The primary research goal in our laboratory is the NMR characterization of structure in solids that are difficult or impossible to examine by more conventional techniques. The relevance of our methods is, perhaps, best demonstrated by our recent characterization of the complete crystal structure of (+)-catechin, a ubiquitous and extensively studied antioxidant that had defied characterization for nearly a century.1 This NMR work emphasizes 13C and 15N shift tensor measurements and relies on computational chemistry methods to tie these results to structure. A secondary area of emphasis involves the search for novel bioactive fungal products with a special focus on identifying unusual antioxidants. Work is each of these areas is described below.
1) NMR crystallography – prediction of complete crystal structures for intractable materials. Conventional crystallographic techniques are often unable to provide structure in materials. The typical limitation lies in difficulty in growing suitable crystals. We have recently demonstrated that accurate crystal structure can often be established without single crystals or even diffraction data if a combination of solid-state NMR and a theoretically crystal structure prediction process are used.2 Remarkably, the structures now being solved in our lab with this methodology and powdered solids rival or surpass the accuracy of single crystal diffraction data.3 This approach promises to open new areas of structural analysis in challenging materials and studies are underway with the goal of characterizing high profile pharmaceuticals that have long defied traditional analysis.
2) Design of superior free radical scavengers. Some effort in our lab involves searching for bioactive fungi within higher plants (i.e. endophytic fungi). These “bioprospecting” studies have now identified several fungal products that have superb antioxidant activity.4 Some of these molecules have unique modes of action as indicated by mechanistic studies involving computational modeling. Presently the products we have examined are unsuited for pharmaceutical use, but it appears that the structural features creating the activity can be reproduced in more favorable products. Computational testing is now underway on a wide variety of candidate antioxidants with the goal of identifying superior radical scavengers with more favorable biocompatibility.
- Harper, J. K.; Doebbler, J. A.; Jacques, E.; Grant, D. M.; Von Dreele, R. “A combined solid-state NMR and synchrotron x-ray diffraction powder study on the structure of the antioxidant (+)-catechin 4.5 hydrate” J. Am. Chem. Soc. 2010, 132, 2928 (Cover).
- Kalakewich, K.; Iuliucci, R.; Harper, J. K. “Establishing accurate high resolution crystal structures in the absence of diffraction data and single crystals” Cryst. Growth Des., 2013, In press.
- Harper, J. K.; Iuliucci, R.; Gruber, M.; Kalakewich, K. “Refining crystal structures with experimental 13C NMR shift tensors and lattice-including electronic structure methods” CrystEngComm, 2013, DOI:10.1039c3ce40108a.
- (a) Heider, E. M.; Harper, J. K.; Grant, D. M.; Hoffman, A.; Dugan, F.; Tomer, D. P.; O’Neill, K. L. “Exploring unusual antioxidant activity in a benzoic acid derivative: a proposed mechanism for citrinin” Tetrahedron, 2006, 62, 1199. (b) Harper, J. K.; Ford, E. J.; Strobel, G. A.; Porco, J. A. Jr.; Tomer, D. P.; O’neill, K. L.; Heider, E. M.; Grant, D. M. “Pestacin: a 1,3-dihydro isobenzofuran from Pestalotiopsis microspora possessing antioxidant and antimicotic activities” Tetrahedron, 2003, 59, 2471. (c) Strobel, G. A.; Ford, E.; Worapong, J.; Harper, J. K.; Arif, A. M.; Grant, D. M.; Fung, P. C. W.; Ming, W. C. R. “Isopestacin, an isobenzofuranone from Pestalotiopsis microspora possessing antifungal and antioxidant activity” Phytochem. 2002, 60, 179.
Expanding Horizons: Episode 2- A New Path to Molecular Structure