19 results on '"Liu, Ligong"'
Search Results
2. Potent Small Agonists of Protease Activated Receptor 2
- Author
-
Yau, Mei Kwan, Suen, Jacky Y., Xu, Weijun, Lim, Junxian, Liu, Ligong, Adams, Mark N., He, Yaowu, Hooper, John D., Reid, Robert C., Fairlie, David P., Yau, Mei Kwan, Suen, Jacky Y., Xu, Weijun, Lim, Junxian, Liu, Ligong, Adams, Mark N., He, Yaowu, Hooper, John D., Reid, Robert C., and Fairlie, David P.
- Abstract
Many proteases cut the PAR2 N-terminus resulting in conformational changes that activate cells. Synthetic peptides corresponding to newly exposed N-terminal sequences of PAR2 also activate the receptor at micromolar concentrations. PAR2-selective small molecules reported here induce PAR2-mediated intracellular calcium signaling at nanomolar concentrations (EC50 = 15-100 nM, iCa2+, CHO-hPAR2 cells). These are the most potent and efficient small molecule ligands to activate PAR2-mediated calcium release and chemotaxis, including for human breast and prostate cancer cells.
- Published
- 2016
3. Biological diversity from a structurally diverse library: Systematically scanning conformational space using a pyranose scaffold
- Author
-
Abbenante, Giovanni, Becker, Bernd, Blanc, Sébastien, Clark, Chris, Condie, Glenn, Fraser, Graeme, Grathwohl, Matthias, Halliday, Judy, Henderson, Senka, Lam, Ann, Liu, Ligong, Mann, Maretta, Muldoon, Craig, Pearson, Andrew, Premraj, Rajaratnam, Ramsdale, Tracie, Rossetti, Tony, Schafer, Karl, Le Thanh, Giang, Tometzki, Gerald, Vari, Frank, Verquin, Géraldine, Waanders, Jennifer, West, Michael, Wimmer, Norbert, Yau, Annika, Zuegg, Johannes, Meutermans, Wim, Abbenante, Giovanni, Becker, Bernd, Blanc, Sébastien, Clark, Chris, Condie, Glenn, Fraser, Graeme, Grathwohl, Matthias, Halliday, Judy, Henderson, Senka, Lam, Ann, Liu, Ligong, Mann, Maretta, Muldoon, Craig, Pearson, Andrew, Premraj, Rajaratnam, Ramsdale, Tracie, Rossetti, Tony, Schafer, Karl, Le Thanh, Giang, Tometzki, Gerald, Vari, Frank, Verquin, Géraldine, Waanders, Jennifer, West, Michael, Wimmer, Norbert, Yau, Annika, Zuegg, Johannes, and Meutermans, Wim
- Abstract
Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of defined chirality and substitution pattern. A systematic scanning library of 490 compounds was thus designed, produced, and screened in vitro for activity at the somatostatin (sst1?5) and melanin-concentrating hormone (MCH1) receptors. Bioactive compounds were found for each target, with specific chemoform preferences identified in each case, which can be used to guide follow-on drug discovery projects without the need for scaffold hopping.
- Published
- 2010
4. Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth
- Author
-
Johnstone, Ken, Karoli, Tomislav, Liu, Ligong, Dredge, Keith, Copeman, Elizabeth, Li, Cai Ping, Davis, Kat, Hammond, Edward, Bytheway, Ian, Kostewicz, Edmund, Chiu, Francis, Shackleford, David, Charman, Susan, Charman, William, Harenberg, Job, Gonda, Thomas, Ferro, Vito, Johnstone, Ken, Karoli, Tomislav, Liu, Ligong, Dredge, Keith, Copeman, Elizabeth, Li, Cai Ping, Davis, Kat, Hammond, Edward, Bytheway, Ian, Kostewicz, Edmund, Chiu, Francis, Shackleford, David, Charman, Susan, Charman, William, Harenberg, Job, Gonda, Thomas, and Ferro, Vito
- Published
- 2010
5. Synthesis, Biological Activity and Preliminary Pharmacokinetic Evaluation of Analogues of a Phosphosulfomannan Angiogenesis Inhibitor (PI-88)
- Author
-
Karoli, Tomislav, Liu, Ligong, Fairweather, Jon, Hammond, Edward, Li, Cai Ping, Cochran, Siska, Bergefall, Kicki, Trybala, Edward, Addison, Russell, Ferro, Vito, Karoli, Tomislav, Liu, Ligong, Fairweather, Jon, Hammond, Edward, Li, Cai Ping, Cochran, Siska, Bergefall, Kicki, Trybala, Edward, Addison, Russell, and Ferro, Vito
- Published
- 2005
6. Discovery of PG545: AHighly Potent and SimultaneousInhibitor of Angiogenesis, Tumor Growth, and Metastasis.
- Author
-
Ferro, Vito, Liu, Ligong, Johnstone, Ken D., Wimmer, Norbert, Karoli, Tomislav, Handley, Paul, Rowley, Jessica, Dredge, Keith, Li, Cai Ping, Hammond, Edward, Davis, Kat, Sarimaa, Laura, Harenberg, Job, and Bytheway, Ian
- Subjects
- *
HEPARAN sulfate , *ANTINEOPLASTIC agents , *NEOVASCULARIZATION inhibitors , *TUMOR growth , *METASTASIS , *CLINICAL trials - Abstract
Increasing the aglycone lipophilicity of a series ofpolysulfatedoligosaccharide glycoside heparan sulfate (HS) mimetics via attachmentof a steroid or long chain alkyl group resulted in compounds withsignificantly improved in vitro and ex vivo antiangiogenic activity.The compounds potently inhibited heparanase and HS-binding angiogenicgrowth factors and displayed improved antitumor and antimetastaticactivity in vivo compared with the earlier series. Preliminary pharmacokineticanalyses also revealed significant increases in half-life followingiv dosing, ultimately supporting less frequent dosing regimens inpreclinical tumor models compared with other HS mimetics. The compoundsalso displayed only mild anticoagulant activity, a common side effectusually associated with HS mimetics. These efforts led to the identificationof 3β-cholestanyl 2,3,4,6-tetra-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β-d-glucopyranoside, tridecasodium salt (PG545, 18) as a clinical candidate. Compound 18was recentlyevaluated in a phase I clinical trial in cancer patients. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
7. A Versatile Synthetic Approach toward Diversity Libraries using Monosaccharide Scaffolds.
- Author
-
Thanh, Giang Le, Abbenante, Giovanni, Adamson, George, Becker, Bernd, Clark, Chris, Condie, Glenn, Falzun, Tania, Grathwohl, Matthias, Gupta, Praveer, Hanson, Michael, Huynh, Ngoc, Katavic, Peter, Kuipers, Krystle, Lam, Ann, Liu, Ligong, Mann, Maretta, Mason, Jeff, McKeveney, Declan, Muldoon, Craig, and Pearson, Andrew
- Published
- 2010
- Full Text
- View/download PDF
8. Chemical Modulators of Mucosal Associated Invariant T Cells.
- Author
-
Mak JYW, Liu L, and Fairlie DP
- Subjects
- Animals, Antigens, Folic Acid chemistry, Folic Acid pharmacology, Humans, Molecular Structure, Protein Folding, Riboflavin analogs & derivatives, Riboflavin chemistry, Riboflavin pharmacology, Structure-Activity Relationship, Mucosal-Associated Invariant T Cells drug effects
- Abstract
Over the past decade, we have contributed to the chemistry of microbial natural products and synthetic ligands, related to riboflavin and uracils, that modulate immune cells called mucosal associated invariant T cells (MAIT cells). These highly abundant T lymphocytes were only discovered in 2003 and have become recognized for their importance in mammalian immunology. Unlike other T cells, MAIT cells are not activated by peptide or lipid antigens. In collaboration with immunology and structural biology research groups, we discovered that they are instead activated by unstable nitrogen-containing heterocycles synthesized by bacteria. The most potent naturally occurring activating compound (antigen) is 5 -(2-oxopropylideneamino)-d-ribitylaminouracil (5-OP-RU). This compound is an imine (Schiff base) formed through condensation between an intermediate in the biosynthesis of riboflavin (vitamin B2) and a metabolic byproduct of mammalian and microbial glycolysis. Although it is very unstable in water due to intramolecular ring closure or hydrolysis, we were able to develop a non-enzymatic synthesis that yields a pure kinetically stable compound in a nonaqueous solvent. This compound has revolutionized the study of MAIT cell immunology due to its potent activation (EC
50 = 2 pM) of MAIT cells and its development into immunological reagents for detecting and characterizing MAIT cells in tissues. MAIT cells are now linked to key physiological processes and disease, including antibacterial defense, tissue repair, regulation of graft- vs -host disease, gastritis, inflammatory bowel diseases, and cancer. 5-OP-RU activates MAIT cells and, like a vaccine, has been shown to protect mice from bacterial infections and cancers. Mechanistic studies on the binding of 5-OP-RU to its dual protein targets, the major histocompatibility complex class I related protein (MR1) and the MAIT cell receptor (MAIT TCR), have involved synthetic chemistry, 2D1 H NMR spectroscopy, mass spectrometry, computer modeling and molecular dynamics simulations, biochemical, cellular, and immunological assays, and protein structural biology. These combined studies have revealed structural influences for 5-OP-RU in solution on protein binding and antigen presentation and potency; informed the development of potent (EC50 = 2 nM) and water stable analogues; led to fluorescent analogues for detecting and tracking binding proteins in and on cells; and enabled discovery of drugs and drug-like molecules that bind MR1 and modulate MAIT cell function. MAIT cells offer new opportunities for chemical synthesis to enhance the stability, potency, selectivity, and bioavailability of small molecule ligands for MR1 or MAIT TCR proteins, and to contribute to the understanding of T cell immunity and the development of prospective new immunomodulating medicines.- Published
- 2021
- Full Text
- View/download PDF
9. HDAC7 Inhibition by Phenacetyl and Phenylbenzoyl Hydroxamates.
- Author
-
Mak JYW, Wu KC, Gupta PK, Barbero S, McLaughlin MG, Lucke AJ, Tng J, Lim J, Loh Z, Sweet MJ, Reid RC, Liu L, and Fairlie DP
- Subjects
- Benzamides chemical synthesis, Benzamides metabolism, Benzeneacetamides chemical synthesis, Benzeneacetamides metabolism, Biphenyl Compounds chemical synthesis, Biphenyl Compounds metabolism, Biphenyl Compounds pharmacology, Histone Deacetylase Inhibitors chemical synthesis, Histone Deacetylase Inhibitors metabolism, Humans, Hydroxamic Acids chemical synthesis, Hydroxamic Acids metabolism, Molecular Docking Simulation, Molecular Structure, Protein Binding, Structure-Activity Relationship, THP-1 Cells, Benzamides pharmacology, Benzeneacetamides pharmacology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Hydroxamic Acids pharmacology
- Abstract
The zinc-containing histone deacetylase enzyme HDAC7 is emerging as an important regulator of immunometabolism and cancer. Here, we exploit a cavity in HDAC7, filled by Tyr303 in HDAC1, to derive new inhibitors. Phenacetyl hydroxamates and 2-phenylbenzoyl hydroxamates bind to Zn
2+ and are 50-2700-fold more selective inhibitors of HDAC7 than HDAC1. Phenylbenzoyl hydroxamates are 30-70-fold more potent HDAC7 inhibitors than phenacetyl hydroxamates, which is attributed to the benzoyl aromatic group interacting with Phe679 and Phe738. Phthalimide capping groups, including a saccharin analogue, decrease rotational freedom and provide hydrogen bond acceptor carbonyl/sulfonamide oxygens that increase inhibitor potency, liver microsome stability, solubility, and cell activity. Despite being the most potent HDAC7 inhibitors to date, they are not selective among class IIa enzymes. These strategies may help to produce tools for interrogating HDAC7 biology related to its catalytic site.- Published
- 2021
- Full Text
- View/download PDF
10. Biased Signaling by Agonists of Protease Activated Receptor 2.
- Author
-
Jiang Y, Yau MK, Kok WM, Lim J, Wu KC, Liu L, Hill TA, Suen JY, and Fairlie DP
- Subjects
- Animals, CHO Cells, Calcium metabolism, Cricetulus, HT29 Cells, Humans, Ligands, MAP Kinase Signaling System drug effects, Receptor, PAR-2 physiology, Structure-Activity Relationship, Transfection, Receptor, PAR-2 agonists, Signal Transduction drug effects
- Abstract
Protease activated receptor 2 (PAR2) is associated with metabolism, obesity, inflammatory, respiratory and gastrointestinal disorders, pain, cancer, and other diseases. The extracellular N-terminus of PAR2 is a common target for multiple proteases, which cleave it at different sites to generate different N-termini that activate different PAR2-mediated intracellular signaling pathways. There are no synthetic PAR2 ligands that reproduce the same signaling profiles and potencies as proteases. Structure-activity relationships here for 26 compounds spanned a signaling bias over 3 log units, culminating in three small ligands as biased agonist tools for interrogating PAR2 functions. DF253 (2f-LAAAAI-NH
2 ) triggered PAR2-mediated calcium release (EC50 2 μM) but not ERK1/2 phosphorylation (EC50 > 100 μM) in CHO cells transfected with hPAR2. AY77 (Isox-Cha-Chg-NH2 ) was a more potent calcium-biased agonist (EC50 40 nM, Ca2+ ; EC50 2 μM, ERK1/2), while its analogue AY254 (Isox-Cha-Chg-A-R-NH2 ) was an ERK-biased agonist (EC50 2 nM, ERK1/2; EC50 80 nM, Ca2+ ). Signaling bias led to different functional responses in human colorectal carcinoma cells (HT29). AY254, but not AY77 or DF253, attenuated cytokine-induced caspase 3/8 activation, promoted scratch-wound healing, and induced IL-8 secretion, all via PAR2-ERK1/2 signaling. Different ligand components were responsible for different PAR2 signaling and functions, clues that can potentially lead to drugs that modulate different pathway-selective cellular and physiological responses.- Published
- 2017
- Full Text
- View/download PDF
11. PAR2 Modulators Derived from GB88.
- Author
-
Yau MK, Liu L, Suen JY, Lim J, Lohman RJ, Jiang Y, Cotterell AJ, Barry GD, Mak JY, Vesey DA, Reid RC, and Fairlie DP
- Abstract
PAR2 antagonists have potential for treating inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders, but few antagonists are known. Derivatives of GB88 ( 3 ) suggest that all four of its components bind at distinct PAR2 sites with the isoxazole, cyclohexylalanine, and isoleucine determining affinity and selectivity, while the C-terminal substituent determines agonist/antagonist function. Here we report structurally similar PAR2 ligands with opposing functions (agonist vs antagonist) upon binding to PAR2. A biased ligand AY117 ( 65 ) was found to antagonize calcium release induced by PAR2 agonists trypsin and hexapeptide 2f-LIGRLO-NH
2 (IC50 2.2 and 0.7 μM, HT29 cells), but it was a selective PAR2 agonist in inhibiting cAMP stimulation and activating ERK1/2 phosphorylation. It showed anti-inflammatory properties both in vitro and in vivo .- Published
- 2016
- Full Text
- View/download PDF
12. Potent Small Agonists of Protease Activated Receptor 2.
- Author
-
Yau MK, Suen JY, Xu W, Lim J, Liu L, Adams MN, He Y, Hooper JD, Reid RC, and Fairlie DP
- Abstract
Many proteases cut the PAR2 N-terminus resulting in conformational changes that activate cells. Synthetic peptides corresponding to newly exposed N-terminal sequences of PAR2 also activate the receptor at micromolar concentrations. PAR2-selective small molecules reported here induce PAR2-mediated intracellular calcium signaling at nanomolar concentrations (EC50 = 15-100 nM, iCa(2+), CHO-hPAR2 cells). These are the most potent and efficient small molecule ligands to activate PAR2-mediated calcium release and chemotaxis, including for human breast and prostate cancer cells.
- Published
- 2015
- Full Text
- View/download PDF
13. Repurposing Registered Drugs as Antagonists for Protease-Activated Receptor 2.
- Author
-
Xu W, Lim J, Goh CY, Suen JY, Jiang Y, Yau MK, Wu KC, Liu L, and Fairlie DP
- Subjects
- Binding, Competitive, Humans, Models, Biological, Molecular Docking Simulation, Molecular Structure, Drug Discovery, Drug Repositioning, Receptor, PAR-2 antagonists & inhibitors
- Abstract
Virtual screening of a drug database identified Carvedilol, Loratadine, Nefazodone and Astemizole as PAR2 antagonists, after ligand docking and molecular dynamics simulations using a PAR2 homology model and a putative binding mode of a known PAR2 ligand. The drugs demonstrated competitive binding and antagonism of calcium mobilization and ERK1/2 phosphorylation in CHO-hPAR2 transfected cells, while inhibiting IL-6 secretion in PAR2 expressing MDA-MB-231 breast cancer cells. This research highlights opportunities for GPCR hit-finding from FDA-approved drugs.
- Published
- 2015
- Full Text
- View/download PDF
14. Cyclic Penta- and Hexaleucine Peptides without N-Methylation Are Orally Absorbed.
- Author
-
Hill TA, Lohman RJ, Hoang HN, Nielsen DS, Scully CC, Kok WM, Liu L, Lucke AJ, Stoermer MJ, Schroeder CI, Chaousis S, Colless B, Bernhardt PV, Edmonds DJ, Griffith DA, Rotter CJ, Ruggeri RB, Price DA, Liras S, Craik DJ, and Fairlie DP
- Abstract
Development of peptide-based drugs has been severely limited by lack of oral bioavailability with less than a handful of peptides being truly orally bioavailable, mainly cyclic peptides with N-methyl amino acids and few hydrogen bond donors. Here we report that cyclic penta- and hexa-leucine peptides, with no N-methylation and five or six amide NH protons, exhibit some degree of oral bioavailability (4-17%) approaching that of the heavily N-methylated drug cyclosporine (22%) under the same conditions. These simple cyclic peptides demonstrate that oral bioavailability is achievable for peptides that fall outside of rule-of-five guidelines without the need for N-methylation or modified amino acids.
- Published
- 2014
- Full Text
- View/download PDF
15. Toward drugs for protease-activated receptor 2 (PAR2).
- Author
-
Yau MK, Liu L, and Fairlie DP
- Subjects
- Amino Acid Sequence, Animals, Antibodies chemistry, Antibodies pharmacology, Gene Knockout Techniques, Humans, Lipopeptides chemistry, Lipopeptides pharmacology, Molecular Sequence Data, Molecular Targeted Therapy, Protein Conformation, Receptor, PAR-2 agonists, Receptor, PAR-2 antagonists & inhibitors, Sequence Homology, Amino Acid, Signal Transduction, Receptor, PAR-2 metabolism
- Abstract
PAR2 has a distinctive functional phenotype among an unusual group of GPCRs called protease activated receptors, which self-activate after cleavage of their N-termini by mainly serine proteases. PAR2 is the most highly expressed PAR on certain immune cells, and it is activated by multiple proteases (but not thrombin) in inflammation. PAR2 is expressed on many types of primary human cells and cancer cells. PAR2 knockout mice and PAR2 agonists and antagonists have implicated PAR2 as a promising target in inflammatory conditions; respiratory, gastrointestinal, metabolic, cardiovascular, and neurological dysfunction; and cancers. This article summarizes salient features of PAR2 structure, activation, and function; opportunities for disease intervention via PAR2; pharmacological properties of published or patented PAR2 modulators (small molecule agonists and antagonists, pepducins, antibodies); and some personal perspectives on limitations of assessing their properties and on promising new directions for PAR2 modulation.
- Published
- 2013
- Full Text
- View/download PDF
16. Biological diversity from a structurally diverse library: systematically scanning conformational space using a pyranose scaffold.
- Author
-
Abbenante G, Becker B, Blanc S, Clark C, Condie G, Fraser G, Grathwohl M, Halliday J, Henderson S, Lam A, Liu L, Mann M, Muldoon C, Pearson A, Premraj R, Ramsdale T, Rossetti T, Schafer K, Le Thanh G, Tometzki G, Vari F, Verquin G, Waanders J, West M, Wimmer N, Yau A, Zuegg J, and Meutermans W
- Subjects
- Amino Acids chemistry, Animals, Binding, Competitive, CHO Cells, Cricetinae, Cricetulus, Databases, Factual, Humans, Models, Molecular, Molecular Conformation, Molecular Mimicry, Monosaccharides pharmacology, Oligopeptides pharmacology, Radioligand Assay, Receptors, Somatostatin antagonists & inhibitors, Stereoisomerism, Structure-Activity Relationship, Monosaccharides chemistry, Oligopeptides chemistry
- Abstract
Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of defined chirality and substitution pattern. A systematic scanning library of 490 compounds was thus designed, produced, and screened in vitro for activity at the somatostatin (sst(1-5)) and melanin-concentrating hormone (MCH(1)) receptors. Bioactive compounds were found for each target, with specific chemoform preferences identified in each case, which can be used to guide follow-on drug discovery projects without the need for scaffold hopping.
- Published
- 2010
- Full Text
- View/download PDF
17. Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth.
- Author
-
Johnstone KD, Karoli T, Liu L, Dredge K, Copeman E, Li CP, Davis K, Hammond E, Bytheway I, Kostewicz E, Chiu FC, Shackleford DM, Charman SA, Charman WN, Harenberg J, Gonda TJ, and Ferro V
- Subjects
- Angiogenesis Inhibitors pharmacokinetics, Angiogenesis Inhibitors pharmacology, Animals, Blood Coagulation drug effects, Drug Resistance, Neoplasm, Fibroblast Growth Factor 1 metabolism, Fibroblast Growth Factor 2 metabolism, Glucuronidase antagonists & inhibitors, Glycosides pharmacokinetics, Glycosides pharmacology, Humans, In Vitro Techniques, Male, Melanoma, Experimental blood supply, Melanoma, Experimental drug therapy, Melanoma, Experimental pathology, Mice, Mice, Inbred C57BL, Molecular Mimicry, Neovascularization, Pathologic drug therapy, Neovascularization, Physiologic drug effects, Oligosaccharides pharmacokinetics, Oligosaccharides pharmacology, Protein Binding, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Sulfuric Acid Esters pharmacokinetics, Sulfuric Acid Esters pharmacology, Vascular Endothelial Growth Factor A metabolism, Xenograft Model Antitumor Assays, Angiogenesis Inhibitors chemical synthesis, Glycosides chemical synthesis, Heparitin Sulfate chemistry, Oligosaccharides chemical synthesis, Sulfuric Acid Esters chemical synthesis
- Abstract
A series of polysulfated penta- and tetrasaccharide glycosides containing alpha(1-->3)/alpha(1-->2)-linked mannose residues were synthesized as heparan sulfate (HS) mimetics and evaluated for their ability to inhibit angiogenesis. The compounds bound tightly to angiogenic growth factors (FGF-1, FGF-2, and VEGF) and strongly inhibited heparanase activity. In addition, the compounds exhibited potent activity in cell-based and ex vivo assays indicative of angiogenesis, with tetrasaccharides exhibiting activity comparable to that of pentasaccharides. Selected compounds also showed good antitumor activity in vivo in a mouse melanoma (solid tumor) model resistant to the phase III HS mimetic 1 (muparfostat, formerly known as PI-88). The lipophilic modifications also resulted in reduced anticoagulant activity, a common side effect of HS mimetics, and conferred a reasonable pharmacokinetic profile in the rat, as exemplified by the sulfated octyl tetrasaccharide 5. The data support the further investigation of this class of compounds as potential antiangiogenic, anticancer therapeutics.
- Published
- 2010
- Full Text
- View/download PDF
18. Molecular recognition of DNA by rigid [N]-polynorbornane-derived bifunctional intercalators: synthesis and evaluation of their binding properties.
- Author
-
Van Vliet LD, Ellis T, Foley PJ, Liu L, Pfeffer FM, Russell RA, Warrener RN, Hollfelder F, and Waring MJ
- Subjects
- Acridines chemistry, Amides chemical synthesis, Amides chemistry, Aminoacridines chemical synthesis, Aminoacridines chemistry, Deoxyribonucleases chemistry, Dialysis, Electrophoresis, Gel, Two-Dimensional, Intercalating Agents chemistry, Naphthalimides chemical synthesis, Naphthalimides chemistry, Norbornanes chemistry, Structure-Activity Relationship, Acridines chemical synthesis, DNA chemistry, Intercalating Agents chemical synthesis, Norbornanes chemical synthesis
- Abstract
We have exploited the concept of multivalency in the context of DNA recognition, using novel chemistry to synthesize a new type of bis-intercalator with unusual sequence-selectivity. Bis-intercalation has been observed previously, but design principles for de novo construction of such molecules are not known. Our compounds feature two aromatic moieties projecting from a rigid, polynorbornane-based scaffold. The length and character of the backbone as well as the identity of the intercalators were varied, resulting in mono- or divalent recognition of the double helix with varying affinity. Our lead compound proved to be a moderately sequence-selective bis-intercalator with an unwinding angle of 27 degrees and a binding constant of about 8 microM. 9-aminoacridine rings were preferred over acridine carboxamides or naphthalimides, and a rigid [3]-polynorbornane scaffold was superior to a [5]-polynorbornane. The flexibility of the linker connecting the rings to the scaffold, although less influential, could affect the strength and character of the DNA binding.
- Published
- 2007
- Full Text
- View/download PDF
19. Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88).
- Author
-
Karoli T, Liu L, Fairweather JK, Hammond E, Li CP, Cochran S, Bergefall K, Trybala E, Addison RS, and Ferro V
- Subjects
- Angiogenesis Inhibitors pharmacokinetics, Animals, Antiviral Agents pharmacology, Blood Platelets enzymology, Cells, Cultured, Chlorocebus aethiops, Fibroblast Growth Factor 1 chemistry, Fibroblast Growth Factor 2 chemistry, Glucuronidase antagonists & inhibitors, Herpesvirus 1, Human drug effects, Humans, Male, Oligosaccharides pharmacokinetics, Rats, Rats, Sprague-Dawley, Surface Plasmon Resonance, Vascular Endothelial Growth Factor A chemistry, Angiogenesis Inhibitors chemical synthesis, Angiogenesis Inhibitors pharmacology, Oligosaccharides chemical synthesis, Oligosaccharides pharmacology
- Abstract
The phosphosulfomannan 1 (PI-88) is a mixture of highly sulfated oligosaccharides that is currently undergoing clinical evaluation in cancer patients. As well as its anticancer properties, 1 displays a number of other interesting biological activities. A series of analogues of 1 were synthesized with a single carbon (pentasaccharide) backbone to facilitate structural characterization and interpretation of biological results. In a fashion similar to 1, all compounds were able to inhibit heparanase and to bind tightly to the proangiogenic growth factors FGF-1, FGF-2, and VEGF. The compounds also inhibited the infection of cells and cell-to-cell spread of herpes simplex virus (HSV-1). Preliminary pharmacokinetic data indicated that the compounds displayed different pharmacokinetic behavior compared with 1. Of particular note was the n-octyl derivative, which was cleared 3 times less rapidly than 1 and may provide increased systemic exposure.
- Published
- 2005
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.