Dale L. Boger
SYNTHETIC ORGANIC AND BIOORGANIC CHEMISTRY
Our research interests include the total synthesis of natural products, development of new synthetic methodology, heterocyclic chemistry, bioorganic and medicinal chemistry, the study of DNA- agent interactions, and the chemistry of antitumor antibiotics. We place special emphasis on investigations to define the structure-function relationships of natural or designed organic agents.
SYNTHETIC METHODOLOGY. Our ongoing investigations emphasize the development and application of hetero Diels-Alder reactions, the thermal reactions of cyclopropenone ketals, inter- and intramolecular acyl radical-alkene addition reactions, medium and large ring cyclization procedures, and the benzannulation reaction of arylchromium carbene complexes. In each instance, the methodology development represents the investigation of chemistry projected as a key step in the total synthesis of a natural or nonnatural product.
NATURAL PRODUCTS TOTAL, SYNTHESIS. Problems currently being addressed include (+)-CC-1065 and functional analogs (antitumor antibiotic possessing sequence selective DNA alkylation properties), duocarmycins (antitumor antibiotics possessing sequence selective DNA alkylation properties), tropoloalkaloids including colchicine, deoxybouvardin/bouvardin, K-13, OF4949-I - OF4949-IV (immunopotentiating agents with confirmed antitumor activity), piperazinomycin, luzopeptins, and sandramycin (DNA- binding peptides with antitumor and antiviral properties), bleomycin A2 (clinically employed antitumor antibiotic), quinolinequinone antitumor antibiotics including streptonigrone, streptonigrin, and lavendamycin (antiviral agents), isochrysohermidin, fredericamycin A and CI-920 (antitumor agents with topoisomerase I and II inhibitory activity), rhizoxin (antitumor antibiotic and potent mitotic inhibitor), combretastatins, azinomycins (antitumor antibiotics with potential DNA cross-linking capabilities), and trikentrin A.
BIOORGANIC CHEMISTRY. The origin of interest in the specific agents detailed above rests with their properties and in many instances represents the selection of agents related by a projected property (e. g ., (+)-CC-1065 and duocarrnvcin). Representatives of such efforts, studies on (+)-CC-1065 have been employed to identify agent structural features contributing to its sequence-selective DNA alkylation properties. Efforts are under way to develop DNA crosslinking agents of a predefined cross-link, to apply and further understand the nature of the covalent and noncovalent agent-DNA interactions, and to apply this understanding to the de novo design of DNA-binding agents. We recently identified the common (+)-CC1065/duocarmycin pharmacophore and introduced a general evaluation protocol of the agents DNA binding properties. Collaborative efforts in securing biological data, ^1H NMR of DNA-agent complexes, molecular modeling studies of large molecule-small molecule interactions, and experimental studies of DNA-agent interactions constitute an integral part of the program.