The Ohio State University

Raymond Doskotch Graduate Fellow

DUTIES:

• Investigate the bioactive chemistry in plants from the rain forests of Vietnam with potential anti-cancer and central nervous system bioactivity.

• Operation of the American Chemical Society (ACS) Paragon Plus manuscript submission system for publication of peer-reviewed manuscripts at the central office of Journal of Natural Products, Columbus, OH.


KEY ACCOMPLISHMENTS:

• Selected for participation in the Mary Frances Picciano Dietary Supplement Research Practicum at the National Institutes of Health, Office of Dietary Supplements, Bethesda, MA, to review toxicological evaluations, exposure assessments, food safety, and conformity with the Food Safety Modernization Act (FSMA) which resulted in an in-depth perspective on the need to standardize and control dietary supplement ingredients.

• Presented an oral lecture at the 2012 International Congress on Natural Products Research (ICNPR) in New York, NY, which resulted in recognition from European collaborators as an outstanding chemist.

• Project leader on an NIH funded thesis dissertation project concerning the isolation, biological evaluation, and structure elucidation of noncompetitive nicotinic receptor antagonistic compounds from the Vietnam rainforest. The project resulted in two review article publications, presentation at two international research conferences, and interdisciplinary collaborations with medicinal chemists, pharmacologists, and botanists.

• Communicated recitation lecture materials to a class of 200 students at The Ohio State University College of Pharmacy Herbal Dietary Supplements class.

California State University, Dominguez Hills

Assistant Professor

DUTIES:

• Grant writing and research in natural products chemistry.

American Chemical Society

ACS Publications Graduate Student & Postdoc Summer Institute

Explored new technologies for use at the American Chemical Society for integration into scientific workflow including:

Mobile devices
Search/discovery and current awareness tools
Citation management tools
Chemistry-enabled word processors
Data publication, visualization, and new publication models

UC Santa Cruz

Post-doctoral research, Chemistry

DUTIES:

• Develop grant proposals for federally funded support from NIH and NSF.

• Collaborate with investigators at the Sandler Neuroscience Center (University of California, San Francisco) on lead compounds that exhibit selectivity at neurological receptors.

• Drug discovery from extracts of marine gram-negative bacteria and sponges.

KEY ACCOMPLISHMENTS:

• Awarded the National Institutes of Health (NIH) Postdoctoral Research Fellowship (PA-12-149), University of California, Santa Cruz (2013), which resulted in one invited review article, one in-press research article, and the mentoring of six undergraduate level chemists.

• Awarded the Carl Storm Underrepresented Minority Travel Fellowship to attend the Gordon Research Conference in Ventura, CA (2014), which resulted in a poster presentation of research results, and communication with research collaborators.

• Teaching service in the Minority Bridge to the Baccalaureate Program (ACCESS) at UC Santa Cruz.

UC Santa Cruz

ACCESS is an academic bridge program for community college students interested in pursuing a career in biomedical research science. Its mission is to provide students with opportunities to acquire knowledge and skills that will increase their transfer eligibility and academic success, and lead to greater diversity among university undergraduates in the biomedical sciences. The program focuses on students whose academic goals and potential have been affected by disadvantageous circumstances and/or students who belong to groups with below-average UC enrollment rates.

Alkaloids from Microcos paniculata with Cytotoxic and Nicotinic Receptor Antagonistic Activities

American Chemical Society

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. Journal of natural products 76.2 (2013): 243-249.

Alkaloids from Microcos paniculata with Cytotoxic and Nicotinic Receptor Antagonistic Activities

American Chemical Society

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. Journal of natural products 76.2 (2013): 243-249.

Alkaloids from Microcos paniculata with Cytotoxic and Nicotinic Receptor Antagonistic Activities

American Chemical Society

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. Journal of natural products 76.2 (2013): 243-249.

Synthesis and Antitumor Activity of Ellagic Acid Peracetate.

ACS Medicinal Chemistry Letters

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.

Alkaloids from Microcos paniculata with Cytotoxic and Nicotinic Receptor Antagonistic Activities

American Chemical Society

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. Journal of natural products 76.2 (2013): 243-249.

Synthesis and Antitumor Activity of Ellagic Acid Peracetate.

ACS Medicinal Chemistry Letters

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.

Potential of Plant-Derived Natural Products in the Treatment of Leukemia and Lymphoma.

Current Drug Targets

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 today are 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 plant-derived agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell malignancies including chronic lymphocytic leukemia. Current drug targets, 11(7), 812.

Alkaloids from Microcos paniculata with Cytotoxic and Nicotinic Receptor Antagonistic Activities

American Chemical Society

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. Journal of natural products 76.2 (2013): 243-249.

Synthesis and Antitumor Activity of Ellagic Acid Peracetate.

ACS Medicinal Chemistry Letters

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.

Potential of Plant-Derived Natural Products in the Treatment of Leukemia and Lymphoma.

Current Drug Targets

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 today are 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 plant-derived agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell malignancies including chronic lymphocytic leukemia. Current drug targets, 11(7), 812.

Nitrogen Deprivation Stimulates Symbiotic Gland Development in Gunnera manicata.

Plant Physiology

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.

Alkaloids from Microcos paniculata with Cytotoxic and Nicotinic Receptor Antagonistic Activities

American Chemical Society

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. Journal of natural products 76.2 (2013): 243-249.

Synthesis and Antitumor Activity of Ellagic Acid Peracetate.

ACS Medicinal Chemistry Letters

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.

Potential of Plant-Derived Natural Products in the Treatment of Leukemia and Lymphoma.

Current Drug Targets

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 today are 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 plant-derived agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell malignancies including chronic lymphocytic leukemia. Current drug targets, 11(7), 812.

Nitrogen Deprivation Stimulates Symbiotic Gland Development in Gunnera manicata.

Plant Physiology

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.

Biosynthetic Products from a Nearshore-Derived Gram-Negative Bacterium Enable Reassessment of the Kailuin Depsipeptides

Journal of Natural Products

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 seawater-based 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.

Alkaloids from Microcos paniculata with Cytotoxic and Nicotinic Receptor Antagonistic Activities

American Chemical Society

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. Journal of natural products 76.2 (2013): 243-249.

Synthesis and Antitumor Activity of Ellagic Acid Peracetate.

ACS Medicinal Chemistry Letters

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.

Potential of Plant-Derived Natural Products in the Treatment of Leukemia and Lymphoma.

Current Drug Targets

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 today are 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 plant-derived agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell malignancies including chronic lymphocytic leukemia. Current drug targets, 11(7), 812.

Nitrogen Deprivation Stimulates Symbiotic Gland Development in Gunnera manicata.

Plant Physiology

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.

Biosynthetic Products from a Nearshore-Derived Gram-Negative Bacterium Enable Reassessment of the Kailuin Depsipeptides

Journal of Natural Products

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 seawater-based 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.

Investigation of Vietnamese Plants for Potential Anticancer Agents.

Phytochemistry Reviews

(2014): 1-13.

Alkaloids from Microcos paniculata with Cytotoxic and Nicotinic Receptor Antagonistic Activities

American Chemical Society

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. Journal of natural products 76.2 (2013): 243-249.

Synthesis and Antitumor Activity of Ellagic Acid Peracetate.

ACS Medicinal Chemistry Letters

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.

Potential of Plant-Derived Natural Products in the Treatment of Leukemia and Lymphoma.

Current Drug Targets

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 today are 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 plant-derived agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell malignancies including chronic lymphocytic leukemia. Current drug targets, 11(7), 812.

Nitrogen Deprivation Stimulates Symbiotic Gland Development in Gunnera manicata.

Plant Physiology

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.

Biosynthetic Products from a Nearshore-Derived Gram-Negative Bacterium Enable Reassessment of the Kailuin Depsipeptides

Journal of Natural Products

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 seawater-based 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.

Investigation of Vietnamese Plants for Potential Anticancer Agents.

Phytochemistry Reviews

(2014): 1-13.

Scrutinizing the Scaffolds of Marine Biosynthetics from Different Source Organisms: Gram-Negative Cultured Bacterial Products Enter Center Stage

Journal of Natural Products

invited review article (J. Nat. Prod., 2014, 77 (3), pp 690–702)