Journal of Microbiology and Biotechnology, Sep 1, 2011
Two new cyclic depsipeptides wewakamide A (1) and guineamide G (2) have been isolated from the ma... more Two new cyclic depsipeptides wewakamide A (1) and guineamide G (2) have been isolated from the marine cyanobacterium Lyngbya semiplena and Lyngbya majuscula, respectively, collected from Papua New Guinea. The amino and hydroxy acid partial structures of wewakamide A and guineamide G were elucidated through extensive spectroscopic techniques, including HR-FABMS, 1D (1)H and (13)C NMR, as well as 2D COSY, HSQC, HSQCTOCSY, and HMBC spectra. The sequence of the residues of wewakamide A was determined through a combination of ESI-MS/MS, HMBC, and ROESY. Wewakamide A possesses a β-amino acid, 3-amino-2-methylbutanoic acid (Maba) residue, which has only been previously identified in two natural products, guineamide B (3) and dolastatin D (4). Although both new compounds (1,2) showed potent brine shrimp toxicity, only guineamide G displayed significant cytotoxicity to a mouse neuroblastoma cell line with LC(50) values of 2.7 micrometer.
Http Dx Doi Org 10 1080 14786410412331271960, Aug 15, 2006
Specimens of the cosmopolitan sea hare Aplysia parvula, collected in the Tsistsikamma National Pa... more Specimens of the cosmopolitan sea hare Aplysia parvula, collected in the Tsistsikamma National Park on the south-east coast of South Africa yielded the new dibromo-C15-acetogenin, (3Z)-bromofucin (1). Standard spectroscopic methods were used to establish the structure of this compound.
Recollection of the tunicate source of the mandelalides has provided new and known analogues that... more Recollection of the tunicate source of the mandelalides has provided new and known analogues that have facilitated expanded analyses of the disputed cancer cytotoxicity of mandelalide A following a number of recent reported total syntheses. Using newly characterized mandelalide E, reisolated natural mandelalides B and C, and synthetic mandelalide A, the cytotoxicity of the mandelalides is demonstrated to be strongly influenced by compound glycosylation and assay cell density. Glycosylated mandelalides reduced the viability of human cancer cells cultured at a high starting density with a rank order of potency A > B ≫ E, yet display dramatically reduced cytotoxic efficacy against low density cultures.
Coibamide A is a cytotoxic lariat depsipeptide isolated from a rare cyanobacterium found within t... more Coibamide A is a cytotoxic lariat depsipeptide isolated from a rare cyanobacterium found within the marine reserve of Coiba National Park, Panama. Earlier testing of coibamide A in the National Cancer Institute in vitro 60 human tumor cell line panel (NCI-60) revealed potent anti-proliferative activity and a unique selectivity profile, potentially reflecting a new target or mechanism of action. In the present study we evaluated the antitumor activity of coibamide A in several functional cell-based assays and in vivo. U87-MG and SF-295 glioblastoma cells showed reduced migratory and invasive capacity and underwent G1 cell cycle arrest as, likely indirect, consequences of treatment. Coibamide A inhibited extracellular VEGFA secreted from U87-MG glioblastoma and MDA-MB-231 breast cancer cells with low nM potency, attenuated proliferation and migration of normal human umbilical vein endothelial cells (HUVECs) and selectively decreased expression of vascular endothelial growth factor rec...
Bacteria can be both highly communicative and highly competitive in natural habitats and antibiot... more Bacteria can be both highly communicative and highly competitive in natural habitats and antibiotics are thought to play a role in both of these processes. The soil bacterium Pseudomonas protegens Pf-5 produces a spectrum of antibiotics, two of which, pyoluteorin and 2,4-diacetylphloroglucinol (DAPG), function in intracellular and intercellular communication, both as autoinducers of their own production. Here, we demonstrate that phloroglucinol, an intermediate in DAPG biosynthesis, can serve as an intercellular signal influencing the expression of pyoluteorin biosynthesis genes, the production of pyoluteorin, and inhibition of Pythium ultimum, a phytopathogenic oomycete sensitive to pyoluteorin. Through analysis of RNAseq data sets, we show that phloroglucinol had broad effects on the transcriptome of Pf-5, significantly altering the transcription of more than two hundred genes. The effects of nanomolar versus micromolar concentrations of phloroglucinol differed both quantitatively and qualitatively, influencing the expression of distinct sets of genes or having opposite effects on transcript abundance of certain genes. Therefore, our results support the concept of hormesis, a phenomenon associated with signaling molecules that elicit distinct responses at different concentrations. Phloroglucinol is the first example of an intermediate of antibiotic biosynthesis that functions as a chemical messenger influencing gene expression in P. protegens.
The chemical and biological diversity of the marine environment is immeasurable and therefore is ... more The chemical and biological diversity of the marine environment is immeasurable and therefore is an extraordinary resource for the discovery of new anticancer drugs. Recent technological and methodologic advances in structure elucidation, organic synthesis, and biological assay have resulted in the isolation and clinical evaluation of various novel anticancer agents. These compounds range in structural class from simple linear peptides, such as dolastatin 10, to complex macrocyclic polyethers, such as halichondrin B; equally as diverse are the molecular modes of action by which these molecules impart their biological activity. This review highlights several marine natural products and their synthetic derivatives that are currently undergoing clinical evaluation as anticancer drugs.
One of the hallmarks of Alzheimer's disease (AD) is the progressive degeneration of cholinerg... more One of the hallmarks of Alzheimer's disease (AD) is the progressive degeneration of cholinergic neurons in the cerebral cortex and hippocampus. It is generally accepted that this neuronal degeneration is due to free-radical-induced damage. These free radicals attack vital structural components of the neurons. This implies that agents that reduce free radical generation could potentially delay the progression of AD. Free radical generation in the brain is assisted by the presence of iron, required by the Fenton reaction. Thus, agents that reduce iron availability for this reaction could potentially reduce free radical formation. Since non steroidal anti-inflammatory drugs (NSAIDS) have been shown to reduce the severity of AD, we investigated the possible mechanism by which indomethacin could afford neuroprotection. Our results show that indomethacin (1 mM) is able to reduce the iron-induced rise in lipid peroxidation in rat brain homogenates. In addition, our NMR data indicate th...
Journal of Microbiology and Biotechnology, Sep 1, 2011
Two new cyclic depsipeptides wewakamide A (1) and guineamide G (2) have been isolated from the ma... more Two new cyclic depsipeptides wewakamide A (1) and guineamide G (2) have been isolated from the marine cyanobacterium Lyngbya semiplena and Lyngbya majuscula, respectively, collected from Papua New Guinea. The amino and hydroxy acid partial structures of wewakamide A and guineamide G were elucidated through extensive spectroscopic techniques, including HR-FABMS, 1D (1)H and (13)C NMR, as well as 2D COSY, HSQC, HSQCTOCSY, and HMBC spectra. The sequence of the residues of wewakamide A was determined through a combination of ESI-MS/MS, HMBC, and ROESY. Wewakamide A possesses a β-amino acid, 3-amino-2-methylbutanoic acid (Maba) residue, which has only been previously identified in two natural products, guineamide B (3) and dolastatin D (4). Although both new compounds (1,2) showed potent brine shrimp toxicity, only guineamide G displayed significant cytotoxicity to a mouse neuroblastoma cell line with LC(50) values of 2.7 micrometer.
Http Dx Doi Org 10 1080 14786410412331271960, Aug 15, 2006
Specimens of the cosmopolitan sea hare Aplysia parvula, collected in the Tsistsikamma National Pa... more Specimens of the cosmopolitan sea hare Aplysia parvula, collected in the Tsistsikamma National Park on the south-east coast of South Africa yielded the new dibromo-C15-acetogenin, (3Z)-bromofucin (1). Standard spectroscopic methods were used to establish the structure of this compound.
Recollection of the tunicate source of the mandelalides has provided new and known analogues that... more Recollection of the tunicate source of the mandelalides has provided new and known analogues that have facilitated expanded analyses of the disputed cancer cytotoxicity of mandelalide A following a number of recent reported total syntheses. Using newly characterized mandelalide E, reisolated natural mandelalides B and C, and synthetic mandelalide A, the cytotoxicity of the mandelalides is demonstrated to be strongly influenced by compound glycosylation and assay cell density. Glycosylated mandelalides reduced the viability of human cancer cells cultured at a high starting density with a rank order of potency A > B ≫ E, yet display dramatically reduced cytotoxic efficacy against low density cultures.
Coibamide A is a cytotoxic lariat depsipeptide isolated from a rare cyanobacterium found within t... more Coibamide A is a cytotoxic lariat depsipeptide isolated from a rare cyanobacterium found within the marine reserve of Coiba National Park, Panama. Earlier testing of coibamide A in the National Cancer Institute in vitro 60 human tumor cell line panel (NCI-60) revealed potent anti-proliferative activity and a unique selectivity profile, potentially reflecting a new target or mechanism of action. In the present study we evaluated the antitumor activity of coibamide A in several functional cell-based assays and in vivo. U87-MG and SF-295 glioblastoma cells showed reduced migratory and invasive capacity and underwent G1 cell cycle arrest as, likely indirect, consequences of treatment. Coibamide A inhibited extracellular VEGFA secreted from U87-MG glioblastoma and MDA-MB-231 breast cancer cells with low nM potency, attenuated proliferation and migration of normal human umbilical vein endothelial cells (HUVECs) and selectively decreased expression of vascular endothelial growth factor rec...
Bacteria can be both highly communicative and highly competitive in natural habitats and antibiot... more Bacteria can be both highly communicative and highly competitive in natural habitats and antibiotics are thought to play a role in both of these processes. The soil bacterium Pseudomonas protegens Pf-5 produces a spectrum of antibiotics, two of which, pyoluteorin and 2,4-diacetylphloroglucinol (DAPG), function in intracellular and intercellular communication, both as autoinducers of their own production. Here, we demonstrate that phloroglucinol, an intermediate in DAPG biosynthesis, can serve as an intercellular signal influencing the expression of pyoluteorin biosynthesis genes, the production of pyoluteorin, and inhibition of Pythium ultimum, a phytopathogenic oomycete sensitive to pyoluteorin. Through analysis of RNAseq data sets, we show that phloroglucinol had broad effects on the transcriptome of Pf-5, significantly altering the transcription of more than two hundred genes. The effects of nanomolar versus micromolar concentrations of phloroglucinol differed both quantitatively and qualitatively, influencing the expression of distinct sets of genes or having opposite effects on transcript abundance of certain genes. Therefore, our results support the concept of hormesis, a phenomenon associated with signaling molecules that elicit distinct responses at different concentrations. Phloroglucinol is the first example of an intermediate of antibiotic biosynthesis that functions as a chemical messenger influencing gene expression in P. protegens.
The chemical and biological diversity of the marine environment is immeasurable and therefore is ... more The chemical and biological diversity of the marine environment is immeasurable and therefore is an extraordinary resource for the discovery of new anticancer drugs. Recent technological and methodologic advances in structure elucidation, organic synthesis, and biological assay have resulted in the isolation and clinical evaluation of various novel anticancer agents. These compounds range in structural class from simple linear peptides, such as dolastatin 10, to complex macrocyclic polyethers, such as halichondrin B; equally as diverse are the molecular modes of action by which these molecules impart their biological activity. This review highlights several marine natural products and their synthetic derivatives that are currently undergoing clinical evaluation as anticancer drugs.
One of the hallmarks of Alzheimer's disease (AD) is the progressive degeneration of cholinerg... more One of the hallmarks of Alzheimer's disease (AD) is the progressive degeneration of cholinergic neurons in the cerebral cortex and hippocampus. It is generally accepted that this neuronal degeneration is due to free-radical-induced damage. These free radicals attack vital structural components of the neurons. This implies that agents that reduce free radical generation could potentially delay the progression of AD. Free radical generation in the brain is assisted by the presence of iron, required by the Fenton reaction. Thus, agents that reduce iron availability for this reaction could potentially reduce free radical formation. Since non steroidal anti-inflammatory drugs (NSAIDS) have been shown to reduce the severity of AD, we investigated the possible mechanism by which indomethacin could afford neuroprotection. Our results show that indomethacin (1 mM) is able to reduce the iron-induced rise in lipid peroxidation in rat brain homogenates. In addition, our NMR data indicate th...
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Papers by Kerry McPhail