Day 1 :
Keynote Forum
James K Bashkin
University of Missouri-St. Louis, USA
Keynote: Polyamides as multifaceted molecules for medicinal chemistry
Time : 10:00-10:30
Biography:
James Bashkin completed his D Phil.at the age of 24 years from Oxford University and postdoctoral studies from Harvard University’s Department of Chemistry. He is Professor of Chemistry and Biochemistry at the University of Missouri-St. Louis and Co-Founder and Director of Chemistry at NanoVir LLC, an antiviral company. He also worked at Monsanto, Pharmacia, and Pfizer, has published more than 73 papers in reputed journals, and has served as an editorial board member and/or associate editor of numerous journals, most notably as an Editorial Advisory Board member of Chemical Reviews from 1991-2014.
Abstract:
We describe polyamides active against human papillomavirus (HPV), vesicular stomatitis virus (VSV), and the ETS superfamily transcription factor PU.1. The MWs of active polyamides range from high to low, and cell uptake by an active mechanism was observed for human keratinocytes infected with HPV. In the case of VSV, X-ray crystallography revealed a polyamide bound to both the viral negative strand RNA genome and the nucleocapsid proteins, and biophysical studies showed changes to the melting temperature of the nucleocapsid-like particle (NLP) in the presence of the active compound, which protected cells from virally induced lysis. Polyamides were not to bind well to RNA. In the case of PU.1, a protein that binds the major groove of DNA, we designed inhibitors using minor groove-binding polyamides. However, one polyamide formed a ternary complex with PU.1 and DNA, causing weak but measurable stabilization of the PU.1-DNA complex. The ternary complex was observed by a variety of analytical techniques, as will be described. This strengthening of protein-DNA binding for a transcription factor by an unadorned polyamide is unexpected and novel, given that large molecular architectures have previously been required to achieve similar effects
Keynote Forum
Daniel P Becker
Loyola University Chicago, USA
Keynote: Design and synthesis of DapE inhibitors as potential antibiotics with a new mechanism of action
Time : 10:30-11:00
Biography:
Daniel Becker earned his PhD at Indiana University in Bloomington, Indiana and worked in the pharmaceutical industry in Searle, Pharmacia, and then Pfizer as a Project Leader and Research Fellow developing new treatments for cancer, arthritis, and cardiovascular diseases. He moved from industry to join Loyola University Chicago in 2004 where he serves as a full Professor of Chemistry performing research in synthetic organic and medicinal chemistry, especially in the discovery of new antibiotics and treatments for cancer, as well as in supramolecular chemistry. He has published more than 50 scientific papers in various areas of chemistry and is an inventor on over 50 US patents.
Abstract:
There is an urgent need for antibacterial agents with new cellular mechanisms of action, and the bacterial enzyme N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) offers an excellent target for the eventual development of new antibiotics. DapE is in the succinylase pathway, which is the primary biosynthetic pathway for producing meso-diaminopimelate (m-DAP) and lysine in all Gram-negative and most Gram-positive bacteria, and is not expressed in mammals, making it a very important bacterial enzyme to study. X-ray crystallography of the DapE enzyme in the presence of our inhibitors has resulted in an atomic resolution (1.3Å) structure. Structural insights from X-ray crystallography have been coupled with molecular dynamics (MD) experiments using NAMD to explore the mechanism of the dramatic enzyme conformational changes that result in substrate binding by DapE and product release, and also using our Products-Based Transition-State Modeling (PBTSM) protocol, as we have recently described. Synthesis of analogs that we have identified from a high-throughput screen including tetrazoles and pyrazoles as well as 6- and 7-indoline sulfonamides will be described, with efforts that have been guided by docking using MOE. Synthetic efforts include methodology to access 7-substituted indolines that have previously eluded synthesis. We will also describe acyl sulfonamides prepared through Click chemistry that have the capacity to interact with both zinc atoms in dimetalloenzymes. DapE enzyme inhibitory potency has been assessed using our recently validated ninhydrin-based assay (Scheme 1) employing N-methyl-L,L-SDAP (succinyl diaminopimelate), synthesized on a large scale via an asymmetric synthesis, as will also be described.
Keynote Forum
Orazio Nicolotti
University of Bari, Italy
Keynote: A knowledge-based approach for drug target and bioactivity prediction
Time : 11:20-11:50
Biography:
Orazio Nicolotti is Professor of Medicinal Chemistry at the University of Bari. Major interests in molecular and data modeling, drug design,
QSAR, predictive toxicology, combinatorial library design, evolutionary algorithms, docking and molecular dynamics. So far, author of 99 research papers, 7 book chapters, 1 international patent. Editor of the book “Computational toxicology” published in 2018 by Humana Press. Principal investigator of many research funded projects and industrial agreements for technology transfer.
Abstract:
Pairing novel compounds to specific drug targets or repositioning old drugs to apparently unrelated diseases is a fascinating and challenging theme of rational drug discovery. In this scenario, we developed an easy-to-run in silico tool for drug target and quantitative bioactivity prediction implementing a multi-fingerprint similarity search algorithm, whose acronym is MuSSeL. Predictions were derived by exploiting a large collection of highly curated experimental bioactivity data available from ChEMBL (version 22.1) and combining results based on similarity search screening employing 13 different molecular fingerprints. Noteworthy, the occurrence of potential activity cliffs was also explicitly accounted in MuSSeL. The last updated version of ChEMBL (version 23) was employed for tuning algorithm parameters and three randomly built external sets were used for measuring model performances. Interestingly, the prospective use of MuSSeL was challenged predicting five real-life bioactive compounds taken from articles just published in Journal of Medicinal Chemistry whose structures and related bioactivity data were not covered in ChEMBL yet. Our approach demonstrated to return a more informed interpretation of drug target and bioactivity prediction and could be of valuable help to assist and speed up early stages of drug discovery programs.
Keynote Forum
Karol S. Bruzik
University of Illinois, USA
Keynote: Approach to GABA-A receptor isoform-selective allosteric agonists
Time : 11:50-12:50
Biography:
Karol Bruzik received his BSc. degree (1972) from the Technical University of Lodz, Poland, and his PhD. (1980) and DSc. (1987) degrees from Polish Academy of Sciences. After postdoctoral work at The Ohio State University (1981-83 and 1990-93), he joined the Department of Medicinal Chemistry and Pharmacognosy at the University of Illinois at Chicago as Assistant Professor, and is now Professor and Associate Head. He is an author of more than 100 peer review publications in the area of organic and bioorganic chemistry, enzyme mechanisms, phosphoinositide signaling and allosteric modulators of ligand-gated ion channels, with emphasis on GABA-A receptors.
Abstract:
Heteropentameric GABA-A receptor is a principal drug target whose function is allosterically modulated by general anesthetics, sedatives and anticonvulsants, such as propofol, etomidate, barbiturates and neurosteroids. The current clinically used general anesthetics have numerous disadvantages including low potency, low receptor-type selectivity among the various Cys-loop receptors, low receptor isoform selectivity and resulting therefrom low therapeutic indices. Determining the locations and structures of modulator sites and the mechanisms that trigger conformational changes to the receptor is essential to the design and development of the next generation of these drugs. The approach presented here garners this information using chemical synthesis of analogs of the general anesthetic drugs equipped with small photoactivatable residues such as a diazirine or an azide, characterization of the pharmacology of the new agents to verify the identity of their binding sites with those of the original drugs, photolabeling of a specific molecular isoform of the receptor, and performing Edman sequencing of the photolabeled fragments of the receptor to determine the position of modification. Using this approach, binding sites of barbiturates (1), propofol (2), etomidate (3), and neurosteroids (4-8) have been determined. This presentation will focus on various synthetic approaches to the general anesthetic analogs (shown), the effect that small structural changes have to ligands’ binding sites and the pharmacological activities, and the use of the ligands in protein photolabeling and identification of the photolabeled sites. Overall, a general picture emerges where agents belonging to the four different classes mentioned above bind to disparate regions of the receptor protein.
Keynote Forum
Daniela Andrei
Dominican University, USA
Keynote: Diazeniumdiolates as HNO/NO donors: Synthesis and biological activity
Time : 13:40-14:05
Biography:
Daniela Andrei earned her PhD at Florida International University in Miami, Florida and after her graduation in 2006, she worked as a postdoctoral fellow for the National Institutes of Health/National Institute of Cancer at Frederick, Maryland. She joined Dominican University in River Forest in 2008 where she serves as a full Professor of Chemistry performing research in synthetic organic and medicinal chemistry. Her research work is on nitric oxide chemistry. She has been working on the synthesis of small biological active molecules known as diazeniumdiolate or NONOates with the goal of expanding the availability of primary amine diazeniumdiolates. She has published several scientific papers in different areas of organic chemistry and is an inventor of 2 U.S. patents.
Abstract:
Diazeniumdiolate ions, also known as NONOates, are extensively used in biochemical, physiological and pharmacological studies due to their ability to slowly release nitric oxide (NO.) and/or their congeneric nitroxyl (HNO) (Fig 1). NONOates of secondary amines have traditionally been used as NO donors and have become the standard for NO donating compounds in chemistry and biology. However, primary amine diazeniumdiolates have been less studied, and essentially IPA/NO and a few alicyclic amine diazeniumdiolates are the only representatives of this class of compounds. The purpose of this work was to synthesize a series of primary amine-based diazeniumdiolates as HNO donors and to determine their efficacy as anticancer and antifungal agents in vivo. Our compounds demonstrated a reduction in proliferation of ovarian and AML cancer cells. Similarly, they have also demonstrated some antifungal activity against various strains of Fusarium. We also used mouse RAW and human THP-1 macrophages cell line to test the compounds for anti- or pro-inflammatory properties, if any. To this end, we determined the impact of individual molecules on the LPS-induced M1 polarization and IL-4-induced M2 polarization, independently. We employed qRT-PCR and flow cytometry techniques to measure M1 and M2 phenotype after treatment with LPS or IL-4, respectively, in the absence or presence of our compounds. In order to gain an insight into the mechanism of action, we simultaneously quantified IEX-1 mRNA expression levels in response to treatment with different doses of compounds. In conclusion, the synthesis and the biological activity of these compounds are going to be discussed in detail during the presentation.
Keynote Forum
Letizia Giampietro
University of Chieti, Italy
Keynote: Novel phenyldiazenyl fibrate analogues as PPAR agonists: Design, synthesis and pharmacological evaluation
Time : 14:05-14:30
Biography:
Letizia Giampietro has completed Degree in Pharmacy (2000) and received her PhD in Medicinal Chemistry (2003) from the University “G. d’Annunzio” of Chieti (Italy). From 2006 to date, she is Assistant Professor of Pharmaceutical Analysis. She has published more than 45 papers in reputed journals. Her research interests include medicinal chemistry and are above all focused towards the synthesis of fibrate derivatives active on Peroxisome Proliferator-Activate Receptors (PPARs). Lately, her research is direct to the synthesis of small molecules with anticancer, neuroprotective and antioxidant activity.
Abstract:
Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear hormone receptors expressed especially in metabolically active tissues. Three different isoforms namely PPARï¡, PPARï§ and PPARï¤ are identified; they play important roles in lipid and glucose homeostasis. The research of dual PPARï¡/ï§ and pan PPAR α/γ/δ agonists could be useful to treat simultaneously dyslipidemia and type 2 diabetes mellitus, reducing side effects of selective PPAR agonists.1 Fibrates active as PPAR agonists have, as typical pharmacophore, a carboxylic acid head and an aromatic ring with or without different spacers. Based on this pharmacophore, in the past, we reported synthesis and biological evaluation of various fibrate analogues. These compounds showed good activation of PPARs.2,3 In particular, a dual PPARα/γ agonist, named GL479 (αEC50=0.6 ïM and γEC50=1.4 ïM), was identified (Figure 1; R = H; X = O; Y = CH2).4 This compound was crystallized with PPARα and PPARγ in order to explain its particular binding mode with the receptors ligand binding domain.5 In view of these results, and to gain more insight on the structure-activity relationships, we synthesized new GL479 analogues with the oxygen of the linker in para to the 2-methyl-2-phenoxypropanoic group and with different substituents in para to the phenyldiazenyl moiety (Figure 1). All compounds were tested in a cell-based transactivation assay to evaluate the agonist activity toward the human PPARα, -γ and -β/δ. The obtained results led to the identification of some fibrate derivatives with promising activity on the three PPAR isoforms. In particular, a docking study of the best candidate clarified the possible binding modes with PPARα, -γ and -β/δ. Moreover, in vitro and ex vivo studies on tested compounds allowed us to discover an interesting lead for the development of a new class of PPAR agonists exploitable for therapy of metabolic syndrome.
Keynote Forum
Alex R. Khomutov
Russian Academy of Sciences, Russia
Keynote: Isomers and diastereomers of C-methylated spermidine and spermine: Synthesis and biochemical application
Time : 14:30-14:55
Biography:
Alex R.Khomutov principle investigator, Engelhardt Institute of Molecular Biology, Moscow, Russia. He graduated Chemical Faculty of Moscow State University in 1976. He got PhD and later D.Sc. degrees in Bioorganic Chemistry in Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow. The main field of the interests are design and synthesis of the inhibitors/unnatural substrates of the enzymes of amino acids metabolism, including those related to biosynthesis and catabolism of biogenic polyamines spermine and spermidine, and investigation of the interaction of these analogues with enzymes and activity in cell cultures. In 2017 he was a chair of Polyamines Gordon Research Conference. A.R.Khomutov is a co-author of more than 120 papers in per-reviewed Journals.
Abstract:
Statement of the Problem: The polyamines, spermidine (1,8-diamino-4-azaoctane, Spd) and spermine (1,12- diamino-4,9-diazadodecane, Spm) are ubiquitous organic polycations present in all eukaryotic cells in µM-mM concentrations and involved in the regulation of numerous vital processes including the differentiation and growth of cells1. Disturbances of polyamines metabolism are associated with the development of many diseases, including malignant tumors, decreased immune response, some types of pancreatitis, Snyder-Robinson's syndrome, and even type 2 diabetes1. Biological evaluation of rationally designed polyamine analogs is one of the cornerstones of polyamine research having obvious basic and practical values. Here we synthesized and characterized C-methylated Spm and Spd analogues possessing a biochemically useful set of properties. Methodology & Theoretical Orientation: The synthesis of title compounds was performed using known methods starting from amino alcohols by subsequent elongation of polyamine backbone, or using convergent synthesis in the case of bis-methylated Spm derivatives2. Findings: Obtained data demonstrated that the biochemical properties of C-methylated polyamine analogs can be regulated by changing the position of the methyl substituent, and at more precise level by changing the configuration of chiral center2-4. Hidden stereospecificity (natural substrates are achiral) was shown for the enzymes of polyamine metabolism using title compounds2. An original approach to alter stereospecificity of FAD-dependent N-acetylpolyamine oxidase (APAO) and to alter stereospecificity and regioselectivity of yeast polyamine oxidase (Fms1) was suggested2,4. Conclusion & Significance: The first metabolically stable functionally active mimetics of Spd, i.e. (R)-1,8-diamino-3-methyl-4-azaoctane and Spm, i.e. (R,R)-2,13-diamino-5,10- diazatetradecane, being suitable for the investigation of the individual cellular functions of partly interchangeable and easily interconvertible Spm and Spd were found2,3.
- Medicinal Chemistry and Drug Design
Location: Edinburgh, Scotland
Chair
Orazio Nicolotti
University of Bari, Italy
Session Introduction
Daniela Andrei
Dominican University, USA
Title: Diazeniumdiolates as HNO/NO donors: Synthesis and biological activity
Time : 13:40-14:05
Biography:
Daniela Andrei earned her PhD at Florida International University in Miami, Florida and after her graduation in 2006, she worked as a postdoctoral fellow for the National Institutes of Health/National Institute of Cancer at Frederick, Maryland. She joined Dominican University in River Forest in 2008 where she serves as a full Professor of Chemistry performing research in synthetic organic and medicinal chemistry. Her research work is on nitric oxide chemistry. She has been working on the synthesis of small biological active molecules known as diazeniumdiolate or NONOates with the goal of expanding the availability of primary amine diazeniumdiolates. She has published several scientific papers in different areas of organic chemistry and is an inventor of 2 U.S. patents.
Abstract:
Diazeniumdiolate ions, also known as NONOates, are extensively used in biochemical, physiological and pharmacological studies due to their ability to slowly release nitric oxide (NO.) and/or their congeneric nitroxyl (HNO) (Fig 1). NONOates of secondary amines have traditionally been used as NO donors and have become the standard for NO donating compounds in chemistry and biology. However, primary amine diazeniumdiolates have been less studied, and essentially IPA/NO and a few alicyclic amine diazeniumdiolates are the only representatives of this class of compounds. The purpose of this work was to synthesize a series of primary amine-based diazeniumdiolates as HNO donors and to determine their efficacy as anticancer and antifungal agents in vivo. Our compounds demonstrated a reduction in proliferation of ovarian and AML cancer cells. Similarly, they have also demonstrated some antifungal activity against various strains of Fusarium. We also used mouse RAW and human THP-1 macrophages cell line to test the compounds for anti- or pro-inflammatory properties, if any. To this end, we determined the impact of individual molecules on the LPS-induced M1 polarization and IL-4-induced M2 polarization, independently. We employed qRT-PCR and flow cytometry techniques to measure M1 and M2 phenotype after treatment with LPS or IL-4, respectively, in the absence or presence of our compounds. In order to gain an insight into the mechanism of action, we simultaneously quantified IEX-1 mRNA expression levels in response to treatment with different doses of compounds. In conclusion, the synthesis and the biological activity of these compounds are going to be discussed in detail during the presentation.
Daniela Andrei
Dominican University, USA
Title: Diazeniumdiolates as HNO/NO donors: Synthesis and biological activity
Biography:
Daniela Andrei earned her PhD at Florida International University in Miami, Florida and after her graduation in 2006, she worked as a postdoctoral fellow for the National Institutes of Health/National Institute of Cancer at Frederick, Maryland. She joined Dominican University in River Forest in 2008 where she serves as a full Professor of Chemistry performing research in synthetic organic and medicinal chemistry. Her research work is on nitric oxide chemistry. She has been working on the synthesis of small biological active molecules known as diazeniumdiolate or NONOates with the goal of expanding the availability of primary amine diazeniumdiolates. She has published several scientific papers in different areas of organic chemistry and is an inventor of 2 U.S. patents
Abstract:
Diazeniumdiolate ions, also known as NONOates, are extensively used in biochemical, physiological and pharmacological studies due to their ability to slowly release nitric oxide (NO.) and/or their congeneric nitroxyl (HNO) (Fig 1). NONOates of secondary amines have traditionally been used as NO donors and have become the standard for NO donating compounds in chemistry and biology. However, primary amine diazeniumdiolates have been less studied, and essentially IPA/NO and a few alicyclic amine diazeniumdiolates are the only representatives of this class of compounds. The purpose of this work was to synthesize a series of primary amine-based diazeniumdiolates as HNO donors and to determine their efficacy as anticancer and antifungal agents in vivo. Our compounds demonstrated a reduction in proliferation of ovarian and AML cancer cells. Similarly, they have also demonstrated some antifungal activity against various strains of Fusarium. We also used mouse RAW and human THP-1 macrophages cell line to test the compounds for anti- or pro-inflammatory properties, if any. To this end, we determined the impact of individual molecules on the LPS-induced M1 polarization and IL-4-induced M2 polarization, independently. We employed qRT-PCR and flow cytometry techniques to measure M1 and M2 phenotype after treatment with LPS or IL-4, respectively, in the absence or presence of our compounds. In order to gain an insight into the mechanism of action, we simultaneously quantified IEX-1 mRNA expression levels in response to treatment with different doses of compounds. In conclusion, the synthesis and the biological activity of these compounds are going to be discussed in detail during the presentation.
Letizia Giampietro
University of Chieti, Italy
Title: Novel phenyldiazenyl fibrate analogues as PPAR agonists: Design, synthesis and pharmacological evaluation
Biography:
Letizia Giampietro has completed Degree in Pharmacy (2000) and received her PhD in Medicinal Chemistry (2003) from the University “G. d’Annunzio” of Chieti (Italy). From 2006 to date, she is Assistant Professor of Pharmaceutical Analysis. She has published more than 45 papers in reputed journals. Her research interests include medicinal chemistry and are above all focused towards the synthesis of fibrate derivatives active on Peroxisome Proliferator-Activate Receptors (PPARs). Lately, her research is direct to the synthesis of small molecules with anticancer, neuroprotective and antioxidant activity.
Abstract:
Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear hormone receptors expressed especially in metabolically active tissues. Three different isoforms namely PPARï¡, PPARï§ and PPARï¤ are identified; they play important roles in lipid and glucose homeostasis. The research of dual PPARï¡/ï§ and pan PPAR α/γ/δ agonists could be useful to treat simultaneously dyslipidemia and type 2 diabetes mellitus, reducing side effects of selective PPAR agonists.1 Fibrates active as PPAR agonists have, as typical pharmacophore, a carboxylic acid head and an aromatic ring with or without different spacers. Based on this pharmacophore, in the past, we reported synthesis and biological evaluation of various fibrate analogues. These compounds showed good activation of PPARs.2,3 In particular, a dual PPARα/γ agonist, named GL479 (αEC50=0.6 ïM and γEC50=1.4 ïM), was identified (Figure 1; R = H; X = O; Y = CH2).4 This compound was crystallized with PPARα and PPARγ in order to explain its particular binding mode with the receptors ligand binding domain.5 In view of these results, and to gain more insight on the structure-activity relationships, we synthesized new GL479 analogues with the oxygen of the linker in para to the 2-methyl-2-phenoxypropanoic group and with different substituents in para to the phenyldiazenyl moiety (Figure 1). All compounds were tested in a cell-based transactivation assay to evaluate the agonist activity toward the human PPARα, -γ and -β/δ. The obtained results led to the identification of some fibrate derivatives with promising activity on the three PPAR isoforms. In particular, a docking study of the best candidate clarified the possible binding modes with PPARα, -γ and -β/δ. Moreover, in vitro and ex vivo studies on tested compounds allowed us to discover an interesting lead for the development of a new class of PPAR agonists exploitable for therapy of metabolic syndrome.
Alex R Khomutov
Russian Academy of Sciences, Russia
Title: Isomers and diastereomers of C-methylated spermidine and spermine: Synthesis and biochemical application
Biography:
Alex R.Khomutov principle investigator, Engelhardt Institute of Molecular Biology, Moscow, Russia. He graduated Chemical Faculty of Moscow State University in 1976. He got PhD and later D.Sc. degrees in Bioorganic Chemistry in Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow. The main field of the interests are design and synthesis of the inhibitors/unnatural substrates of the enzymes of amino acids metabolism, including those related to biosynthesis and catabolism of biogenic polyamines spermine and spermidine, and investigation of the interaction of these analogues with enzymes and activity in cell cultures. In 2017 he was a chair of Polyamines Gordon Research Conference. A.R.Khomutov is a co-author of more than 120 papers in per-reviewed Journals.
Abstract:
Statement of the Problem: The polyamines, spermidine (1,8-diamino-4-azaoctane, Spd) and spermine (1,12- diamino-4,9-diazadodecane, Spm) are ubiquitous organic polycations present in all eukaryotic cells in µM-mM concentrations and involved in the regulation of numerous vital processes including the differentiation and growth of cells1. Disturbances of polyamines metabolism are associated with the development of many diseases, including malignant tumors, decreased immune response, some types of pancreatitis, Snyder-Robinson's syndrome, and even type 2 diabetes1. Biological evaluation of rationally designed polyamine analogs is one of the cornerstones of polyamine research having obvious basic and practical values. Here we synthesized and characterized C-methylated Spm and Spd analogues possessing a biochemically useful set of properties. Methodology & Theoretical Orientation: The synthesis of title compounds was performed using known methods starting from amino alcohols by subsequent elongation of polyamine backbone, or using convergent synthesis in the case of bis-methylated Spm derivatives2. Findings: Obtained data demonstrated that the biochemical properties of C-methylated polyamine analogs can be regulated by changing the position of the methyl substituent, and at more precise level by changing the configuration of chiral center2-4. Hidden stereospecificity (natural substrates are achiral) was shown for the enzymes of polyamine metabolism using title compounds2. An original approach to alter stereospecificity of FAD-dependent N-acetylpolyamine oxidase (APAO) and to alter stereospecificity and regioselectivity of yeast polyamine oxidase (Fms1) was suggested2,4. Conclusion & Significance: The first metabolically stable functionally active mimetics of Spd, i.e. (R)-1,8-diamino-3-methyl-4-azaoctane and Spm, i.e. (R,R)-2,13-diamino-5,10- diazatetradecane, being suitable for the investigation of the individual cellular functions of partly interchangeable and easily interconvertible Spm and Spd were found2,3.
Alessandra Ammazzalorso
University of Chieti, Italy
Title: Synthesis and cytotoxicity evaluation of novel amide and sulfonimide PPARaï¡ antagonists
Time : 14:55-15:20
Biography:
Alessandra Ammazzalorso obtained her PhD in Pharmaceutical Sciences from the University of Chieti, Italy, in 2001. Since 2004 she has been an Assistant Professor of Medicinal Chemistry at the University of Chieti Department of Pharmacy. Her research interests include the design and synthesis of small-molecule drugs, mainly compounds targeting Peroxisome Proliferator-Activated Receptors, aromatase and nitric oxide synthase.
Abstract:
Peroxisome Proliferator-Activated Receptors (PPARs) have been widely studied in the last decades, and they attracted the attention of scientists as promising therapeutic targets. Intensive efforts by researchers produced a wide panel of drugs targeting the three PPAR subtypes (PPARï¡, PPARï§, PPARï¤) able to modulate important metabolic functions. PPAR activation is involved in several physiologic pathways, as lipid and glucose metabolism, insulin sensitivity, energy homeostasis, and cell differentiation. Fibrates and thiazolidinediones, respectively synthetic PPARï¡ and PPARï§ agonists, are currently used for the treatment of hyperlipidemia and hyperglycemia, in patients affected by type 2 diabetes and metabolic syndrome. In recent years, an increased expression of PPARï¡ has been found in different tumors: it is well known that cancer cells present altered metabolic pathways, switching from the glycolysis to fatty acid oxidation metabolism. In this scenario, PPARï¡ antagonists emerged as novel potential drugs in tumors overexpressing PPARï¡, by interfering with cellular survival and metastasis formation [1]. In vitro anticancer effects were found for PPARï¡ antagonists in chronic lymphocytic leukemia [2], renal cancer [3], colorectal and pancreatic cancer [4], paraganglioma [5]. In this study we report on the synthesis of novel amide and sulfonimide PPARï¡ antagonists, starting from the structure of PPARï¡ agonists, previously synthesized in our laboratory. Furthermore, we explored the possible cytotoxicity of the novel compounds in different cancer cell lines (colorectal, pancreatic and paraganglioma) expressing PPARï¡
Mary Anti Chama
University of Ghana, Ghana
Title: Antibacteria, antiparasitic and in silico studies of dichapetalum madagascariense Poire
Biography:
Mary Chama has her research interest in the area of Medicinal plant Natural Product where she and her team are involved in isolation, characterization, and biological testing of active compounds from medicinal plants. Biological testing for anticancer, tropical infectious disease such as anti-hookworm, antischistosomiasis, antitrypanosomiasis and antimalarial has been her recent focus. She has worked on Scoparia dulcis, plants from some Dichapetalum species and currently researching on species from the Fabaceae and Annonaceae families. Her research also involves the application of in silico studies towards understanding the mode of action of therapeutic medicinal plants and active isolates which she acquired on her Post-doctoral fellowship at the Chemistry department of the University of Cambridge in UK.
Abstract:
Dichapetalum madagascariense (Dichapetalaceae) is used to treat bacterial infections, jaundice, urethritis and viral hepatitis. Its root has been investigated to contain broad spectrum biologically active dichapetalins. To evaluate the plant’s antibacterial and antiparasitic potentials coupled with in silico methods, we isolated and identified the known dichapetalins A and M from the roots. Both dichapetalins were tested together with the leaf (DML) and root (DMR) ethanol extracts on six ATCC bacteria strains (Shigella flexneri, Bacillus cereus, Salmonella paratyphi B, Listeria monocytogenes, Escherichia coli, Staphylococcus aureus) and three parasites; Trypanosoma brucei brucei, Leishmania donovani and Plasmodium falciparum 3D7 strain using the Alamar Blue Assay. Dichapetalins A and M were potent against B. cereus with IC50, 11.15 and 3.15 µg/ml respectively compared with ampicillin (IC50, 1.70 µg/ml). DML (IC50, 0.45 µg/ml) was threefold more potent than ampicillin (IC50, 1.5 µg/ml) against S. paratyphi B and more active (IC50, 12.65 µg/ml) against S. flexneri than ampicillin (IC50, 14.02 µg/ml). Dichapetalins A (IC50, 74.22 µg/ml) and M (IC50, 72.34 µg/ml) were only active against T. b. brucei compared to the standard extract of Coptis japonica (IC50, 3.6 µg/ml) and suramin (IC50, 4.96 µg/ml). Dichapetalin M showed moderate activity against L. donovani (IC50, 0.21 µg/ml) with IC50, 16.80 µg/ml. DML and DMR gave IC50, 9.66 and 11.17 µg/ml respectively against T. b. brucei when compared with C. japonica (IC50, 3.6 µg/ml) and suramin (IC50, 4.96 µg/ml). Target prediction with PIDGIN software indicated NR1I2 as a plausible target for dichapetalin A. Protein BLASTing the protein sequence of this xenobiotic sensor nuclear receptor to the used species suggested that dichapetalin A may have a bacteriostatic effect through the nucleotide hydrolase NUDIX (T. brucei), or the uncharacterised protein YagA or ydbH (S. flexneri). However, the understanding of the exact mechanism of the dichapetalin’s antibiotic effect requires further research.
James K Bashkin
University of Missouri-St. Louis, USA
Title: Broad-spectrum binding to human papillomavirus DNA
Biography:
James Bashkin completed his D.Phil. at the age of 24 years from Oxford University and postdoctoral studies from Harvard University’s Department of Chemistry. He is Professor of Chemistry and Biochemistry at the University of Missouri-St. Louis and Co-Founder and Director of Chemistry at NanoVir LLC, an antiviral company. He also worked at Monsanto, Pharmacia, and Pfizer, has published more than 73 papers in reputed journals, and has served as an editorial board member and/or associate editor of numerous journals, most notably as an Editorial Advisory Board member of Chemical Reviews from 1991-2014.
Abstract:
We describe the biophysical behavior of polyamides active against human papillomavirus (HPV) types 16, 18, and 31. The MWs of active polyamides are high, and we observed active uptake for human keratinocytes infected with HPV. We have measured binding constants for a group of active anti-HPV compounds on viral DNA, largely but not exclusively in the long control region (LCR). All of our most active polyamides to date contain guanidine and tetramethylguanidine N-termini, in partial mimicry of the natural product netropsin. These compounds include asymmetric hairpins as shown below, where not every heterocycle finds an analogous ring in the opposite strand of the hairpin. Binding constants were determined by quantitative DNase I footprinting and capillary electrophoresis. Binding constants do not correlate with antiviral activity, but there is a loose correlation between binding promiscuity and antiviral efficacy in cell culture. These and other recent results, including new observations of polyamide-DNA binding stoichiometry, are of interest. In particular, greater than 1:1 polyamide:DNA stoichiometries were observed. Evidence for such stoichiometries has been reported in the literature without comment, and here we will interpret these results as per our recent paper.1