Papers by Jennifer Compton
Tetrahedron, 2007
The structures and biological properties of peptides produced by two genera of marine-derived fun... more The structures and biological properties of peptides produced by two genera of marine-derived fungi, an atypical Acremonium sp., and a Metarrhizium sp. were explored. The Acremonium strain was isolated from a marine sponge and has previously been shown by our group to produce peptides from the efrapeptin and RHM families. The isolation and structure elucidation of the new linear pentadecapeptides efrapeptins Eα (1), H (2) and N-methylated octapeptides RHM3 (3) and RHM4 (4) were carried out through a combination of 1D and 2D NMR techniques and tandem MS. Additional known efrapeptins E, F, G and the known syctalidamides A and B were also isolated. The absolute configurations of 1 -4 are proposed to be the same as the original compound families. The marine-sponge derived Metarrhizium sp. was shown to produce destruxin cyclic depsipeptides including A, B, B2, desmethyl B, E chlorohydrin and E2 chlorohydrin. Efrapeptins Eα (1), F and G each displayed IC 50 S of 1.3 nM against H125 cells, and destruxin E2 chlorohydrin displayed an IC 50 of 160 nM against HCT-116 cells. An initial therapeutic assessment suggested a continuous (168 h) exposure of at least 2 ng/ml, or a daily (24 h) exposure of at least 300 ng/ml for H125 cells treated with efrapeptin G, and a continuous (168 h) exposure of at least 190 ng/ml for HCT-116 cells treated with destruxin E2 chlorohydrin, will cause 90% tumor cell death in vitro.
Journal of Natural Products, 2005
The isolation and structure elucidation of three new secondary metabolites, chaetoglobosin-510 (1... more The isolation and structure elucidation of three new secondary metabolites, chaetoglobosin-510 (1), -540 (2), and -542 (3), are described. These compounds were produced by cultures of the marine-derived fungus Phomopsis asparagi, challenged with the known F-actin inhibitor jasplakinolide. Chaetoglobosin-542 (3) displayed antimicrofilament activity and was cytotoxic toward murine colon and leukemia cancer cell lines.
Journal of Natural Products, 2007
A new compound of mixed polyketide synthase-nonribosomal peptide synthetase (PKS/NRPS) origin, 11... more A new compound of mixed polyketide synthase-nonribosomal peptide synthetase (PKS/NRPS) origin, 11-Omethylpseurotin A (1), was identified from a marine-derived Aspergillus fumigatus. Bioassay-guided fractionation using a yeast halo assay with wild-type and cell cycle-related mutant strains of Saccharomyces cereVisiae resulted in the isolation of 1, which selectively inhibited a Hof1 deletion strain. Techniques including 1D and 2D NMR, HRESIMS, optical rotation, J-based analysis, and biosynthetic parallels were used in the elucidation of the planar structure and absolute configuration of 1. A related known compound, pseurotin A (2), was also isolated and found to be inactive in the yeast screen.
Developmental Cell, 2011
In the field of breast biology, there is a growing appreciation for the ''gatekeeping function'' ... more In the field of breast biology, there is a growing appreciation for the ''gatekeeping function'' of basal cells during development and disease processes yet mechanisms regulating the generation of these cells are poorly understood. Here, we report that the proliferation of basal cells is controlled by SLIT/ ROBO1 signaling and that production of these cells regulates outgrowth of mammary branches. We identify the negative regulator TGF-b1 upstream of Robo1 and show that it induces Robo1 expression specifically in the basal layer, functioning together with SLIT2 to restrict branch formation. Loss of SLIT/ROBO1 signaling in this layer alone results in precocious branching due to a surplus of basal cells. SLIT2 limits basal cell proliferation by inhibiting canonical WNT signaling, increasing the cytoplasmic and membrane pools of b-catenin at the expense of its nuclear pool. Together, our studies provide mechanistic insight into how specification of basal cell number influences branching morphogenesis.
Current Biology, 1998
Cyclins and cyclin-dependent kinases induce and coordinate the events of the cell cycle, although... more Cyclins and cyclin-dependent kinases induce and coordinate the events of the cell cycle, although the mechanisms by which they do so remain largely unknown. In budding yeast, a pathway used by the Clb2 cyclin to control bud growth during mitosis provides a good model system in which to understand how cyclin-dependent kinases control cell-cycle events. In this pathway, Clb2 initiates a series of events that lead to the mitosis-specific activation of the Gin4 protein kinase. A protein called Nap1 is required in vivo for the activation of Gin4, and is able to bind to both Gin4 and Clb2. We have used a simple genetic screen to identify additional proteins that function in this pathway. We have found that the Cdc42 GTPase and a member of the PAK kinase family called Cla4 both function in the pathway used by Clb2 to control bud growth during mitosis. Cdc42 and Cla4 interact genetically with Gin4 and Nap1, and both are required in vivo for the mitosis-specific activation of the Gin4 kinase. Furthermore, Cla4 undergoes a dramatic hyperphosphorylation in response to the combined activity of Nap1, the Clb2-Cdc28 kinase complex, and the GTP-bound form of Cdc42. Evidence is presented which suggests that the hyperphosphorylated form of Cla4 is responsible for relaying the signal to activate Gin4. Previous studies have suggested that cyclin-dependent kinases control the cell cycle by directly phosphorylating proteins involved in specific events, such as nuclear lamins, microtubule-associated proteins and histones. In contrast, our results demonstrate that the Clb2-Cdc28 cyclin-dependent kinase complex controls specific cell-cycle events through a pathway that involves a GTPase and at least two different kinases. This suggests that cyclin-dependent kinases may control many cell-cycle events through GTPase-linked signaling pathways that resemble the intricate signaling pathways known to control many other cellular events.
Bioorganic & Medicinal Chemistry, 2010
Human African trypanosomiasis (HAT, commonly known as African sleeping sickness) is categorized a... more Human African trypanosomiasis (HAT, commonly known as African sleeping sickness) is categorized as a neglected disease, as it afflicts > 50,000 people annually in sub-saharan Africa, and there are few formal programs in the world focused on drug discovery approaches for this disease. In this study, we examined the crude extracts of two fungal strains (Aspergillus fumigatus and Nectria inventa) isolated from deep water sediment which provided >99% growth inhibition at 1 μg/mL of Trypanosoma brucei, the causative parasite of HAT. A collection of fifteen natural products was supplemented with six semi-synthetic derivatives and one commercially available compound. Twelve of the compounds, each containing a diketopiperazine core, showed excellent activity against T. brucei (IC 50 = 0.002 -40 μM), with selectivity over mammalian cells as great as 20-fold. The trypanocidal diketopiperazines were also tested against two cysteine protease targets Rhodesain and TbCatB, where five compounds showed inhibition activity at concentrations less than 20 μM. A preliminary activity pattern is described and analyzed.
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Papers by Jennifer Compton