Papers by Patrick Still
Higher plants continue to afford humankind with many new drugs, for a variety of disease types. I... more Higher plants continue to afford humankind with many new drugs, for a variety of disease types. In this review, recent phytochemical and biological progress is presented for part of a collaborative multi-institutional project directed towards the discovery of new antitumor agents. The specific focus is on bioactive natural products isolated and characterized structurally from tropical plants collected in Vietnam. The plant collection, identification, and processing steps are described, and the natural products isolated from these species are summarized with their biological activities.
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Hematologic malignancies account for a substantial percentage of cancers worldwide, and the heter... more Hematologic malignancies account for a substantial percentage of cancers worldwide, and the heterogeneity
and biological characteristics of leukemias and lymphomas present unique therapeutic challenges. Although treatment
options exist for most of these diseases, many types remain incurable and the emergence of drug resistance is pervasive.
Thus, novel treatment approaches are essential to improve outcome. Nearly half of the agents used in cancer therapy todayare either natural products or derivatives of natural products. The enormous chemical diversity in nature, coupled with millennia of biological selection, has generated a vast and underexplored reservoir of unique chemical structures with
biologic activity. This review will describe the investigation and application of natural products derived from higher
plants in the treatment of leukemia and lymphoma and the rationale behind these efforts. In addition to the approved vinca
alkaloids and the epipodophyllotoxin derivatives, a number of other plant compounds have shown promise in clinical
trials and in preclinical investigations. In particular, we will focus on the discovery and biological evaluation of the plantderived
agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell
malignancies including chronic lymphocytic leukemia.
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Microcos paniculata is a large shrub or small tree
that grows in several countries in South and ... more Microcos paniculata is a large shrub or small tree
that grows in several countries in South and Southeast Asia. In the present study, three new piperidine alkaloids, microgrewiapines A−C (1−3), as well as three known compounds, inclusive of microcosamine A (4), 7′-(3′,4′-dihydroxyphenyl)-N-[4-methoxyphenyl)ethyl]propenamide (5), and liriodenine (6), were isolated from cytotoxic fractions of the separate chloroform-soluble extracts of the stem bark, branches, and leaves of M. paniculata. Compounds 1−6 and 1a (microgrewiapine A 3-acetate) showed a range of cytotoxicity values against the HT-29 human colon cancer cell line. When evaluated for their effects on human α3β4 or α4β2 nicotinic acetylcholine receptors (nAChRs), several of these compounds were shown to be active as nAChR antagonists. As a result of this study, microgrewiapine A (1) was found to be a selective cytotoxic agent for colon cancer cells over normal colon cells and to exhibit nicotinic receptor antagonistic activity for both the hα3β4 and hα4β2 receptor subtypes.
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Compounds from macro marine organisms are
presumed to owe their biosynthetic origins to associate... more Compounds from macro marine organisms are
presumed to owe their biosynthetic origins to associated
microbial symbionts, although few definitive examples exist.
An upsurge in the recent literature from 2012 to 2013 has
shown that four compounds previously reported from macro
marine organisms are in fact biosynthesized by non-photosynthetic Gram-negative bacteria (NPGNB). Structural
parallels between compounds isolated from macro marine
organisms and NPGNB producers form the basis of this review. Although less attention has been given to investigating the
chemistry of NPGNB sources, there exists a significant list of structural parallels between NPGNB and macro marine organism derived compounds. Alternatively, of the thousands of compounds isolated from Gram-positive actinomycetes, few structural
parallels with macro marine organisms are known. A summary of small molecules isolated from marine NPGNB sources is
presented, including compounds isolated from marine myxobacteria. From this assemblage of structural parallels and diverse chemical structures, it is hypothesized that the potential for the discovery of inspirational molecules from NPGNB sources is vast and that the recent spike in the literature of macro marine compounds owing their biosynthetic origin to NPGNB producers represents a turning point in the field.
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Ellagic acid (1) was synthesized for the first time from methyl gallate through α-pentagalloylglu... more Ellagic acid (1) was synthesized for the first time from methyl gallate through α-pentagalloylglucose (α-PGG),
and ellagic acid peracetate (3,4,3′,4′-tetra-O-acetylellagic acid, 2) was derived from 1 by acetylation. Oral administration of 2 suppressed melanoma growth significantly in C7BL/6 immunocompetent mice without having any effect on natural killer (NK) cell activity. Comparison of the immunoenhancing activities of 1 and 2 indicated that the latter compound increased white blood
cell quantities in peripheral blood and immune cells enriched from the bone marrow and liver of mice. Therefore, both the
antitumor efficacy and the immunity enhancement by 2 were greater than those by 1. In addition, on oral administration, neither 1 nor 2 resulted in whole body, liver, or spleen weight changes of normal, tumor-free mice, indicating that these compounds are potentially nontoxic to mice. It was shown that ellagic acid peracetate (2) inhibits B16 melanoma cell growth in vitro and induces B16 cell apoptosis, corresponding to BCL-2 down-regulation. Collectively, the present data imply that 2 can suppress tumor growth by enhancing mouse immunity and inducing tumor cell apoptosis without apparent side effects.
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Gunnera is the only genus of angiosperms known to host cyanobacteria and the only group of land p... more Gunnera is the only genus of angiosperms known to host cyanobacteria and the only group of land plants that hosts cyanobacteria intracellularly. Motile filaments of cyanobacteria, known as hormogonia, colonize Gunnera plants through cells in the plant’s specialized stem glands. It is commonly held that Gunnera plants always possess functional glands for symbiosis. We found, however, that stem gland development did not occur when Gunnera manicata plants were grown on nitrogen (N)-replete medium but, rather, was initiated at predetermined positions when plants were deprived of combined N. While N status was the main determinant for gland development, an exogenous carbon source (sucrose) accelerated the process. Furthermore, a high level of sucrose stimulated the formation of callus-like tissue in place of the gland under N-replete conditions. Treatment of plants with the auxin transport inhibitor 1-naphthylphthalamic acid prevented gland development on N-limited medium, most likely by preventing resource reallocation from leaves to the stem. Optimized conditions were found for in vitro establishment of the Nostoc-Gunnera symbiosis by inoculating mature glands with hormogonia from Nostoc punctiforme, a cyanobacterium strain for which the full genome sequence is available. In contrast to uninoculated plants, G. manicata plants colonized by N. punctiforme were able to continue their growth on N-limited medium. Understanding the nature of the Gunnera plant’s unusual adaptation to an N-limited environment may shed light on the evolution of plant-cyanobacterium symbioses and may suggest a route to establish productive associations between N-fixing cyanobacteria and crop plants.
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Sampling of California nearshore sediments
resulted in the isolation of a Gram-negative bacterium... more Sampling of California nearshore sediments
resulted in the isolation of a Gram-negative bacterium,
Photobacterium halotolerans, capable of producing unusual
biosynthetic products. Liquid culture in artificial seawaterbased
media provided cyclic depsipeptides including four known
compounds, kailuins B−E (2−5), and two new analogues,
kailuins G and H (7 and 8). The structures of the new and
known compounds were confirmed through extensive spectroscopic and Marfey’s analyses. During the course of these studies, a correction was made to the previously reported double-bond geometry of kailuin D (4). Additionally, through the application of a combination of derivatization with Mosher’s reagent and extensive 13C NMR shift analysis, the previously unassigned chiral center at position C-3 of the β-acyloxy group of all compounds was determined. To evaluate bioactivity and structure− activity relationships, the kailuin core (13) and kailuin lactam (14) were prepared by chiral synthesis using an Fmoc solid-phase peptide strategy followed by solution-phase cyclization. All isolated compounds and synthetic cores were assayed for solid tumor cell cytotoxicity and showed only minimal activity, contrary to other published reports. Additional phenotypic screenings were done on 4 and 5, with little evidence of activity.
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Dissertation by Patrick Still
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Talks by Patrick Still
Still, P.C., Niadj, L., Milian-Lobo, L., Valeriote, F., Shamloo, M., Whistler, J., and Crews, P. ... more Still, P.C., Niadj, L., Milian-Lobo, L., Valeriote, F., Shamloo, M., Whistler, J., and Crews, P. Amalgamating Neurobiological Experimental Design with Agelas-Derived Cyclobutane Alkaloids to Study GRCR Receptor Modulation (2014). Gordon Research Conference on Marine Natural Products. Ventura, CA, USA. (poster presentation)
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Still, P.C. Chemical Look-a-Likes Across Sponges, Bacteria, and Plants: An Old Concept Inspires N... more Still, P.C. Chemical Look-a-Likes Across Sponges, Bacteria, and Plants: An Old Concept Inspires New Research. American Chemical Society Western Regional Meeting (2014) Santa Clara, CA. (oral presentation)
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Still, P.C., Yi, B., Pavlovicz, R., González-Cestari, T. F., Pan, L., Chai, H.-B., Ninh, T. H., S... more Still, P.C., Yi, B., Pavlovicz, R., González-Cestari, T. F., Pan, L., Chai, H.-B., Ninh, T. H., Soejarto, D. D., Li, C., Fuchs, J. R., McKay, D., Kinghorn, A. D. Alkaloids From Microcos paniculata With Cytotoxic and Non-competetive Nicotinic Receptor Antagonistic Activities. International Congress on Natural Products Research (ICNPR) (2012) New York, NY. (oral presentation)
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Still, P.C., Rutan, S.C., and Chiu, W.L. (2006). Chemical Profiling and Quantitation in the Gunne... more Still, P.C., Rutan, S.C., and Chiu, W.L. (2006). Chemical Profiling and Quantitation in the Gunnera manicata Stem Gland. Virginia Commonwealth University Department of Chemistry Graduate Poster Session. Richmond, VA, USA. (poster presentation)
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Chiu,W.L., Peters, G.A., Levieille, G., Still, P.C., Cousins,S., Osborne, B., and Elhai, J. (2004... more Chiu,W.L., Peters, G.A., Levieille, G., Still, P.C., Cousins,S., Osborne, B., and Elhai, J. (2004). The Role of Flavonoids in the Gunnera-Nostoc Symbiosis. University of Maryland Plant Molecular Biology Symposium (ATRIUM–Arabidopsisthaliana Research Initiative at University of Maryland). College Park, MD, USA. (poster presentation)
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Papers by Patrick Still
and biological characteristics of leukemias and lymphomas present unique therapeutic challenges. Although treatment
options exist for most of these diseases, many types remain incurable and the emergence of drug resistance is pervasive.
Thus, novel treatment approaches are essential to improve outcome. Nearly half of the agents used in cancer therapy todayare either natural products or derivatives of natural products. The enormous chemical diversity in nature, coupled with millennia of biological selection, has generated a vast and underexplored reservoir of unique chemical structures with
biologic activity. This review will describe the investigation and application of natural products derived from higher
plants in the treatment of leukemia and lymphoma and the rationale behind these efforts. In addition to the approved vinca
alkaloids and the epipodophyllotoxin derivatives, a number of other plant compounds have shown promise in clinical
trials and in preclinical investigations. In particular, we will focus on the discovery and biological evaluation of the plantderived
agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell
malignancies including chronic lymphocytic leukemia.
that grows in several countries in South and Southeast Asia. In the present study, three new piperidine alkaloids, microgrewiapines A−C (1−3), as well as three known compounds, inclusive of microcosamine A (4), 7′-(3′,4′-dihydroxyphenyl)-N-[4-methoxyphenyl)ethyl]propenamide (5), and liriodenine (6), were isolated from cytotoxic fractions of the separate chloroform-soluble extracts of the stem bark, branches, and leaves of M. paniculata. Compounds 1−6 and 1a (microgrewiapine A 3-acetate) showed a range of cytotoxicity values against the HT-29 human colon cancer cell line. When evaluated for their effects on human α3β4 or α4β2 nicotinic acetylcholine receptors (nAChRs), several of these compounds were shown to be active as nAChR antagonists. As a result of this study, microgrewiapine A (1) was found to be a selective cytotoxic agent for colon cancer cells over normal colon cells and to exhibit nicotinic receptor antagonistic activity for both the hα3β4 and hα4β2 receptor subtypes.
presumed to owe their biosynthetic origins to associated
microbial symbionts, although few definitive examples exist.
An upsurge in the recent literature from 2012 to 2013 has
shown that four compounds previously reported from macro
marine organisms are in fact biosynthesized by non-photosynthetic Gram-negative bacteria (NPGNB). Structural
parallels between compounds isolated from macro marine
organisms and NPGNB producers form the basis of this review. Although less attention has been given to investigating the
chemistry of NPGNB sources, there exists a significant list of structural parallels between NPGNB and macro marine organism derived compounds. Alternatively, of the thousands of compounds isolated from Gram-positive actinomycetes, few structural
parallels with macro marine organisms are known. A summary of small molecules isolated from marine NPGNB sources is
presented, including compounds isolated from marine myxobacteria. From this assemblage of structural parallels and diverse chemical structures, it is hypothesized that the potential for the discovery of inspirational molecules from NPGNB sources is vast and that the recent spike in the literature of macro marine compounds owing their biosynthetic origin to NPGNB producers represents a turning point in the field.
and ellagic acid peracetate (3,4,3′,4′-tetra-O-acetylellagic acid, 2) was derived from 1 by acetylation. Oral administration of 2 suppressed melanoma growth significantly in C7BL/6 immunocompetent mice without having any effect on natural killer (NK) cell activity. Comparison of the immunoenhancing activities of 1 and 2 indicated that the latter compound increased white blood
cell quantities in peripheral blood and immune cells enriched from the bone marrow and liver of mice. Therefore, both the
antitumor efficacy and the immunity enhancement by 2 were greater than those by 1. In addition, on oral administration, neither 1 nor 2 resulted in whole body, liver, or spleen weight changes of normal, tumor-free mice, indicating that these compounds are potentially nontoxic to mice. It was shown that ellagic acid peracetate (2) inhibits B16 melanoma cell growth in vitro and induces B16 cell apoptosis, corresponding to BCL-2 down-regulation. Collectively, the present data imply that 2 can suppress tumor growth by enhancing mouse immunity and inducing tumor cell apoptosis without apparent side effects.
resulted in the isolation of a Gram-negative bacterium,
Photobacterium halotolerans, capable of producing unusual
biosynthetic products. Liquid culture in artificial seawaterbased
media provided cyclic depsipeptides including four known
compounds, kailuins B−E (2−5), and two new analogues,
kailuins G and H (7 and 8). The structures of the new and
known compounds were confirmed through extensive spectroscopic and Marfey’s analyses. During the course of these studies, a correction was made to the previously reported double-bond geometry of kailuin D (4). Additionally, through the application of a combination of derivatization with Mosher’s reagent and extensive 13C NMR shift analysis, the previously unassigned chiral center at position C-3 of the β-acyloxy group of all compounds was determined. To evaluate bioactivity and structure− activity relationships, the kailuin core (13) and kailuin lactam (14) were prepared by chiral synthesis using an Fmoc solid-phase peptide strategy followed by solution-phase cyclization. All isolated compounds and synthetic cores were assayed for solid tumor cell cytotoxicity and showed only minimal activity, contrary to other published reports. Additional phenotypic screenings were done on 4 and 5, with little evidence of activity.
Dissertation by Patrick Still
Talks by Patrick Still
and biological characteristics of leukemias and lymphomas present unique therapeutic challenges. Although treatment
options exist for most of these diseases, many types remain incurable and the emergence of drug resistance is pervasive.
Thus, novel treatment approaches are essential to improve outcome. Nearly half of the agents used in cancer therapy todayare either natural products or derivatives of natural products. The enormous chemical diversity in nature, coupled with millennia of biological selection, has generated a vast and underexplored reservoir of unique chemical structures with
biologic activity. This review will describe the investigation and application of natural products derived from higher
plants in the treatment of leukemia and lymphoma and the rationale behind these efforts. In addition to the approved vinca
alkaloids and the epipodophyllotoxin derivatives, a number of other plant compounds have shown promise in clinical
trials and in preclinical investigations. In particular, we will focus on the discovery and biological evaluation of the plantderived
agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell
malignancies including chronic lymphocytic leukemia.
that grows in several countries in South and Southeast Asia. In the present study, three new piperidine alkaloids, microgrewiapines A−C (1−3), as well as three known compounds, inclusive of microcosamine A (4), 7′-(3′,4′-dihydroxyphenyl)-N-[4-methoxyphenyl)ethyl]propenamide (5), and liriodenine (6), were isolated from cytotoxic fractions of the separate chloroform-soluble extracts of the stem bark, branches, and leaves of M. paniculata. Compounds 1−6 and 1a (microgrewiapine A 3-acetate) showed a range of cytotoxicity values against the HT-29 human colon cancer cell line. When evaluated for their effects on human α3β4 or α4β2 nicotinic acetylcholine receptors (nAChRs), several of these compounds were shown to be active as nAChR antagonists. As a result of this study, microgrewiapine A (1) was found to be a selective cytotoxic agent for colon cancer cells over normal colon cells and to exhibit nicotinic receptor antagonistic activity for both the hα3β4 and hα4β2 receptor subtypes.
presumed to owe their biosynthetic origins to associated
microbial symbionts, although few definitive examples exist.
An upsurge in the recent literature from 2012 to 2013 has
shown that four compounds previously reported from macro
marine organisms are in fact biosynthesized by non-photosynthetic Gram-negative bacteria (NPGNB). Structural
parallels between compounds isolated from macro marine
organisms and NPGNB producers form the basis of this review. Although less attention has been given to investigating the
chemistry of NPGNB sources, there exists a significant list of structural parallels between NPGNB and macro marine organism derived compounds. Alternatively, of the thousands of compounds isolated from Gram-positive actinomycetes, few structural
parallels with macro marine organisms are known. A summary of small molecules isolated from marine NPGNB sources is
presented, including compounds isolated from marine myxobacteria. From this assemblage of structural parallels and diverse chemical structures, it is hypothesized that the potential for the discovery of inspirational molecules from NPGNB sources is vast and that the recent spike in the literature of macro marine compounds owing their biosynthetic origin to NPGNB producers represents a turning point in the field.
and ellagic acid peracetate (3,4,3′,4′-tetra-O-acetylellagic acid, 2) was derived from 1 by acetylation. Oral administration of 2 suppressed melanoma growth significantly in C7BL/6 immunocompetent mice without having any effect on natural killer (NK) cell activity. Comparison of the immunoenhancing activities of 1 and 2 indicated that the latter compound increased white blood
cell quantities in peripheral blood and immune cells enriched from the bone marrow and liver of mice. Therefore, both the
antitumor efficacy and the immunity enhancement by 2 were greater than those by 1. In addition, on oral administration, neither 1 nor 2 resulted in whole body, liver, or spleen weight changes of normal, tumor-free mice, indicating that these compounds are potentially nontoxic to mice. It was shown that ellagic acid peracetate (2) inhibits B16 melanoma cell growth in vitro and induces B16 cell apoptosis, corresponding to BCL-2 down-regulation. Collectively, the present data imply that 2 can suppress tumor growth by enhancing mouse immunity and inducing tumor cell apoptosis without apparent side effects.
resulted in the isolation of a Gram-negative bacterium,
Photobacterium halotolerans, capable of producing unusual
biosynthetic products. Liquid culture in artificial seawaterbased
media provided cyclic depsipeptides including four known
compounds, kailuins B−E (2−5), and two new analogues,
kailuins G and H (7 and 8). The structures of the new and
known compounds were confirmed through extensive spectroscopic and Marfey’s analyses. During the course of these studies, a correction was made to the previously reported double-bond geometry of kailuin D (4). Additionally, through the application of a combination of derivatization with Mosher’s reagent and extensive 13C NMR shift analysis, the previously unassigned chiral center at position C-3 of the β-acyloxy group of all compounds was determined. To evaluate bioactivity and structure− activity relationships, the kailuin core (13) and kailuin lactam (14) were prepared by chiral synthesis using an Fmoc solid-phase peptide strategy followed by solution-phase cyclization. All isolated compounds and synthetic cores were assayed for solid tumor cell cytotoxicity and showed only minimal activity, contrary to other published reports. Additional phenotypic screenings were done on 4 and 5, with little evidence of activity.