Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(E)-4-[1-[4-[2-(Dimethylamino)ethoxy]phenyl]-2-(4-isopropyl) phenyl]-1-butenyl]phenyl monophosphate (TAT-59) is a new drug for the treatment of breast cancer. Physical and chemical stability of mixtures of TAT-59 and microcrystalline cellulose (1:9) compressed at 0, 300, 600 and 1400 kg/cm2 was evaluated by determination of water content, porosity and the amount of hydrolysis product, DP-TAT-59, formed. The water contents and porosity of these tablets scarcely changed during 57 d at 25-60 degrees C under 50% relative humidity (RH). The degradation rate of TAT-59 increased with increasing compression pressure as well as temperature. The apparent activation energy and frequency factor were determined from an Arrhenius plot of the degradation rate. Activation energy of these tablets was almost the same, while the frequency factor tended to increase with increasing compression pressure. The porosity and pore sizes in TAT-59-containing tablets decreased with increasing compressive force. We speculated from these observations that the increase in compression pressure decreased the distance and increased the contact area between TAT-59 and microcrystalline cellulose. The proximity between TAT-59 and moisture presented at the surface of microcrystalline cellulose by compression was considered to enhance the degradation of TAT-59.
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PMID:Effects of compression pressure on physical and chemical stability of tablets containing an anticancer drug TAT-59. 769 76

(E)-4-[1-[4-[2-(Dimethylamino)ethoxy]phenyl]-2-(4-isopropyl) phenyl]-1-butenyl]phenyl monophosphate (TAT-59) is a new drug for the treatment of breast cancer. Physical and chemical stability of a tablet consisting of TAT-59 powder and a few excipients (Formulated tablet), a tablet consisting of only TAT-59 powder (TAT-59 tablet) and TAT-59 powder itself was evaluated based on water content, tensile strength, porosity, the amount of TAT-59 and its hydrolysis product, DP-TAT-59. The water content of Formulated tablet increased with relative humidity (RH), whereas that of TAT-59 tablet and TAT-59 powder scarcely changed. The equilibrium water content of Formulated tablet was much greater than that of the TAT-59 tablet or TAT-59 powder due to adsorbed moisture by the excipients. The tensile strength and porosity of Formulated tablet decreased and increased linearly, respectively, with increasing water content. The degradation rate of TAT-59 decreased in the following order: Formulated tablet > TAT-59 tablet > TAT-59 powder. The relationship between equilibrium water content and degradation rate of the Formulated tablet was determined by the Carstensen equation, in which the interaction order between the drug and water content was 1.9, and the degradation of TAT-59 in Formulated tablet was related to water content. Thus, it was found that the degradation of TAT-59 was accelerated by compression and addition of excipients.
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PMID:Effects of water content on physical and chemical stability of tablets containing an anticancer drug TAT-59. 850 75

The effects of grinding and tableting on the physicochemical stability of TAT-59, (E)-4-[1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-(4-isopropyl) phenyl]-1-butenyl]phenyl monophosphate, were studied. The crystallinity of TAT-59 ground in a planetary ball mill for 0-120 min or compressed at 0-4500 kg/cm2 was evaluated by X-ray diffraction analysis and differential scanning calorimetry (DSC). The surface of TAT-59 was measured under a scanning electron microscope (SEM). The physicochemical stability of TAT-59, ground or compressed, was determined by measurements of water content, crystallinity and the amount of hydrolysis product, DP-TAT-59, formed. The crystallinity of ground TAT-59 decreased with increasing grinding time, and the amount of DP-TAT-59 increased with decrease in the crystallinity. Similar to ground TAT-59, the crystallinity of TAT-59 tablet gradually decreased with increasing compression pressure, and the amount of DP-TAT-59 tended to increase with decreasing crystallinity. These findings suggested that the decrease of the crystallinity of TAT-59 by mechanical force, such as grinding and tableting, raised the drug's reactivity and affected its stability.
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PMID:Effects of grinding and tableting on physicochemical stability of an anticancer drug, TAT-59. 890 22

In this study, an anaerobic fluidized bed reactor (AFBR) was used to treat a synthetically produced pink water waste stream containing trinitrotoluene (TNT). The synthesized waste consisted of 95 mg/l-TNT, the main contaminant in pink water, which was to be co-metabolized with 560-mg/l ethanol. Granular activated carbon was used as the attachment medium for biological growth. TNT was reduced to a variety of compounds, mainly 2,4,6-triaminotoluene (2,4,6-TAT), 2,4-diamino-6-nitrotoluene (2,4-DA-6-NT), 2,6-diamino-4-nitrotoluene (2,6-DA-4-NT), 2-amino-4,6-dinitrotoluene (2-A-4,6-DNT), and 4-amino-2,6-dinitrotoluene (4-A-2,6-DNT). These conversions resulted through the oxidation of ethanol to carbon dioxide under anoxic conditions, or reduction to methane under methanogenic conditions. The anaerobic reactor was charged with 1.0 kg of 16 x 20 U.S. Mesh Granular Activated Carbon (GAC) and was pre-loaded with 200 g of TNT prior to the addition of the mixed seed culture. During the first three weeks of operation, ethanol was completely degraded and no methane was produced. Effluent inorganic carbon revealed stoichiometric conversion of the feed ethanol to dissolved inorganic carbon with accumulation of carbon dioxide in the headspace of the reactor. GAC extraction showed incremental reduction of the nitro groups to amino groups, with 2,4,6-TAT as the final product. After three weeks, the oxygen from the nitro groups was depleted and methane production commenced. The reproducibility of this phenomenon was confirmed by repeating the experiment in the same manner using an identical AFBR. Furthermore, serum bottle tests were conducted using TNT loading ratios of 0.2, 0.4, 0.8, 1.0 g-TNT/g-GAC as well as experiments in the absence of GAC. Similar behavior to that of the columns was observed, with degradation rates varying according to the particular condition. GAC greatly enhanced the degradation rates and the higher TNT loading resulted in slower degradation rates of ethanol.
Water Sci Technol 2001
PMID:Anaerobic degradation of 2,4,6-trinitrotoluene in granular activated carbon fluidized bed and batch reactors. 1137 14

Cell-penetrating peptides (CPPs) traverse cell membranes of cultured cells very efficiently by a mechanism not yet identified. Recent theories for the translocation suggest either the binding of the CPPs to extracellular glycosaminoglycans or the formation of inverted micelles with negatively charged lipids. In the present study, the binding of the protein transduction domains (PTD) of human (HIV-1) and simian immunodeficiency virus (SIV) TAT peptide (amino acid residues 47-57, electric charge z(p) = +8) to membranes containing various proportions of negatively charged lipid (POPG) is characterized. Monolayer expansion measurements demonstrate that TAT-PTD insertion between lipids requires loosely packed monolayer films. For densely packed monolayers (pi > 29 mN/m) and lipid bilayers, no insertion is possible, and binding occurs via electrostatic adsorption to the membrane surface. Light scattering experiments show an aggregation of anionic lipid vesicles when the electric surface charge is neutralized by TAT-PTD, the observed stoichiometry being close to the theoretical value of 1:8. Membrane binding was quantitated with isothermal titration calorimetry and three further methods. The reaction enthalpy is Delta H degrees approximately equal to -1.5 kcal/mol peptide and is almost temperature-independent with Delta C(p) degrees approximately 0 kcal/(mol K), indicating equal contributions of polar and hydrophobic interactions to the reaction heat capacity. The binding of TAT-PTD to the anionic membrane is described by an electrostatic attraction/chemical partition model. The electrostatic attraction energy, calculated with the Gouy-Chapman theory, accounts for approximately 80% of the binding energy. The overall binding constant, K(app), is approximately 10(3)-10(4) M(-1). The intrinsic binding constant (K(p)), corrected for electrostatic effects and describing the partitioning of the peptide between the lipid-water interface and the membrane, is small and is K(p) approximately 1-10 M(-1). Deuterium and phosphorus-31 nuclear magnetic resonance demonstrate that the lipid bilayer remains intact upon TAT-PTD binding. The NMR data provide no evidence for nonbilayer structures and also not for domain formation. This is further supported by the absence of dye efflux from single-walled lipid vesicles. The electrostatic interaction between TAT-PTD and anionic phosphatidylglycerol is strong enough to induce a change in the headgroup conformation of the anionic lipid, indicating a short-lived but distinct correlation between the TAT-PTD and the anionic lipids on the membrane outside. TAT-PTD has a much lower affinity for lipid membranes than for glycosaminoglycans, making the latter interaction a more probable pathway for CPP binding to biological membranes.
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PMID:Protein transduction domains of HIV-1 and SIV TAT interact with charged lipid vesicles. Binding mechanism and thermodynamic analysis. 1288 53

To elucidate the role of enhanced phosphoinositide-3-kinase (PI3-kinase) activity in memory, a synthetic phosphopeptide (TAT-YPMDM) containing the p85 regulatory subunit receptor-binding motif (YXXM) coupled to the cell transduction domain of HIV-TAT protein was employed. This phosphopeptide bound the p85 subunit of PI3-kinase, and was internalized by both granule and pyramidal neurons when injected into the hippocampus. Increased lipid kinase activity and enhanced phosphorylation of the PI3-kinase substrates Akt (protein kinase B) and ribosomal S6 kinase were associated with TAT-YPMDM administration. Bilateral infusion of the phosphopeptide into the dorsal hippocampus after training improved performance in three hippocampus-dependent memory tasks: contextual fear conditioning, trace fear conditioning, and the Morris water maze. Both the biochemical and behavioral effects of the TAT-YPMDM phosphopeptide could be blocked by wortmannin. No effect was observed when a nonphosphorylated peptide (TAT-YMDM), or a second, unrelated phosphopeptide (TAT-YPLDL) was utilized. In addition, infusion of the TAT-YPMDM phosphopeptide did not interfere with memory acquisition or 4 hr memory. In addition, pretesting administration did not affect the ability to recall a previously established long-term memory. These findings suggest that stimulation of PI3-kinase activity by phosphorylated receptor fragments containing the YMDM motif augments long-term memory.
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PMID:Performance in long-term memory tasks is augmented by a phosphorylated growth factor receptor fragment. 1521 87

Water-in-oil (w/o) microemulsion synthesis of 70 nm size monodisperse TAT (a cell penetrating peptide, CPP) conjugated, FITC (fluorescein isothiocyanate) doped silica nanoparticles (TAT-FSNPs) is reported; human lung adenocarcinoma (A549) cells (in vitro) and rat brain tissue (in vivo) were successfully labeled using TAT-FSNPs.
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PMID:TAT conjugated, FITC doped silica nanoparticles for bioimaging applications. 1559 18

Thermodynamic parameters of melting process (DeltaHm, Tm, DeltaTm) of calf thymus DNA, poly(dA)poly(dT) and poly(d(A-C)).poly(d(G-T)) were determined in the presence of various concentrations of TOEPyP(4) and its Zn complex. The investigated porphyrins caused serious stabilization of calf thymus DNA and poly poly(dA)poly(dT), but not poly(d(A-C))poly(d(G-T)). It was shown that TOEpyp(4) revealed GC specificity, it increased Tm of satellite fraction by 24 degrees C, but ZnTOEpyp(4), on the contrary, predominantly bound with AT-rich sites and increased DNA main stage Tm by 18 degrees C, and Tm of poly(dA)poly(dT) increased by 40 degrees C, in comparison with the same polymers without porphyrin. ZnTOEpyp(4) binds with DNA and poly(dA)poly(dT) in two modes--strong and weak ones. In the range of r from 0.005 to 0.08 both modes were fulfilled, and in the range of r from 0.165 to 0.25 only one mode--strong binding--took place. The weak binding is characterized with shifting of Tm by some grades, and for the strong binding Tm shifts by approximately 30-40 degrees C. Invariability of DeltaHm of DNA and poly(dA)poly(dT), and sharp increase of Tm in the range of r from 0.08 to 0.25 for thymus DNA and 0.01-0.2 for poly(dA)poly(dT) we interpret as entropic character of these complexes melting. It was suggested that this entropic character of melting is connected with forcing out of H2O molecules from AT sites by ZnTOEpyp(4) and with formation of outside stacking at the sites of binding. Four-fold decrease of calf thymus DNA melting range width DeltaTm caused by increase of added ZnTOEpyp(4) concentration is explained by rapprochement of AT and GC pairs thermal stability, and it is in agreement with a well-known dependence, according to which DeltaT approximately TGC-TAT for DNA obtained from higher organisms (L. V. Berestetskaya, M. D. Frank-Kamenetskii, and Yu. S. Lazurkin. Biopolymers 13, 193-205 (1974)). Poly (d(A-C))poly(d(G-T)) in the presence of ZnTOEpyp(4) gives only one mode of weak binding. The conclusion is that binding of ZnTOEpyp(4) with DNA depends on its nucleotide sequence.
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PMID:Microcalorimetric investigation of DNA, poly(dA)poly(dT) and poly[d(A-C)]poly[d(G-T)] melting in the presence of water soluble (meso tetra (4 N oxyethylpyridyl) porphyrin) and its Zn complex. 1809 36

The design and construction of effective delivery vectors for drugs is very important. We have discovered that octadecyl quaternized carboxymethyl chitosan (OQCMC) in combination with cholesterol (Chol) could form stable vesicles with structure similar to that of conventional liposomes prepared from phosphatidylcholine/cholesterol (PC/Chol). Compared to conventional liposomes, our polymeric liposomes formed by OQCMC/Chol have many excellent features, such as good physical and thermal stability, excellent solubility in water, and high effectiveness in drug encapsulation. Trans-activating transcriptional activator protein (TAT peptide) could be connected on the surface of cationic polymeric liposomes by using cross-linking reagent N-hydroxysuccinimidyl-3-(2-pyridyldithio) propionate (SPDP). Also, oil-soluble magnetic nanoparticles were used to verify the bilayer structure of the polymeric liposomes and their ability to solublize hydrophobic materials. Using different preparation methods, OQCMC/Chol could easily be made into nanoscale particles by encapsulating both hydrophilic and hydrophobic components. We have successfully prepared polymeric liposomes encapsulating quantum dots (QDs), superparamagnetic nanoparticles, or both. Vincristine was also encapsulated in the polymeric liposomes with high drug encapsulation efficiency (90.1%). Vincristine-loaded magnetic polymeric liposomes were stable in aqueous solution and exhibited slow, steady release action over 2 weeks under physiologic pH (7.4). This allows the use of multifunctional cationic polymeric liposomes, such as those developed here from modified chitosan, in various applications such as cancer diagnosis and treatment.
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PMID:Characterization of novel multifunctional cationic polymeric liposomes formed from octadecyl quaternized carboxymethyl chitosan/cholesterol and drug encapsulation. 1856 60

G-quadruplexes are a highly studied DNA motif with a potential role in a variety of cellular processes and more recently are considered novel targets for drug therapy in aging and anticancer research. In this work, we have investigated the thermodynamic contributions of the loops on the stable formation of G-quadruplexes. Specifically, we use a combination of UV, circular dichroism (CD) and fluorescence spectroscopies, and differential scanning calorimetry (DSC) to determine thermodynamic profiles, including the differential binding of ions and water, for the unfolding of the thrombin aptamer: d(GGT2GGTGTGGT2GG) that is referred to as G2. The sequences in italics, TGT and T2, are known to form loops. Other sequences examined contained base substitutions in the TGT loop (TAT, TCT, TTT, TAPT, and UUU), in the T2 loops (T4, U2), or in both loops (UGU and U2, UUU and U2). The CD spectra of all molecules show a positive band centered at 292 nm, which corresponds to the "chair" conformation. The UV and DSC melting curves of each G-quadruplex show monophasic transitions with transition temperatures (T(M)s) that remained constant with increasing strand concentration, confirming their intramolecular formation. These G-quadruplexes unfold with T(M)s in the range from 43.2 to 56.5 degrees C and endothermic enthalpies from 22.9 to 37.2 kcal/mol. Subtracting the contribution of a G-quartet stack from each experimental profile indicated that the presence of the loops stabilize each G-quadruplex by favorable enthalpy contributions, larger differential binding of K+ ions (0.1-0.6 mol K+/ mol), and a variable uptake/release of water molecules (-6 to 8 mol H2O/mol). The thermodynamic contributions for these specific base substitutions are discussed in terms of loop stacking (base-base stacking within the loops) and their hydration effects.
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PMID:Unfolding thermodynamics of intramolecular G-quadruplexes: base sequence contributions of the loops. 1901 84


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