the application of these strategies to the synthesis of several medicinally relevant targets. He notes that of particular interest is the construction of the tricyclic ring skeleton of the tiglane and daphnane diterpenes and that members of these classes of compounds have been widely studied, primarily because of their ability to promote tumor formation. It is indicated that analogs of the phorbol esters will be constructed and used to probe the nature of the binding of phorbol esters to the diacylglycerol binding site of protein kinase C, their biological receptor. It is noted that structure-activity studies of this type are currently not feasible due to the absence of general routes to the phorbol skeleton. The principal investigator states that in addition, an approach to the DNA alkylating subunit of CC-1065 and the duocarmycins will be developed. He indicates that this approach is expected to provide general access to a variety of derivatives of CC-1065 and the duocarmycins that will enhance our understanding of the mechanism of action of these powerful antitumor agents.
