18F-Fluorination of Unactivated C-H Bonds in Branched Aliphatic Amino Acids: Direct Synthesis of Oncological PET Imaging Agents

A mild and selective photocatalytic C-H 18F-fluorination reaction has been developed that provides direct access to 18F-fluorinated amino acids. The biodis-tribution and uptake of three 18F-labelled leucine ana-logues via LAT1 mediated transport in several cancer cell lines is reported. PET imaging of mice bearing PC3 (pros-tate) or U87 (glioma) xenografts using 5-[18F]-fluoro-homoleucine showed high tumor uptake and excellent tumor visualization, highlighting the utility of this strat-egy for rapid tracer discovery for oncology

Wintertime phytoplankton bloom in the subarctic Pacific supported by continental margin iron

Author Posting. © American Geophysical Union, 2006. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 20 (2006): GB1006, doi:10.1029/2005GB002557.Heightened biological activity was observed in February 1996 in the high-nutrient low-chlorophyll (HNLC) subarctic North Pacific Ocean, a region that is thought to be iron-limited. Here we provide evidence supporting the hypothesis that Ocean Station Papa (OSP) in the subarctic Pacific received a lateral supply of particulate iron from the continental margin off the Aleutian Islands in the winter, coincident with the observed biological bloom. Synchrotron X-ray analysis was used to describe the physical form, chemistry, and depth distributions of iron in size fractionated particulate matter samples. The analysis reveals that discrete micron-sized iron-rich hot spots are ubiquitous in the upper 200 m at OSP, more than 900 km from the closest coast. The specifics of the chemistry and depth profiles of the Fe hot spots trace them to the continental margins. We thus hypothesize that iron hot spots are a marker for the delivery of iron from the continental margin. We confirm the delivery of continental margin iron to the open ocean using an ocean general circulation model with an iron-like tracer source at the continental margin. We suggest that iron from the continental margin stimulated a wintertime phytoplankton bloom, partially relieving the HNLC condition.This work was supported by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research (KP1202030) to J. K. B and by NSFATM-9987457 to I. F. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, Division of Materials Sciences and Division of Chemical Sciences, Geosciences, and Biosciences of the U.S. Department of Energy at Lawrence Berkeley National Laboratory under contract DE-AC03-76SF00098

Synthesis of biologically active marine natural product analogues

Natural products have long been a source of inspiration for many drugs in human use. The Andersen lab examines compounds from marine sources that can be used as lead structures for drug discovery. Synthetic studies, structure-activity relationships (SAR) and biological findings of two such compounds are described in this thesis. The first is pelorol, a meroterpene isolated from a tropical sponge Dactylospongia elegans. Pelorol is a small molecule activator of SHIP 1, a phosphatase that is a negative regulator of the P13K pathway in hematopoetic cells. Using a synthetic route from a previous co-worker, Lu Yang, a series of SHIP 1 activating compounds based on pelorol were synthesized. These compounds were evaluated for selectivity, potency, and efficacy in a series of biological studies, leading to the discovery of 2.27 as a preclinical lead compound. Water-soluble prodrugs of the SHIP 1-activating compounds were also synthesized and their properties reported. The second compound examined is ceratamine A, an alkaloid isolated from the sponge Pseudoceratina sp. from Papua New Guinea. Ceratamines A and B are microtubule stabilizing antimitotic agents that may be useful in cancer chemotherapy. The core imidazo[4,5,d]azepine heterocycle of the ceratamines has no precedent among known synthetic or natural compounds. The relatively simple structure of the ceratamines and the novel antimitotic phenotype they generate makes them attractive targets. Desbromo ceratamine A (3.44) was synthesized by an efficient and scaleable route, confirming the structure of ceratamine A and validating the biological activity of the core pharmacophore. Synthetic efforts towards ceratamine A were ultimately thwarted by the inability to install the bromine atoms present in the natural product. A significant finding is that the bromine atoms in ceratamine A contribute significantly to the antimitotic potency of the compound necessitating a bioisosteric approach to more potent antimitotic ceratamine-based agents.Science, Faculty ofChemistry, Department ofGraduat

A Subfamily of Bacterial Ribokinases Utilizes a Hemithioacetal for Pyridoxal Phosphate Salvage

Pyridoxal 5′-phosphate (PLP) is the active vitamer of vitamin B₆ and acts as an essential cofactor in many aspects of amino acid and sugar metabolism. The virulence and survival of pathogenic bacteria such as Mycobacterium tuberculosis depend on PLP, and deficiencies in humans have also been associated with neurological disorders and inflammation. While PLP can be synthesized by a de novo pathway in bacteria and plants, most higher organisms rely on a salvage pathway that phosphorylates either pyridoxal (PL) or its related vitamers, pyridoxine (PN) and pyridoxamine (PM). PL kinases (PLKs) are essential for this phosphorylation step and are thus of major importance for cellular viability. We recently identified a pyridoxal kinase (SaPLK) as a target of the natural product antibiotic rugulactone (Ru) in Staphylococcus aureus. Surprisingly, Ru selectively modified SaPLK not at the active site cysteine, but on a remote cysteine residue. Based on structural and biochemical studies, we now provide insight into an unprecedented dual Cys charge relay network that is mandatory for PL phosphorylation. The key component is the reactive Cys 110 residue in the lid region that forms a hemithioactetal intermediate with the 4′-aldehyde of PL. This hemithioacetal, in concert with the catalytic Cys 214, increases the nucleophilicity of the PL 5′-OH group for the inline displacement reaction with the γ-phosphate of ATP. A closer inspection of related enzymes reveals that Cys 110 is conserved and thus serves as a characteristic mechanistic feature for a dual-function ribokinase subfamily herein termed CC-PLKs

¹⁸F‑Fluorination of Unactivated C–H Bonds in Branched Aliphatic Amino Acids: Direct Synthesis of Oncological Positron Emission Tomography Imaging Agents

A mild and selective photocatalytic C–H ¹⁸F-fluorination reaction has been developed that provides direct access to ¹⁸F-fluorinated amino acids. The biodistribution and uptake of three ¹⁸F-labeled leucine analogues via LAT1 mediated transport in several cancer cell lines is reported. Positron emission tomography imaging of mice bearing PC3 (prostate) or U87 (glioma) xenografts using 5-[¹⁸F]-fluorohomoleucine showed high tumor uptake and excellent tumor visualization, highlighting the utility of this strategy for rapid tracer discovery for oncology

Lipoprotein biogenesis in Gram-positive bacteria:knowing when to hold 'em, knowing when to fold 'em

Gram-positive bacterial lipoproteins are a functionally diverse and important class of peripheral membrane proteins. Recent advances in molecular biology and the availability of whole genome sequence data have overturned many long-held assumptions about the export and processing of these proteins, most notably the recent discovery that not all lipoproteins are exported as unfolded substrates through the general secretion pathway. Here, we review recent discoveries concerning the export and processing of these proteins, their role in virulence in Gram-positive bacteria and their potential as vaccine candidates or targets for new antimicrobials