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Synthetic Analogues of the Microtubule-Stabilizing Agent (+)-Discodermolide: Preparation and Biological Activity
Title
Synthetic Analogues of the Microtubule-Stabilizing Agent (+)-Discodermolide: Preparation and Biological Activity.
Creator
Gunasekera, Sarath P., Mickel, Stuart J., Daeffler, Robert, Niederer, Daniel, Wright, Amy E., Linley, P. A., Pitts, Tara P.
Date Issued
2004
PURL
http://purl.flvc.org/FCLA/DT/3164107
Subject Headings
Microtubules, Cancer --Research, Biopharmaceutics, Molecular biology, Stereochemistry
Format
Document (PDF)
Chitin Microparticles (CMPs) Induce M1 Macrophage Activation via Intracellular TLR2 Signaling Mechanism
Title
Chitin Microparticles (CMPs) Induce M1 Macrophage Activation via Intracellular TLR2 Signaling Mechanism.
Creator
Davis, Spring, Shibata, Yoshimi, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biological Sciences
Abstract/Description
Chitin Microparticles (CMPs, 1-10um), a special form of the ubiquitous and nontoxic polysaccharide Chitin (GlcNAc), is capable of inducing a switch in macrophages from the wound-healing M2 phenotype to the classically activated pro-inflammatory M1 phenotype; which has therapeutic implications in allergy and cancer. We hypothesized that TLR2 forms a complex with CMPs and Chitin-Binding Proteins (CBPs) at the surface of peritoneal macrophages and remains with that complex after internalization...
Show moreChitin Microparticles (CMPs, 1-10um), a special form of the ubiquitous and nontoxic polysaccharide Chitin (GlcNAc), is capable of inducing a switch in macrophages from the wound-healing M2 phenotype to the classically activated pro-inflammatory M1 phenotype; which has therapeutic implications in allergy and cancer. We hypothesized that TLR2 forms a complex with CMPs and Chitin-Binding Proteins (CBPs) at the surface of peritoneal macrophages and remains with that complex after internalization to initiate downstream signaling events, leading to the production of the M1 cytokine, TNFalpha. Our results from experiments performed in RAW 264.7 cells show that TLR2 and TLR1, but not TLR6, are associated with the CMP binding fraction, and that both TLR1 and TLR2 might be important for M1 activation as a result of CMP phagocytosis. This project sheds light on CMP as a potential therapeutic agent and provides more evidence for a phagocytosis-dependent TLR2 signaling pathway.
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Date Issued
2016
PURL
http://purl.flvc.org/fau/fd/FA00004762, http://purl.flvc.org/fau/fd/FA00004762
Subject Headings
Biopharmaceutics., Macrophages., Cell receptors., Ligands (Biochemistry), High performance processors.
Format
Document (PDF)
Synthesis and In Vitro Evaluation of Some Novel Nucleoside analogs and DNA lntercalators as Potential Anticancer or Antiviral Agents
Title
Synthesis and In Vitro Evaluation of Some Novel Nucleoside analogs and DNA lntercalators as Potential Anticancer or Antiviral Agents.
Creator
Zhao, Yuxiang, Florida Atlantic University, Parkanyi, Cyril, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description
Thiadiazoles can be considered as analogs of pyrimidines because of the well known analogy between a -CH=CH- group in benzenoid hydrocarbons and bivalent sulfur, -S-, in aromatic heterocycles. Therefore, 5-amino-2H-1 ,2,4-thiadiazole-3-one and 5-amino-3H-1 ,3,4-thiadiazole-2-one are the analogs of cytosine. In our first project, the preparation of six thiadiazole nucleoside analogs is reported: 5-diacetylamino-1 ,2,4- thiadiazol-3-one (1), 5-amino-2-(tetrahydrofuran-2-yl)-1 ,2,4-thiadiazol-3...
Show moreThiadiazoles can be considered as analogs of pyrimidines because of the well known analogy between a -CH=CH- group in benzenoid hydrocarbons and bivalent sulfur, -S-, in aromatic heterocycles. Therefore, 5-amino-2H-1 ,2,4-thiadiazole-3-one and 5-amino-3H-1 ,3,4-thiadiazole-2-one are the analogs of cytosine. In our first project, the preparation of six thiadiazole nucleoside analogs is reported: 5-diacetylamino-1 ,2,4- thiadiazol-3-one (1), 5-amino-2-(tetrahydrofuran-2-yl)-1 ,2,4-thiadiazol-3-one (2), 5- amino-3-((2' -hydroxyethoxy)methyl)-1 ,3,4-thiadiazol-2-one (3), 5-amino-3-( 4' -hydroxy- 2' -hydroxyrnethyl-butyl)-1 ,3,4-thiadiazole-2-thione ( 4), (R)-5-am ino-3-(2' ,3' - dihydroxypropyl)-1 ,3,4-thiadiazole-2-thione (5), and (S)-5-amino-3-(2' ,3 ' - dihydroxypropyl )-1 ,3,4-thiadiazole-2-thione (6). (R)-5-amino-3-(2' ,3' -dihydroxypropyl)-1,3,4-thiadiazole-2-thione (5) and (S)-5-amino-3-(2' ,3' -dihydroxypropyl)-1 ,3,4- thiadiazole-2-thione (6) are stereoisomers. Their racemic mixture 7 was also prepared and tested. The synthesis, characterization, and properties of these new synthesized thiadiazole derivatives are discussed. A dimerization of 5-amino-3H-1 ,3 ,4-thiadiazole-2- thione (18) to produce di-(5-amino-1 ,3,4-thiadiazol-2-yl) disulfide (23) by sodium nitrite with either acetic acid or stannic chloride is also reported. Preliminary results indicate that 3 and 23 possess antimicrobial activity. In the second project, the synthesis of three series of bis-aminochloropyrimidine derivatives with different types of linkers as potential DNA intercalators is described. The first series are aminochloropyrimidines bridged by polyrnethylene chain linkers with various lengths. The second series are bridged by polyether linkers to lower the lipophilicity. The third series are bridged by linkers containing benzene rings to limit the flexibility. The spectral data and other physical properties of the new compounds are discussed. The preliminary screening results indicate that many new synthesized bisintercalators are biologically active. The relationship between bioactivity and structure is discussed as well.
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Date Issued
2007
PURL
http://purl.flvc.org/fau/fd/FA00000886
Subject Headings
Biopharmaceutics, Antineoplastic agents--Pharmacodynamics, Nucleosides--Metabolism, Pharmaceutical chemistry, Antiviral agents--Synthesis
Format
Document (PDF)
Cell-surface glycan-lectin interactions for biomedical applications
Title
Cell-surface glycan-lectin interactions for biomedical applications.
Creator
Rodriguez Benavente, Maria Carolina, Lepore, Salvatore D., Cudic, Predrag, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description
Carbohydrate recognition is one of the most sophisticated recognition processes in biological systems, mediating many important aspects of cell-cell recognition, such as inflammation, cell differentiation, and metastasis. Consequently, lectin-glycan interactions have been intensively studied in order to mimic their actions for potential bioanalytical and biomedical applications. Galectins, a class of ß-galactoside-specific animal lectins, have been strongly implicated in inflammation and...
Show moreCarbohydrate recognition is one of the most sophisticated recognition processes in biological systems, mediating many important aspects of cell-cell recognition, such as inflammation, cell differentiation, and metastasis. Consequently, lectin-glycan interactions have been intensively studied in order to mimic their actions for potential bioanalytical and biomedical applications. Galectins, a class of ß-galactoside-specific animal lectins, have been strongly implicated in inflammation and cancer. Galectin-3 is involved in carbohydrate-mediated metastatic cell heterotypic and homotypic adhesion via interaction with Thomsen-Friedenreich (TF) antigen on cancer-associated MUC1. However, the precise mechanism by which galectin-3 recognizes TF antigen is poorly understood. Our thermodynamic studies have shown that the presentation of the carbohydrate ligand by MUC1-based peptide scaffolds can have a major impact on recognition, and may facilitate the design of more potent and specific galectin-3 inhibitors that can be used as novel chemical tools in dissecting the precise role of galectin-3 in cancer and inflammatory diseases. Another lectin, odorranalectin (OL), has been recently identified from Odorrana grahami skin secretions as the smallest cyclic peptide lectin, has a particular selectivity for L-fucose and very low toxicity and immunogenicity, rendering OL an excellent candidate for drug delivery to targeted sites, such as: (1) tumor-associated fucosylated antigens implicated in the pathogenesis of several cancers, for overcoming the nonspecificity of most anticancer agents; (2) the olfactory epithelium of nasal mucosa for enhanced delivery of peptide-based drugs to the brain.
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Date Issued
2015
PURL
http://purl.flvc.org/fau/fd/FA00004405
Subject Headings
Biopharmaceutics, Carbohydrates -- Therapeutic use, Cell differentiation, Drug delivery systems, Glycoproteins, Glycoslation, Mice as laboratory animals, Peptides -- Derivatives, Pharmaceutical biotechnology
Format
Document (PDF)
Investigating the Role of CHI3L1 in Promoting Tumor Growth and Metastasis Using Mammary Tumor Models
Title
Investigating the Role of CHI3L1 in Promoting Tumor Growth and Metastasis Using Mammary Tumor Models.
Creator
Libreros, Stephania, Iragavarapu-Charyulu, Vijaya, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
Metastasis is the primary cause of mortality in women with breast cancer. Recently, elevated serum levels of a glycoprotein known as chitinase-3 likeprotein- 1 (CHI3L1) has been correlated with poor prognosis and shorter survival of patients with cancer and inflammatory diseases. The biological and physiological functions of CHI3L1 in tumor progression have not yet been elucidated. In this document, we describe the role of CHI3L1 in tumor growth and metastasis and its relationship with...
Show moreMetastasis is the primary cause of mortality in women with breast cancer. Recently, elevated serum levels of a glycoprotein known as chitinase-3 likeprotein- 1 (CHI3L1) has been correlated with poor prognosis and shorter survival of patients with cancer and inflammatory diseases. The biological and physiological functions of CHI3L1 in tumor progression have not yet been elucidated. In this document, we describe the role of CHI3L1 in tumor growth and metastasis and its relationship with inflammation. Using well-established models of breast cancer, we show that CHI3L1 is increased in the serum of tumor bearing mice. We found that CHI3L1 levels are increased at both the “pre-metastatic” and “metastatic stage” and that tumor cells, splenic, alveolar and interstitial macrophages; and myeloid derived population produce CHI3L1. Furthermore, we demonstrated that CHI3L1 has an inhibitory role on the expression of interferon-gamma (IFN γ) by T cells, while enhancing the production of pro-inflammatory mediators by macrophages such as Cchemokine ligand 2 (CCL2/MCP-1), Chemokine CX motif ligand 2 (CXCL2/IL-8) and matrix metalloproteinase-9 (MMP-9), all of which promote tumor growth and metastasis. We demonstrated that in vivo treatment of tumor-bearing mice with chitin microparticles, a TH1 adjuvant and a substrate for CHI3L1, promoted immune effector functions with increased production of IFN-γ but decreased CCL2/MCP-1, CXCL2/IL-8 and MMP-9 expression by splenic and pulmonary macrophages. Significantly, in vivo administration of chitin microparticles decreased tumor growth and pulmonary metastasis in mammary tumor bearing mice. These results suggest that CHI3L1 may play a role in tumor progression. Inflammation plays a pivotal role during tumor progression and metastasis by promoting the production of pro-inflammatory molecules such as CHI3L1. However, little is known about how CHI3L1 expression can affect secondary sites to enhance metastasis. In these studies, we demonstrated that CHI3L1 alters the cellular composition and inflammatory mediators that aid in the establishment of a metastatic niche for the support of infiltrating tumor cells leading to accelerated tumor progression. Since previous studies showed that CHI3L1 modulates inflammation, we determined the role of CHI3L1 in the context of pre-existing inflammation and metastasis. We found that CHI3L1 deficient mice with preexisting inflammation had decreased pro-inflammatory mediators, and significant reduction in tumor volume and metastasis compared to wild type controls. Preexisting inflammation and CHI3L1 may be driving the establishment of a premetastatic milieu in the lungs and aiding in the establishment of metastasis. Understanding the role of CHI3L1 in inflammation during tumor progression could result in the design of targeted therapies for breast cancer patients.
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Date Issued
2015
PURL
http://purl.flvc.org/fau/fd/FA00004517, http://purl.flvc.org/fau/fd/FA00004517
Subject Headings
Biopharmaceutics, Breast -- Cancer -- Etiology, Breast -- Cancer -- Molecular aspects, Cell differentiation, Chitinase, Glycoproteins -- Metabolism, Inflammation, Mice as laboratory animals
Format
Document (PDF)