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We examine the role of preshearing on the flow properties of polymer solutions containing essentially an acrylamide-based copolymer obtained from an emulsified polymer emulsion inverted by a surfactant. The polymer solutions were presheared using three methods: (1) a Buddeberg disperser, (2) an Ultra-Turrax disperser, and (3) pressure-driven flow through a capillary. Shearing the polymer solution was done under fast flow to induce high stretching of the polymer chains and thus promote the break-up of the longest ones (i.e., decrease in relaxation time and shear-thinning level). The unsheared and presheared polymer solutions were forced through sand packs to compare their corresponding flow resistances. We observed that the reduction in the viscosity and screen factor of the presheared polymer solutions is path independent regardless of the shearing device. We found a critical Weissenberg number (Wic ∼ 13) above which the viscosity of the polymer solutions started to decrease. The resistance factor for the polymer solutions presheared with the Ultra-Turrax disperser at an energy input of 31.3 and 290.7 MJ/m3 was nearly 3 and 7 times, respectively, lower than for the unsheared polymer solution, while the viscosity decreased only by 27 and 48%, respectively. The sand-pack experiments were successfully interpreted using a numerical model taking into account time-dependent retention. The model showed that the flow of the presheared polymer solutions through the sand packs was enhanced mainly due to the breaking of the longest polymer chains, which results in smaller mechanical entrapment. This preshearing of the water-soluble polymers can be used in multiple industrial applications, including chemical enhanced oil recovery and optimization of polymer processing.

Synthetic polymers in the emulsion form have been exploited for enhanced oil recovery applications especially in harsh environments for instance offshore or remote onshore locations. Polymer solutions can be prepared on-the-fly using saline make-up water like formation water or sea water. Use of an inverter surfactant accelerates the inversion of the polymer emulsion. For this study two highly efficient inverter surfactants at different price level were selected and their impact on the performance of an acrylamide-based emulsion copolymer was investigated. Polymer solutions prepared with the inverter surfactants S1 and S2 at different concentrations and conditioned by defined shear treatment were characterized by rheology, filter tests and injectivity behavior in sand packs. Significant impact of inverter surfactant on rheological properties and especially on injectivity performance is demonstrated. Viscosities of polymer solutions prepared with surfactant S1 are slightly higher (than viscosities with surfactant S2) and decrease with increasing surfactant concentration at constant polymer content. Besides, RRF values as a measure for injectivity behavior strongly decrease at ascending surfactant content. More intense conditioning leads to favorable injectivity of an otherwise plugging polymer solution. At lower concentrations surfactant S1 seems to adversely interact with the polymer and form polymer-surfactant complexes which are retained in the sand pack during injection. For surfactant S2 viscosities of polymer solutions are independent of surfactant concentration and RRF values are low even at low surfactant concentration. This surfactant ensures good injectivities over a broad range of conditions. Being the economically more favorable surfactant it adds value to polymer flooding projects.

Synthetic polymers, in the emulsified form, have been utilized for enhanced oil recovery applications by using saline make-up water. However, there are concerns that have been raised about their injectivity. The large entangled polymer chains can clog the pore throats, giving a tendency to cause injectivity reduction. In this study, processing techniques were used to condition an acrylamide-based copolymer inverse emulsion system at a salinity of 50,000 ppm TDS before being injected into porous media. The investigated polymer solution contained 4,000 ppm active emulsion-polymer and 2,400 ppm surfactant, providing a zero-shear rate viscosity of 13 mPas. Shearing with two agitators, a disperser and Ultra-Turrax, at different intensities and pressure-driven flow into a thin capillary reduces the size of the largest polymer and disentangles the polymer chains while maintaining its viscosifying power as much as possible. Subsequently, the filtration ratios (퐹푅) with optimum between 1–1.2 were determined by performing filtration tests in a 1-micron polycarbonate membrane to evaluate the plugging behavior. This was followed by sand-pack flooding tests of differently sheared solutions in order to investigate the impact of pre-conditioning on injectivity. Bulk experiments enabled the establishment of master curves showing viscosity and screen factor dependences on accumulated energy during pre-shearing, regardless of shear origin. The injected unsheared polymer solution has an 퐹푅 of 1.6 and an injectivity gradient, e.g. ratio of resistance factor over 10 pore volumes, of 2.4. All injected pre-conditioned solutions have an 퐹푅 in the optimal range between 1 to 1.2. By imposing 15 MJ/m3, the disperser-sheared solution improves the injectivity by decreasing the injectivity gradient to 1.3, while the viscosifying power is reduced by 2% and the screen factor by 30%. To reach the same injectivity gradient of 1.3 with Ultra-Turrax, 31 MJ/m3 were imposed, which reduces the viscosity and screen factor by 11% and 44% respectively. The sheared solution into a capillary imposes 50 MJ/m3, giving an injectivity gradient of 2.7. Both viscosity and screen factor are reduced by 19% and 53% respectively. This indicates that the injectivity performance is shear-origin dependent and the resulting polymer structure, when sheared through contractions, has a different alignment as compared to shearing with the agitators, the disperser and Ultra-Turrax. In conclusion, the rheological dependencies of sheared polymer solutions form a master curve dependent of accumulated energy during shearing with different shearing devices. Further, the proven beneficial impact of pre-conditioning with agitators before injection enables a better utilization of polymer flooding operations by reducing the risk of pore plugging.

The discovery of novel, reversible and competitive tripeptide inhibitors of the Hepatitis C virus NS3/4A serine protease is described. These inhibitors are characterized by the presence of a C-terminal phenethyl amide group, which extends into the prime side of the enzyme. Initial SAR together with molecular modeling and data from site-directed mutagenesis suggest an interaction of the phenethyl amide group with Lys-136.

The difluoromethyl group was designed by computational chemistry methods as a mimetic of the canonical P1 cysteine thiol for inhibitors of the hepatitis C virus NS3 protease. This modification led to the development of competitive, non-covalent inhibitor 4 (Ki 30 nM) and reversible covalent inhibitors (6, Ki 0.5 nM; and 8 Ki∗ 10 pM).

Few structures of viral serine proteases, those encoded by the Sindbis and Semliki Forest viruses, hepatitis C virus (HCV) and cytomegalovirus, have been reported. In the life cycle of HCV a crucial role is played by a chymotrypsin-like serine protease encoded at the N–terminus of the viral NS3 protein, the solution structure of which we present here complexed with a covalently bound reversible inhibitor. Unexpectedly, the residue in the P2 position of the inhibitor induces an effective stabilization of the catalytic His–Asp hydrogen bond, by shielding that region of the protease from the solvent. This interaction appears crucial in the activation of the enzyme catalytic machinery and represents an unprecedented observation for this family of enzymes. Our data suggest that natural substrates of this serine protease could contribute to the enzyme activation by a similar induced-fit mechanism. The high degree of similarity at the His–Asp catalytic site region between HCV NS3 and other viral serine proteases suggests that this behaviour could be a more general feature for this category of viral enzymes.

New methodology was developed toward the synthesis of 8-de-ethyl-8-vinylchlorophyll-a 1. Such 8-de-ethyl-8-vinyl derivatives of the green plant pigment chlorophyll-a 2 have been proposed to be inte...

The partial synthesis of 10,22-dihydro-4,5-dioxo-4,5-secopheophorbide a (1) from pheophorbide a methyl ester (2) is described. A regioselective, photooxygenolytic reaction of (pheophorbidato a methyl ester)cadmium(II)(3) provides the entry to the crucial 4,5-secoporphinoid structure in form of the (10,22-dihydro-4,5-dioxo-4,5-seco-pheophorbidato a methyl ester)cadmium(II) (4). The hydride reduction of this 4,5-dioxo-4,5-secophytoporphyrin ester occurs selectively at the ‘eastern’ meso-position to lead (after demetallation) to 10,22-dihydro-4,5-dioxo-4,5-secopheophorbide a methyl ester (5). This oxobilin-carbaldehyde has the structure assigned earlier to an ester of an isolation form of the red pigment(s) from Chlorella protothecoides. Hydrolysis of the propanoate ester function of 5, selectively catalyzed by pig liver esterase, then yields the title compound 1. The red tetrapyrrole 1 may represent an intermediary chlorophyll catabolite in degreening plants.

The o-nitrophenylselenoethyl functionality is a useful protected vinyl group in porphyrins and chlorins, and its use is demonstrated in the Vilsmeier formylation reaction which has been shown to adversely affect unmodified vinyl groups in tetrapyrrole systems. The X-ray crystal structure for 3-(2-o-nitro-phenylselenoethyl)-3-devinylchlorin-e6 trimethyl ester 14 is reported.

Partial syntheses of two 8-vinyl-derivatives (3 and 6) of chlorin-e6 trimethyl ester 5 are reported; in certain organisms, 8-de-ethyl-8-vinylchlorophyll-a 3 has been proposed to be a biosynthetic precursor of the plant chlorophylls and of the bacteriochlorophylls.

Azachlorins rac-10a,b, rac-11, and rac-16, a novel type of hydroporphinoid compounds, were synthesized from azaporphyrins 8 and 13 by regioselective cycloaddition of singlet oxygen and further transformation by amide acetal Claisen rearrangement. The azaporphyrins are readily accessible from the naturally occurring bile pigment bilirubin (5). The photophysical properties of the azachlorins recommend these chlorin derivatives as potential photosensitizers for Photodynamic Therapy (PDT).

The photophysical and photochemical properties of a 5-azaprotoporphyrin derivative ([5]AZPP), a zinc-15-azaporphyrin derivative (Zn-[15]AZIDP) and an E-Z isomeric mixture of a 5-azachlorin derivative ([5]AZCH) were studied in various solvents. The quantum yields of fluorescence phi F0, S1-T1 intersystem crossing phi T0 and singlet oxygen (1 delta g) formation phi delta were measured and the Stern-Volmer constants for the quenching of the S1 states by oxygen and the rate constants of quenching of O2(1 delta g) by the different azaporphyrinoid compounds were obtained. The fluorescence quantum yield (phi F0 = 0.23), the strong absorption in the red (lambda max = 674 nm, epsilon max = 66,000 M-1 cm-1) and the high value of the quantum yield for singlet oxygen (1 delta g) formation (phi delta = 0.65) observed for [5]AZCH recommend azachlorin derivatives as potential markers and photosensitizers for tumour therapy.

Azachlorins 2b a novel type of hydroporphinoid compounds 2 have been synthesized from a readily accessable azaporphyrin 5b by regioselective cycloaddition of singlet oxygen. The photophysical properties of the azachlorins 2b recommend these chlorin derivatives as potential markers and photosensitizers for tumor therapy.

Azaspirographis porphyrins2a and2b were prepared as precursors for the synthesis of geminally dialkylated azachlorins, a new class of potential long wavelength photosensitizers for photodynamic therapy of cancer.

Partial syntheses of two 8-vinyl-derivatives (3 and 6) of chlorin-e6 trimethyl ester 5 are reported; in certain organisms, 8-de-ethyl-8-vinylchlorophyll-a 3 has been proposed to be a biosynthetic precursor of the plant chlorophylls and of the bacteriochlorophylls.

The o-nitrophenylselenoethyl functionality is a useful protected vinyl group in porphyrins and chlorins, and its use is demonstrated in the Vilsmeier formylation reaction which has been shown to adversely affect unmodified vinyl groups in tetrapyrrole systems. The X-ray crystal structure for 3-(2-o-nitro-phenylselenoethyl)-3-devinylchlorin-e6 trimethyl ester 14 is reported.

Azachlorins 2b a novel type of hydroporphinoid compounds 2 have been synthesized from a readily accessable azaporphyrin 5b by regioselective cycloaddition of singlet oxygen. The photophysical properties of the azachlorins 2b recommend these chlorin derivatives as potential markers and photosensitizers for tumor therapy.

N-terminal truncation of the hexapeptide ketoacid 1 gave rise to potent tripeptide inhibitors of the hepatitis C virus NS3 protease/NS4A cofactor complex. Optimization of these tripeptides led to ketoacid 30 with an IC50 of 0.38 microM. The SAR of these tripeptides is discussed in the light of the recently published crystal structures of a ternary tripetide/NS3/NS4A complexes.

The replication of the hepatitis C virus (HCV), an important human pathogen, crucially depends on the proteolytic maturation of a large viral polyprotein precursor. The viral nonstructural protein 3 (NS3) harbors a serine protease domain that plays a pivotal role in this process, being responsible for four out of the five cleavage events that occur in the nonstructural region of the HCV polyprotein. We here show that hexapeptide, tetrapeptide, and tripeptide alpha-ketoacids are potent, slow binding inhibitors of this enzyme. Their mechanism of inhibition involves the rapid formation of a noncovalent collision complex in a diffusion-limited, electrostatically driven association reaction followed by a slow isomerization step resulting in a very tight complex. pH dependence experiments point to the protonated catalytic His 57 as an important determinant for formation of the collision complex. K(i) values of the collision complexes vary between 3 nM and 18.5 microM and largely depend on contacts made by the peptide moiety of the inhibitors. Site-directed mutagenesis indicates that Lys 136 selectively participates in stabilization of the tight complex but not of the collision complex. A significant solvent isotope effect on the isomerization rate constant is suggestive of a chemical step being rate limiting for tight complex formation. The potency of these compounds is dominated by their slow dissociation rate constants, leading to complex half-lives of 11-48 h and overall K(i) values between 10 pM and 67 nM. The rate constants describing the formation and the dissociation of the tight complex are relatively independent of the peptide moiety and appear to predominantly reflect the intrinsic chemical reactivity of the ketoacid function.

Chlorin type sensitizers have ideal photophysical properties for an application in PDT. The basic chlorin framework of these sensitizers has to be modified by attachment of lipophilic and hydrophilic residues to achieve a good cell uptake and tumor enrichment. In the present study we describe the selective synthesis of amphiphilic chlorins starting from the readily accessible red blood pigment heme. The photophysical properties of the well defined synthetic chlorins are characterized by photophysical investigations. The kinetic of cell uptake, the localization in the cell and the photodynamic behavior of the amphiphilic sensitizers are demonstrated by incubation of A 375 cancer cell lines with structurally different chlorins.

Photodynamic therapy (PDT) is a promising approach for the treatment of cancer, and is presently being evaluated worldwide. PDT is based on the ability of photosensitizers to accumulate selectively in tumor tissue. On irradiation fluorescence of the sensitizer allows tumor localization. Singlet oxygen formed by sensitization causes tumor destruction. Hematoporphyrin derivatives and Photofrin IIR, at the present the only practically used sensitizers in PDT, absorb light only weakly ((epsilon) approximately equals 5.000 at (lambda) equals 620 nm). It has been shown that Photofrin IIR is a multicomponent mixture of different porphyrins with only a few therapeutically active components. In contrast to porphyrins, chlorins and azachlorins have ideal photophysical properties with strong absorption ((epsilon) approximately equals 50.000) in a spectral region ((lambda) equals 650 nm) where tissue transmits much better. Molecular properties of porphinoid structures, which are responsible for tumor uptake and tumor enrichment, are connected with lipophilicity and aggregation behavior. Therefore our aim was to synthesize well defined chlorins with lipophilic properties similar to those of the active fractions of Photofrin IIR.

Azaspirographis porphyrins2a and2b were prepared as precursors for the synthesis of geminally dialkylated azachlorins, a new class of potential long wavelength photosensitizers for photodynamic therapy of cancer.