Scholar Profile

Daniel E. Kahne

Professor
Department of Chemistry & Chemical Biology
Harvard University
12 Oxford Street
Cambridge, MA 02138
Voice: 617-496-0208
Fax: 617-496-0215
Email: kahne@chemistry.harvard.edu
Personal Homepage
1989 Searle Scholar
Former Member of Advisory Board (2003 -)

Research Interests

Synthetic Organic Chemistry

Our research group uses synthetic organic chemistry to study problems in chemistry and biology. One area of interest is the synthesis of biologically active oligosaccharides. Although many advances have been made in carbohydrate synthesis in recent years, constructing oligosaccharides and glycopeptides remains a formidable synthetic challenge. There are two key problems in oligosaccharide synthesis. The first problem is that there are no general methods to construct ß glycosidic bonds (this is one aspect of the larger problem of controlling the stereochemistry of the anomeric linkage), and the second is that obtaining good yields in many glycosylation reactions is difficult. We are developing a glycosylation method that has the potential to solve both these problems. In this method, an anomeric sulfoxide is activated with trillic anhydride to generate an extraordinarily reactive glycosylating agent. This method is allowing us to synthesize some very complicated oligosaccharides whose biological roles we are interested in studying.

We are interested in carbohydrate-DNA interactions. At the moment we are studying three structurally related drugs: calicheamicin, chromomycin, and ciclamicin. For example calicheamicin is an antitumor antibiotic that binds to and cleaves DNA. The carbohydrate portion of calicheamicin has been shown to be important for cleavage activity, presumably by contributing to DNA binding. However, its role has not been further characterized, in part because it is difficult to selectively modify the oligosaccharide in the natural product. Using the methodology mentioned above, we have completed the synthesis of the calicheamicin aryloligosaccharide. We are now beginning to study its DNA-binding behavior by a variety of methods. We have also undertaken NMR studies of the natural product in solution and bound to a DNA duplex.

We have also begun to look at how carbohydrate moieties in glycopeptides influ ence peptide structure. Our approach is to synthesize biologically relevant glycopeptides for which there is some evidence that the carbohydrate influences the conformation of the peptide and then conduct NMR experiments to obtain structural information. The structures of the glycopeptides and their nonglycosylated analogues will be compared to evaluate the effect of the sugar moieties.

Another area of interest concerns the study of amphiphilic surfaces. It has been shown that key peptide hormones whose receptors are membrane bound contain amphiphilic regions that bind to the membranes, thereby targeting the hormones to their receptors. We are exploring the possibility of replacing amphiphilic regions in selected peptides and proteins with entirely synthetic amphiphiles. One question we have is whether synthetic amphiphiles can stabilize the secondary structure of an attached peptide. If the artificial surfaces we have constructed can stabilize secondary structure in peptides, there are a number of possible applications, including incorporation of rigid synthetic amphiphiles into hybrid proteins to engineer increased stability. We are also interested in targeting certain molecules to or even across mem branes using our synthetic amphiphiles.