Showing papers in "ACS Combinatorial Science in 2004"
TL;DR: This work describes an approach to optimizing preparative LC-MS methods that provides significantly better chromatographic resolution and, hence, better compound purity than generic preparativeLC methods consuming the same amount of time.
Abstract: One of the remaining challenges in providing effective preparative LC-MS purification is balancing throughput and compound purity. We describe here an approach to optimizing preparative LC-MS methods that provides significantly better chromatographic resolution and, hence, better compound purity than generic preparative LC methods consuming the same amount of time. This approach is easier to implement, is more rugged, and permits significantly greater flexibility than previously reported approaches. The instrument configurations and protocols presented here are specifically tailored for open access support, but the basic approach is equally suitable and effective in high-throughput situations.
214 citations
TL;DR: Results are presented on the screening of carbon-supported platinum catalysts of varying platinum metal loading on carbon (and thus, particle size) in order to demonstrate the speed and sensitivity of the screening methodology.
Abstract: Combinatorial methods have been applied to the preparation and screening of fuel cell electrocatalysts. Hardware and software have been developed for fast sequential measurements of cyclic voltammetric and steady-state currents in 64-element half-cell arrays. The arrays were designed for the screening of high-surface-area supported electrocatalysts. Analysis software developed allowed the semiautomated processing of the large quantities of data, applying filters that defined figures of merit relevant to fuel cell catalyst activity and tolerance. Results are presented on the screening of carbon-supported platinum catalysts of varying platinum metal loading on carbon (and thus, particle size) in order to demonstrate the speed and sensitivity of the screening methodology. CO electro-oxidation, oxygen reduction, and methanol oxidation on a series of such catalysts reveal clear trends in characteristics and activities. Catalysts with smaller particle sizes reveal structure in the CO stripping voltammetry that can be associated with edge sites in addition to the closely packed planes, and this is concomitantly reduced as particle size is increased. Specific activity for steady-state methanol oxidation and oxygen reduction at room temperature in H(2)SO(4) electrolyte is found to be a maximum for the largest particle sizes, in agreement with the literature. These trends in activity are significantly smaller than the differences in activities of promoted platinum-based alloy catalysts for the same reaction.
170 citations
TL;DR: A library consisting of about half of 800 000 possible peptidotriazoles on 450 000 beads was prepared by solid-phase peptide synthesis combined with a regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition between a resin-bound alkyne and a protected amino azide, and the formation of the triazole could be performed quantitatively in a randomized fashion.
Abstract: A library consisting of about half of 800 000 possible peptidotriazoles on 450 000 beads was prepared by solid-phase peptide synthesis combined with a regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition between a resin-bound alkyne and a protected amino azide. The central [1,2,3]-triazole was flanked on each side by two randomized amino acids introduced in a combinatorial approach. Importantly, the formation of the triazole could be performed quantitatively in a randomized fashion. The library was screened on solid phase for inhibitory effect against a recombinant cysteine protease, Leishmania mexicana CPB2.8ΔCTE and sorted by a high-throughput instrument, COPAS beadsorter (up to 200 000 beads/h). Forty-eight hits were analyzed by MALDI-TOF MS providing structural information about the protease specificity, and 23 peptidotriazoles were resynthesized and evaluated in solution, with the best inhibitor displaying a Ki value of 76 nM. A one-pot procedure was used to convert Fmoc-amino azides into thei...
145 citations
TL;DR: Efficient solution-phase protocols for the high-throughput synthesis of 6-(1,2,3-triazol-1-yl)-dihydropyrimidones are reported and a library of 27 compounds was prepared with 4 points of diversity.
Abstract: Efficient solution-phase protocols for the high-throughput synthesis of 6-(1,2,3-triazol-1-yl)-dihydropyrimidones are reported. The multistep sequence involves the initial bromination of dihydropyrimidones precursors (DHPMs, Biginelli compounds) at the C6-methyl position, using a recyclable polymer-supported brominating agent under rapid flow-through conditions (residence time of 1 min). The 6-bromomethyldihydropyrimidone intermediates were subsequently subjected to a microwave-assisted azidation step (25 min), providing the key 6-azidomethyldihydropyrimidone precursors. In the final step of the sequence, the azides were treated with terminal acetylenes under Cu(I) catalysis (azide-acetylene ligation, "click chemistry") to provide the target 6-(1,2,3-triazol-1-yl)-dihydropyrimidones in a regiospecific fashion (1,4-triazoles) in moderate overall yield utilizing controlled microwave irradiation (20 min). In total, a library of 27 compounds was prepared with 4 points of diversity.
127 citations
122 citations
TL;DR: The development of an efficient method for producing libraries of 4-aminoquinolines variant in the side chain portion of the molecule is reported, revealing four potent compounds active against drug-resistant strains.
Abstract: Due to growing problems with drug resistance, there is an outstanding need for new, cost-effective drugs for the treatment of malaria. The 4-aminoquinolines have provided a number of useful antimalarials, and Plasmodium falciparum, the causative organism for the most deadly form of human malaria, is generally slow to develop resistance to these drugs. Therefore, diverse screening libraries of quinolines continue to be useful for antimalarial drug discovery. We report herein the development of an efficient method for producing libraries of 4-aminoquinolines variant in the side chain portion of the molecule. The effects of these substitutions were evaluated by screening this library for activity against P. falciparum, revealing four potent compounds active against drug-resistant strains.
65 citations
TL;DR: This short review of general and rapid methods to monitor the transformation of functional groups present in molecules supported on insoluble supports with an Experimental Section that describes the procedure successfully applied to bead analyses in laboratories.
Abstract: One of the unresolved problems of solid-phase organic synthesis (SPOS) is the availability of general and rapid methods to monitor the transformation of functional groups present in molecules supported on insoluble supports. Color tests, far from providing the ultimate solution, may help in detection (and sometimes in quantification) of different functional groups. In this short review, we have collected most of the methods available and applied in SPOS with an Experimental Section that describes the procedure we have successfully applied to bead analyses in our laboratories.
64 citations
TL;DR: It is shown that the combinatorial approach can reduce the time and effort needed to establish libraries of sensor materials by a factor of at least 1000 and be a promising tool for speeding up the search for new sensor materials.
Abstract: We present a combinatorial approach for development of materials for use in optical gas sensors, with oxygen being used as an exemplary target gas. Combinatorial chemistry is shown to be a promising tool for speeding up the search for new sensor materials. The method is based on the use of various polymers, solvents, indicators, plasticizers, and other additives. Solutions of the respective materials are prepared in appropriate organic solvents, and a robotic station is programmed to mix the components. Spots of the sensing materials are deposited in the wells of glass substrates resembling microtiterplates. After drying off the solvent, the sensor spots are automatically analyzed in a test stand, where they are exposed to a carrier gas containing oxygen in various concentrations. Changes in the decay time of fluorescence of the indicator probes are measured and used (along with sensor response time) as a main criterion for sensor assessment. It is shown that the combinatorial approach can reduce the time and effort needed to establish libraries of sensor materials by a factor of at least 1000. We describe in detail the device for preparation of sensor libraries and for testing the respective materials. The potential of the system is demonstrated for the characterization of optical oxygen sensors.
63 citations
TL;DR: A novel and highly diverse tagged triazine library incorporating a triethylene glycol-based linker was synthesized using an orthogonal combinatorial approach on the solid phase and covalently immobilized on a glass substrate as a small molecule microarray (SMM).
Abstract: A novel and highly diverse tagged triazine library incorporating a triethylene glycol-based linker was synthesized using an orthogonal combinatorial approach on the solid phase and covalently immobilized on a glass substrate as a small molecule microarray (SMM) The SMM was screened with a fluorophore-conjugated human IgG, and 4 novel binders from a library of 2688 compounds were identified from the fully spatially addressable array without the need for compound decoding Using surface plasmon resonance (SPR) analysis, binding seen on the array was confirmed, and a binding constant as low as Kd = 202 × 10-6 M was measured
62 citations
TL;DR: Materials possessing gradients in composition or structure are of interest for a range of applications, including the construction of functionally graded structural materials, as novel sensor and actuator platforms, and to control the site-specific binding of proteins and cells on surfaces.
Abstract: Materials possessing gradients in composition or structure are of interest for a range of applications, including the construction of functionally graded structural materials, as novel sensor and actuator platforms, and to control the site-specific binding of proteins and cells on surfaces. Gradients can also be used as sample libraries for combinatorial materials discovery that present an extremely dense sample set.
60 citations
TL;DR: This work demonstrates the versatility of encoded libraries for preparing a large number of analogues of a given hit while simultaneously generating a large collection of compounds for screening against other targets.
Abstract: The design, synthesis, characterization, and screening of a large, encoded thiazolidinone library are described. Three sets of 35 building blocks were combined by encoded split-pool synthesis to give a library containing more than 42 000 members. Building block selection was based in part on a novel small molecule follicle stimulating hormone receptor agonist hit and in part for diversity. HPLC/MS techniques were applied at the single-bead level to build confidence in the reliability of library construction. Application of two distinct screening strategies resulted in the identification of compounds with significantly improved potency over the initial hit. This work demonstrates the versatility of encoded libraries for preparing a large number of analogues of a given hit while simultaneously generating a large collection of compounds for screening against other targets.
TL;DR: In this paper, various methods for fraction collection in high-throughput chromatography are discussed, and a logical AND combination of UV- and mass-triggered collection is shown for three examples.
Abstract: In this paper, we discuss various methods for fraction collection in high-throughput chromatography. UV-triggered fractionation allows precise cutting of peaks. However, valuable fraction collector space is wasted, because many undesired compounds are collected. In mass-triggered fraction collection, the collector space is used more efficiently, because only peaks containing the desired products are collected. Unfortunately, mass peaks are broader than UV peaks, and therefore, fractions contaminated by a closely following peak are often collected. This can be avoided if the collection in preparative LC/MS occurs by a logical AND combination of UV- and mass-triggered collection. The success of this optimal collection mode is shown for three examples.
TL;DR: Palladium-catalyzed carbonylation, which was based on a ligand exchange reaction, efficiently converted immobilized aryl halides to amides under mild reaction conditions using molybdenum hexacarbonyl [Mo(CO)(6)] as the carbon monoxide source.
Abstract: Palladium-catalyzed carbonylation, which was based on a ligand exchange reaction, efficiently converted immobilized aryl halides to amides under mild reaction conditions using molybdenum hexacarbonyl [Mo(CO)6] as the carbon monoxide source. The method easily operates without irradiating with microwaves and yields a wide range of highly pure amides after cleaving from the resin. The method could also be applied to the carbonylation of immobilized amines with aryl halides and to construct heterocyclic systems via a carbonylative cyclization.
TL;DR: Parallel synthesis of an N-alkylated dihydropteridinone library has been accomplished in five steps starting from two displacement reactions of 4,6-dichloro-5-nitropyrimidine, first with fluorous amino acids, then with secondary amines.
Abstract: Parallel synthesis of an N-alkylated dihydropteridinone library has been accomplished in five steps starting from two displacement reactions of 4,6-dichloro-5-nitropyrimidine, first with fluorous amino acids, then with secondary amines. The hydrogenation of the nitro group followed by microwave-assisted cyclization gave the dihydropteridinones. Further diversification was achieved by the reaction of dihydropteridinones with benzyl halides to afford mono-N-alkylated products. All the reaction intermediates and final products were purified by SPE or precipitation without the need to perform chromatography.
TL;DR: A diverse set of 16 high-throughput organic synthesis libraries, consisting of 48 samples per library, has been purified by both preparative supercritical fluid chromatography and preparative high-performance liquid chromatography.
Abstract: A diverse set of 16 high-throughput organic synthesis libraries, consisting of 48 samples per library, has been purified by both preparative supercritical fluid chromatography (SFC) and preparative high-performance liquid chromatography (HPLC). This paper details the relative effectiveness of these two purification techniques in terms of success, yield, and purity of final product.
TL;DR: A novel mask design for the combinatorial synthesis of a ternary composition spreads library, which allows such libraries to be deposited through a series of simple masks on a rotatable mount, which eliminates the use of complicated actuation of a heated substrate.
Abstract: We report on a novel mask design for the combinatorial synthesis of a ternary composition spreads library, which allows such libraries to be deposited through a series of simple masks on a rotatabl...
TL;DR: A new protein-ligand binding assay that is amenable to high-throughput screening applications and can be used to efficiently screen peptide ligands in a model combinatorial library for binding to a model protein system, the S-protein.
Abstract: Here, we describe a new protein−ligand binding assay that is amenable to high-throughput screening applications. The assay involves the use of SUPREX (stability of unpurified proteins from rates of H/D exchange), a new H/D exchange and mass spectrometry-based technique we recently developed for the quantitative analysis of protein−ligand binding interactions. As part of this work, we describe a new high-throughput SUPREX protocol, and we demonstrate that this protocol can be used to efficiently screen peptide ligands in a model combinatorial library for binding to a model protein system, the S-protein. The high-throughput SUPREX protocol developed here is generally applicable to a wide variety of protein ligands, including DNA, small molecules, metals, and other proteins. On the basis of the results of the model study in this work, one person with access to one MALDI mass spectrometer should be able to screen ∼10 000 compounds per 24-h period using the protocol described here. With full automation and the...
TL;DR: This work has shown that C2-symmetrical bisoxazolines have been found to be very valuable for a wide range of metal-catalyzed reactions, and thus, much effort has been devoted to the creation of superior bis oxazoline-based ligands by varying amino alcohols, bridging linkers, 5 or backbones.
Abstract: Combinatorial chemistry offers the premise of increasing the efficiency to discover new catalysts for asymmetric transformations. 1 In this context, rapid construction of diverse chiral ligands with different activities and selectivities is one of the most important issues. 2 C2-symmetrical bisoxazolines have been found to be very valuable for a wide range of metal-catalyzed reactions, 3 and thus, much effort has been devoted to the creation of superior bisoxazoline-based ligands by varying amino alcohols, 4 bridging linkers, 5 or backbones, 6
TL;DR: Polystyrene-Supported Phosphine Catalyzed Aza-Baylis-Hillman Reactions and the Relationship Between Resin Loading Level and Catalyst Efficiency
Abstract: Polystyrene-Supported Phosphine Catalyzed Aza-Baylis-Hillman Reactions and the Relationship Between Resin Loading Level and Catalyst Efficiency Lin-Jing Zhao, Helen Song He, Min Shi,* and Patrick H. Toy* School of Chemistry & Pharmaceutics, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, People’s Republic of China, State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China, and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of China mshi@pub.sioc.ac.cn and phtoy@hku.hk
TL;DR: FTIR spectroscopy in reflection mode combined with a focal plane array (FPA) detector was employed for high-throughput screening of activity of catalysts in n-pentane hydroisomerization by using the reflection setup, and a higher degree of parallelization was possible.
Abstract: FTIR spectroscopy in reflection mode combined with a focal plane array (FPA) detector was employed for high-throughput screening of activity of catalysts in n-pentane hydroisomerization. The reactor system was evaluated using reference catalysts Pt-MOR and γ-alumina of known catalytic activity. By using the reflection setup, a higher degree of parallelization was possible, as compared to previous reports, in which transmission cells had been used. The 49-channel parallel reactor in combination with the FPA-IR optical setup was able to provide reliable information about the activity of different catalysts with relative data error of less than ±20%.
TL;DR: A 192-member library was designed and successfully constructed on the basis of the natural products tyrocidines, streptocidins, and loloatins to increase the therapeutic indices of these antibiotics to find promising leads for drug development against drug-resistant bacteria.
Abstract: A previously developed method for cyclic peptide synthesis was demonstrated to be able to provide convenient access to large combinatorial libraries of analogues, and this methodology was applied to the optimization of natural product cyclic decapeptides. Using this method, a 192-member library was designed and successfully constructed on the basis of the natural products tyrocidines, streptocidins, and loloatins to increase the therapeutic indices of these antibiotics. Library screening identified nine analogues whose therapeutic indices were increased by up to 90-fold in comparison to the natural products. Three of these analogues showed significant increase in antibacterial potency and concurrent drastic decrease in hemolytic activity. Since the natural products target the bacterial cell wall, the newly discovered analogues are promising leads for drug development against drug-resistant bacteria.
UCB1
TL;DR: Using Kobayashi's modification of the Grieco reaction, diverse 4-phenylthio-1,2,3,4-tetrahydroquinolines are synthesized, which possess potentially interesting VLA-4 antagonist properties.
Abstract: Using Kobayashi's modification of the Grieco reaction, we were able to synthesize diverse 4-phenylthio-1,2,3,4-tetrahydroquinolines. These intermediates were oxidized and subsequently pyrolized to provide the corresponding quinolines. This new approach to 2-substituted quinolines was exemplified by liquid-phase production of a 25-member library. This was extended to solid-phase chemistry, starting from (l)-4-nitrophenylalanine on Wang resin, for production of a 16-member library. The latter compounds possess potentially interesting VLA-4 antagonist properties.
TL;DR: It was found that highly basic reaction conditions favor the reaction with the exception of Cu(TMEDA), which is active at a lower pH range, and under optimized conditions, Cu(DAPHEN) catalyzes the transformation of veratryl alcohol to the corresponding aldehyde with 100% conversion.
Abstract: A simple and efficient parallel screening method to evaluate the catalytic activities of homogeneous copper complexes for the oxidation of benzylic alcohols in aqueous solutions with molecular oxygen is reported Copper(II) sulfate was treated in situ with 22 nitrogen donor ligands, and the catalytic activities of these combinations were studied at four different pH values with two substrates (benzyl alcohol and 3,4-dimethoxy benzyl alcohol (veratryl alcohol)), resulting in 176 oxidation experiments in the primary screening stage Copper complexes based on N,N,N',N'-tetramethyl ethylenediamine (TMEDA), 9,10-diaminephenanthrene (DAPHEN), and 1,2-diaminocyclohexane (DACH) were determined to be the most active catalysts In the second screenings, the influence of reaction conditions on Cu(DACH)-, Cu(TMEDA)-, and Cu(DAPHEN)-catalyzed reactions were investigated in more detail It was found that highly basic reaction conditions favor the reaction with the exception of Cu(TMEDA), which is active at a lower pH r
TL;DR: A furanose sugar amino acid has been utilized as a library scaffold for the first time and the novel amide formation was achieved in good yield and purity with high structural confidence.
Abstract: A furanose sugar amino acid (SAA) has been utilized as a library scaffold for the first time. Two furanose SAA scaffolds were examined to illustrate their potential for derivatization. The resulting 99-member library contained three orthogonal points of diversification that allowed easy access to ethers and carbamates from a hydroxyl moiety, a range of ureas from an azide (via an amine), and a range of amides from a methyl ester. The novel amide formation (by displacement of the methoxide from the methyl ester moiety) was achieved in good yield and purity with high structural confidence. Full characterization of several library intermediates (including a crystal structure) was obtained. The library was submitted for antibacterial screening.
TL;DR: A high-throughput purification system to purify combinatorial libraries at a 50-100-mg scale with a throughput of 250 samples/instrument/day is developed with an accelerated retention window method to shorten the purification time and targeted one fraction per injection to simplify data tracking, lower QC workload, and simplify the postpurification processing.
Abstract: We have developed a high-throughput purification system to purify combinatorial libraries at a 50−100-mg scale with a throughput of 250 samples/instrument/day. We applied an accelerated retention window method to shorten the purification time and targeted one fraction per injection to simplify data tracking, lower QC workload, and simplify the postpurification processing. First, we determined the accurate retention time and peak height for all compounds using an eight-channel parallel LC/UV/MS system, and calculated the specific preparative HPLC conditions for individual compounds. The preparative HPLC conditions include the compound-specific gradient segment for individual compounds with a fixed gradient slope and the compound-specific UV or ELSD threshold for triggering a fraction collection device. A unique solvent composition or solvent strength was programmed for each compound in the preparative HPLC in order to elute all compounds at the same target time. Considering the possible deviation of the pr...
TL;DR: The DNPH test was demonstrated for poly(ethylene glycol)-polystyrene, aminomethyl polystyrene (AMP), cross-linked ethoxylate acrylate resin (CLEAR), and acryloylated O,O'-bis(2-aminopropyl)poly(ethylenes glycol) (PEGA) supports and gave results visible to the naked eye at levels as low as 18 micromol of aldehyde per gram of
Abstract: A simple and rapid method to achieve colorimetric monitoring of resin-bound aldehydes, based on ambient temperature reaction with 2,4-dinitrophenylhydrazine (DNPH) in the presence of dilute acid, has been developed as an adjunct to solid-phase organic synthesis and combinatorial chemistry. By this test, the presence of aldehydes is indicated by a red to dark-orange appearance, within a minute. Alternatively, resins that are free of aldehydes or in which aldehyde functions have reacted completely retain their original color. The DNPH test was demonstrated for poly(ethylene glycol)−polystyrene (PEG−PS), aminomethyl polystyrene (AMP), cross-linked ethoxylate acrylate resin (CLEAR), and acryloylated O,O‘-bis(2-aminopropyl)poly(ethylene glycol) (PEGA) supports and gave results visible to the naked eye at levels as low as 18 μmol of aldehyde per gram of resin.
TL;DR: A resin capture and release strategy for making a combinatorial array of 2,4,5-trisubstituted pyrimidines is demonstrated by capturing beta-ketoesters and Beta-ketoamides on a solid-supported piperazine.
Abstract: A resin capture and release strategy for making a combinatorial array of 2,4,5-trisubstituted pyrimidines is demonstrated by capturing β-ketoesters and β-ketoamides on a solid-supported piperazine. Through a cyclocondensation reaction, the solid-supported enaminone is reacted with several guanidines under heating or microwave irradiation affording the corresponding pyrimidines in good yield and chemical purity directly on solution. After this final step, the support can be effectively recycled.