Monday, September 19, 2011
Our MIDSCI reporter's blog on "The Discovery and Surprises with Natural Products" by Professor Erick Carreira at the UW-Madison Department of Chemistry Abott Symposium .
Natural products, secondary metabolites produced by biological sources, are often utilized as sources of novel small molecules for drug discovery. However, biologically-active natural products, such as the antifungal agent Amphotericin B (AmB), are of little use if they cannot be produced in quantities to meet patient demand. Many synthetic organic chemists have risen to this challenge by devising “total syntheses” of natural products from readily-available starting materials. Professor Erick Carreira has long been revered in his field for his total syntheses of stereochemically-complex natural products such as Macrolactin A and Erithronolide A and his use of challenging asymmetric bond forming reactions. In his seminar at UW-Madison’s Abott Symposium, Carreira outlined total syntheses of three natural products that associate with biological membranes, as well as structural analogs that were used to study structure-activity relationships (SARS). As a result of his work, Carriera has been able to draw conclusions about how these molecules behave in their natural settings.
AmB is the drug of choice for treating Aspirgillosis, a fungal disease most common in immune-compromised and cancer patients. AmB has a rigid, cigar-shaped structure and works by self-assembling into a transmembrane channel, causing electrolyte loss. Interestingly, the length of AmB and a typical fungal cell membrane are 20 and 40 Å, respectively; it has thus been hypothesized that the AmB ion channels consist of AmB subunits arranged in a head-to-tail fashion. It has been suggested that the hydroxyl groups on AmB could be essential to the activity of this antifungal agent should this head-to-tail arrangement be necessary for activity. Thus, Carreira set out to synthesize several deoxy analogs of AmB. The synthetic strategy involved synthesizing three components of AmB and combining them to form the final macrocycle. The syntheses of these AmB analogs revealed that the C35 hydroxy group is essential for activity—the C35 deoxy AmB analog was about 18 fold less active in S. cerevisiae as compared the parent AmB molecule. This suggests that the C35 hydroxy group is critical in forming transmembrane channels. Other work by Carriera and coworkers has shed light upon other AmB moieties necessary for activity; for example, the C2 hydroxy group on the mycosamine sugar is essential for antifungal activity.
Carriera outlined syntheses of other bioactive molecules and their analogs, such as the antibacterial guanacastepenes, and has been using his molecules to draw conclusions about SARS and modes of action, similar to his work with AmB. These types of strategies could allow for the modification and optimization of natural bioactive scaffolds to yield potent drug candidates.
Szpilman AM, Cereghetti DM, Manthorpe JM, Wurtz NR, Carreira EM. Synthesis and Biophysical Studies on 35-Deoxy Amphotericin B Methyl Ester. Chemistry—A European Journal 2009; 15: 7117-7128