Biomedical subjects

James K Harper

Publications and source records attributed to James K Harper.

5 recordsLinked to original sources

PubMed2006

Characterizing challenging microcrystalline solids with solid-state NMR shift tensor and synchrotron X-ray powder diffraction data: structural analysis of ambuic acid.

Synchrotron X-ray powder diffraction and solid-state (13)C NMR shift tensor data are combined to provide a unique path to structure in microcrystalline organic solids. Analysis is demonstrated on ambuic acid powder, a widely occurring natural product, to provide the complete crystal structure. The NMR data verify phase purity, specify one molecule per asymmetric unit, and provide an initial structural model including relative stereochemistry and molecular conformation. A refinement of X-ray data from the initial model establishes that ambuic acid crystallizes in the P2(1) space group with unit cell parameters a = 15.5047(7), b = 4.3904(2), and c = 14.1933(4) A and beta = 110.3134(3) degrees . This combined analysis yields structural improvements at two dihedral angles over prior NMR predictions with differences of 103 degrees and 37 degrees found. Only minor differences of +/-5.5 degrees , on average, are observed at all remaining dihedral angles. Predicted hydroxyl hydrogen-bonding orientations also fit NMR predictions within +/-6.9 degrees . This refinement corrects chemical shift assignments at two carbons and reduces the NMR error by approximately 16%. This work demonstrates that the combination of long-range order information from synchrotron powder diffraction data together with the accurate shorter range structure given by solid-state NMR measurements is a powerful tool for studying challenging organic solids.

Cyclohexanones↗

PubMed2003

Kakadumycins, novel antibiotics from Streptomyces sp NRRL 30566, an endophyte of Grevillea pteridifolia.

An endophytic streptomycete (NRRL 30566) is described and partially characterized from a fern-leaved grevillea (Grevillea pteridifolia) tree growing in the Northern Territory of Australia. This endophytic streptomycete produces, in culture, novel antibiotics - the kakadumycins. Methods are outlined for the production and chemical characterization of kakadumycin A and related compounds. This antibiotic is structurally related to a quinoxaline antibiotic, echinomycin. Each contains, by virtue of their amino acid compositions, alanine, serine and an unknown amino acid. Other biological, spectral and chromatographic differences between these two compounds occur and are given. Kakadumycin A has wide spectrum antibiotic activity, especially against Gram-positive bacteria, and it generally displays better bioactivity than echinomycin. For instance, against Bacillus anthracis strains, kakadumycin A has minimum inhibitory concentrations of 0.2-0.3 microg x ml(-1) in contrast to echinomycin at 1.0-1.2 microg x ml(-1). Both echinomycin and kakadumycin A have impressive activity against the malarial parasite Plasmodium falciparum with LD(50)s in the range of 7-10 ng x ml(-1). In macromolecular synthesis assays both kakadumycin A and echinomycin have similar effects on the inhibition of RNA synthesis. It appears that the endophytic Streptomyces sp. offer some promise for the discovery of novel antibiotics with pharmacological potential.

Anti-Bacterial Agents↗

PubMed2003

Stereochemical analysis by solid-state NMR: structural predictions in ambuic acid.

Relative stereochemistry is predicted for ambuic acid using a novel solid-state NMR approach. This NMR technique entails a comparison of measured shift tensor principal values with computed values for all diastereomers, allowing the selection of a best-fit structure. The proposed method extends previous solution NMR structural data by simultaneously modeling with high statistical probability hydrogen-bonding arrangements and molecular conformation at two positions. A dimeric structure is proposed for ambuic acid based on the initial poor fit of the carboxyl carbon tensors to a monomeric model. The dimer model, consisting of hydrogen bonding between pairs of neighboring carboxyl groups, reduces the root mean square error at the carboxy tensor by a factor of 2.7. Lattice details are thus also described by the proposed approach. The structural characterization method presented is of general applicability and may be especially useful for characterizing difficult to crystallize or hydrogen-poor materials.

Carbon Isotopes↗

PubMed2002

13C NMR investigation of solid-state polymorphism in 10-deacetyl baccatin III.

To investigate the origins of solid-state NMR shift differences in polymorphs, carbon NMR chemical shift tensors are measured for two forms of solid 10-deacetyl baccatin III: a dimethyl sulfoxide (DMSO) solvate and an unsolvated form. A comparison of ab initio computed tensors that includes and omits the DMSO molecules demonstrates that lattice interactions cannot fully account for the shift differences in the two forms. Instead, conformational differences in the cyclohexenyl, benzoyl, and acetyl moieties are postulated to create the differences observed. X-ray analysis of six baccatin III analogues supports the suggested changes in the cyclohexenyl and benzoyl systems. The close statistical match of the (13)C chemical shifts of both polymorphic forms with those calculated using the X-ray geometry of 10-deacetyl baccatin III supports the contention that the B, C, and D rings are fairly rigid. Therefore, the observed tensor differences appear to arise primarily from conformational variations in ring substituents and the cyclohexenyl ring.

Carbon Isotopes↗

PubMed2002

Isopestacin, an isobenzofuranone from Pestalotiopsis microspora, possessing antifungal and antioxidant activities.

Isopestacin is an isobenzofuranone obtained from the endophytic fungus Pestalotiopsis microspora. While a few other isobenzofuranones are known from natural sources, isopestacin is the only one having a substituted benzene ring attached at the C-3 position of the furanone ring. The compound was isolated from culture broths of the fungus and crystallized and its structure was determined by X-ray crystallography. Both proton and carbon NMR spectral assignments are also reported for isopestacin. This compound possesses antifungal activity and, as measured by electron spin resonance specroscopy, it also behaves as an antioxidant scavenging both superoxide and hydroxy free radicals.

Antifungal Agents↗