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Maurizio Taddei - One of the best experts on this subject based on the ideXlab platform.
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solution phase synthesis of mixed amide libraries by simultaneous addition of functionalities spsaf to a diketopiperazine tetracarboxylic acid scaffold monitored by gc analysis of isobutyl alcohol
European Journal of Organic Chemistry, 2000Co-Authors: Massimo Falorni, Giampaolo Giacomelli, Andrea Porcheddu, Maurizio TaddeiAbstract:A symmetric diketopiperazine scaffold 2 has been prepared in a very simple two-step procedure from L-aspartic acid dimethyl ester. This product (a tetracarboxylic acid equally protected at the two symmetric positions) has been employed as a template for the synthesis of mixed amide libraries in the solution phase using the SPSAF (simultaneous addition of functionalities) strategy. By judicious choice of the amines employed, it is possible to prepare parallel libraries containing hundreds of products using just a small number of different amines. We have also developed a simple method for monitoring the required conversion of the acid into amides based on an assay of the amount of iBuOH (determined by GC) formed during the coupling mediated by isobutyl chloroformate. We have observed that a conversion higher than 90% (iBuOH by GC) guarantees correct formation of the desired amides. This indirect method for assessing the conversion in a Combinatorial Reaction employing mixed reactants (SPSAF) can conveniently be used for the routine determination of libraries prepared in the solution phase. In a broader perspective, the present results contribute as a further step in the development of new and simple systems for monitoring the progress and evolution of Combinatorial Reactions
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Solution‐Phase Synthesis of Mixed Amide Libraries by Simultaneous Addition of Functionalities (SPSAF) to a Diketopiperazine Tetracarboxylic Acid Scaffold Monitored by GC Analysis of Isobutyl Alcohol
European Journal of Organic Chemistry, 2000Co-Authors: Massimo Falorni, Giampaolo Giacomelli, Andrea Porcheddu, Maurizio TaddeiAbstract:A symmetric diketopiperazine scaffold 2 has been prepared in a very simple two-step procedure from L-aspartic acid dimethyl ester. This product (a tetracarboxylic acid equally protected at the two symmetric positions) has been employed as a template for the synthesis of mixed amide libraries in the solution phase using the SPSAF (simultaneous addition of functionalities) strategy. By judicious choice of the amines employed, it is possible to prepare parallel libraries containing hundreds of products using just a small number of different amines. We have also developed a simple method for monitoring the required conversion of the acid into amides based on an assay of the amount of iBuOH (determined by GC) formed during the coupling mediated by isobutyl chloroformate. We have observed that a conversion higher than 90% (iBuOH by GC) guarantees correct formation of the desired amides. This indirect method for assessing the conversion in a Combinatorial Reaction employing mixed reactants (SPSAF) can conveniently be used for the routine determination of libraries prepared in the solution phase. In a broader perspective, the present results contribute as a further step in the development of new and simple systems for monitoring the progress and evolution of Combinatorial Reactions
Heinz Koeppl - One of the best experts on this subject based on the ideXlab platform.
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Markov chain aggregation and its applications to Combinatorial Reaction networks
Journal of Mathematical Biology, 2014Co-Authors: Arnab Ganguly, Tatjana Petrov, Heinz KoepplAbstract:We consider a continuous-time Markov chain (CTMC) whose state space is partitioned into aggregates, and each aggregate is assigned a probability measure. A sufficient condition for defining a CTMC over the aggregates is presented as a variant of weak lumpability, which also characterizes that the measure over the original process can be recovered from that of the aggregated one. We show how the applicability of de-aggregation depends on the initial distribution. The application section is devoted to illustrate how the developed theory aids in reducing CTMC models of biochemical systems particularly in connection to protein-protein interactions. We assume that the model is written by a biologist in form of site-graph-rewrite rules. Site-graph-rewrite rules compactly express that, often, only a local context of a protein (instead of a full molecular species) needs to be in a certain configuration in order to trigger a Reaction event. This observation leads to suitable aggregate Markov chains with smaller state spaces, thereby providing sufficient reduction in computational complexity. This is further exemplified in two case studies: simple unbounded polymerization and early EGFR/insulin crosstalk.
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approximate model reductions for Combinatorial Reaction systems
European Control Conference, 2013Co-Authors: Tatjana Petrov, Heinz KoepplAbstract:The paper considers a model reduction technique that is well-suited for biochemical Reaction systems giving rise to the assembly of a large number of different molecular species. The reduction is performed by grouping species with common properties, directly from the model specification in terms of a rule-based language. In recent works, general algorithms for the exact reductions of rule-based models were established, but the state space often remains Combinatorial. We extend this line of research by introducing approximate reductions, and an error measure which allows us to quantitatively study the effect of approximate model reductions.
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Markov chain aggregation and its applications to Combinatorial Reaction networks
arXiv: Discrete Mathematics, 2013Co-Authors: Arnab Ganguly, Tatjana Petrov, Heinz KoepplAbstract:We consider a continuous-time Markov chain (CTMC) whose state space is partitioned into aggregates, and each aggregate is assigned a probability measure. A sufficient condition for defining a CTMC over the aggregates is presented as a variant of weak lumpability, which also characterizes that the measure over the original process can be recovered from that of the aggregated one. We show how the applicability of de-aggregation depends on the initial distribution. The application section is a major aspect of the article, where we illustrate that the stochastic rule-based models for biochemical Reaction networks form an important area for usage of the tools developed in the paper. For the rule-based models, the construction of the aggregates and computation of the distribution over the aggregates are algorithmic. The techniques are exemplified in three case studies.
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ECC - Approximate model reductions for Combinatorial Reaction systems
2013 European Control Conference (ECC), 2013Co-Authors: Tatjana Petrov, Heinz KoepplAbstract:The paper considers a model reduction technique that is well-suited for biochemical Reaction systems giving rise to the assembly of a large number of different molecular species. The reduction is performed by grouping species with common properties, directly from the model specification in terms of a rule-based language. In recent works, general algorithms for the exact reductions of rule-based models were established, but the state space often remains Combinatorial. We extend this line of research by introducing approximate reductions, and an error measure which allows us to quantitatively study the effect of approximate model reductions.
Massimo Falorni - One of the best experts on this subject based on the ideXlab platform.
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solution phase synthesis of mixed amide libraries by simultaneous addition of functionalities spsaf to a diketopiperazine tetracarboxylic acid scaffold monitored by gc analysis of isobutyl alcohol
European Journal of Organic Chemistry, 2000Co-Authors: Massimo Falorni, Giampaolo Giacomelli, Andrea Porcheddu, Maurizio TaddeiAbstract:A symmetric diketopiperazine scaffold 2 has been prepared in a very simple two-step procedure from L-aspartic acid dimethyl ester. This product (a tetracarboxylic acid equally protected at the two symmetric positions) has been employed as a template for the synthesis of mixed amide libraries in the solution phase using the SPSAF (simultaneous addition of functionalities) strategy. By judicious choice of the amines employed, it is possible to prepare parallel libraries containing hundreds of products using just a small number of different amines. We have also developed a simple method for monitoring the required conversion of the acid into amides based on an assay of the amount of iBuOH (determined by GC) formed during the coupling mediated by isobutyl chloroformate. We have observed that a conversion higher than 90% (iBuOH by GC) guarantees correct formation of the desired amides. This indirect method for assessing the conversion in a Combinatorial Reaction employing mixed reactants (SPSAF) can conveniently be used for the routine determination of libraries prepared in the solution phase. In a broader perspective, the present results contribute as a further step in the development of new and simple systems for monitoring the progress and evolution of Combinatorial Reactions
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Solution‐Phase Synthesis of Mixed Amide Libraries by Simultaneous Addition of Functionalities (SPSAF) to a Diketopiperazine Tetracarboxylic Acid Scaffold Monitored by GC Analysis of Isobutyl Alcohol
European Journal of Organic Chemistry, 2000Co-Authors: Massimo Falorni, Giampaolo Giacomelli, Andrea Porcheddu, Maurizio TaddeiAbstract:A symmetric diketopiperazine scaffold 2 has been prepared in a very simple two-step procedure from L-aspartic acid dimethyl ester. This product (a tetracarboxylic acid equally protected at the two symmetric positions) has been employed as a template for the synthesis of mixed amide libraries in the solution phase using the SPSAF (simultaneous addition of functionalities) strategy. By judicious choice of the amines employed, it is possible to prepare parallel libraries containing hundreds of products using just a small number of different amines. We have also developed a simple method for monitoring the required conversion of the acid into amides based on an assay of the amount of iBuOH (determined by GC) formed during the coupling mediated by isobutyl chloroformate. We have observed that a conversion higher than 90% (iBuOH by GC) guarantees correct formation of the desired amides. This indirect method for assessing the conversion in a Combinatorial Reaction employing mixed reactants (SPSAF) can conveniently be used for the routine determination of libraries prepared in the solution phase. In a broader perspective, the present results contribute as a further step in the development of new and simple systems for monitoring the progress and evolution of Combinatorial Reactions
Jonathan S. Lindsey - One of the best experts on this subject based on the ideXlab platform.
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Complexity in structure-directed prebiotic chemistry. Unexpected compositional richness from competing reactants in tetrapyrrole formation
New Journal of Chemistry, 2016Co-Authors: Richard M. Deans, Ana R. M. Soares, Masahiko Taniguchi, Vanampally Chandrashaker, Marcin Ptaszek, Dana R. Chambers, Jonathan S. LindseyAbstract:Robustness is a key feature of any credible prebiotic Reaction process. Two studies are presented concerning the role of analogous yet defective reactants (spanning a range of reactivity) in a model for the prebiogenesis of tetrapyrrole macrocycles in aqueous solution under mild conditions. The Reaction entails condensation of an α-aminoketone (e.g., δ-aminolevulinic acid) with a 1,5-dimethoxypentan-2,4-dione bearing a 3-acetic acid unit (β-diketone 1-AcOH) to form a porphobilinogen analogue, which self-condenses to form a mixture of porphyrinogens. Here, the inclusion of an analogous β-diketone lacking the acetic acid substituent (1,5-dimethoxypentan-2,4-dione, 1-H) formed a partially defective (weakly reactive) pyrrole, which upon Combinatorial Reaction with the normal pyrrole (derived from 1-AcOH) severely crimped the yield of the latter yet all porphyrinogens derivable from both β-diketones 1-H and 1-AcOH were observed upon mass spectrometric analysis. Detection of the porphyrinogens by mass spectrometry revealed a compositional richness beneath the limits of detection by routine absorption spectroscopy. A similar Reaction of 1-amino-2-butanone and 1,5-dimethoxy-3-methylpentan-2,4-dione in aqueous micelles leading to etioporphyrinogens was examined in the presence of four β-diketones. Linear offsets of yield as well as Combinatorial inhibition were observed depending on the dione structure. Taken together, the results provide a nuanced, quantitative view of the effects of reactant analogues in a chemical model of a structure-directed prebiotic process. The adverse effects of such reactant analogues provide a cautionary tale about the viability of structure-directed processes as a sole means for creation of architecturally complex molecules in a primordial broth.
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expanded Combinatorial formation of porphyrin macrocycles in aqueous solution containing vesicles a prebiotic model
New Journal of Chemistry, 2013Co-Authors: Ana R. M. Soares, Masahiko Taniguchi, Vanampally Chandrashaker, Jonathan S. LindseyAbstract:The role of Combinatorial processes in the origin of life remains relatively unexplored. In a chemical model for the possible prebiogenesis of tetrapyrrole macrocycles reported previously, a tandem Combinatorial Reaction of two diones (substituents = methyl, acetic acid) and two aminoketones (substituents = ethyl, propanoic acid) afforded up to 538 porphyrins (upon oxidation of the corresponding porphyrinogens). The Reaction was performed at a 1 : 1 ratio of hydrophobic and hydrophilic substituents in each pool of reactants, and the resulting porphyrins partitioned in ∼1 : 1 ratio between aqueous solution and phosphatidylcholine vesicle membranes. Here, a change in the ratio of hydrophobic and hydrophilic substituents of the [2 × 2] Reaction gave corresponding changes in the polarity profile of the resulting porphyrins (3.5–9.0% yield). Reaction of four diones and four aminoketones (bearing hydrophilic or hydrophobic substituents) in the presence of lipid vesicles followed by photooxidation afforded porphyrins in 8.7% yield. The resulting porphyrins partitioned in ∼1 : 1 ratio between phosphatidylcholine vesicles and aqueous solution, as observed previously for the [2 × 2] Reaction. Both the aqueous fraction and the vesicles fraction were photochemically active as evidenced by the fluorescence quantum yield (Φf ∼ 0.1). Software (PorphyrinViLiGe) for virtual library generation indicates that the [4 × 4] Reaction affords up to 131 464 porphyrins. The relative insensitivity of physicochemical properties (partitioning, photoactivity) toward Combinatorial expansion may be a valuable yet unappreciated attribute for prebiotic functionality.
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Self-organization of tetrapyrrole constituents to give a photoactive protocell
Chemical Science, 2012Co-Authors: Ana R. M. Soares, Masahiko Taniguchi, Vanampally Chandrashaker, Jonathan S. LindseyAbstract:A tandem Combinatorial Reaction of four acyclic, colorless compounds (two α-aminoketones and two diones; one polar and one nonpolar for each) in aqueous solution (30 mM each, 60 °C, pH 7, 24 h) containing lipid vesicles and with or without quinones and solar illumination affords a distribution of up to 538 porphyrins in 1.6–3.9% overall yield. The Reactions leading to the porphyrins can occur in either or both the aqueous phase and the hydrophobic membrane of the vesicles. The porphyrins encompass a broad range of polarity and partition in the aqueous-lipid medium. Two fractions obtained by size-exclusion chromatography include porphyrins associated with the lipid vesicles and porphyrins in the aqueous phase. The porphyrins in both phases are photoactive as demonstrated by fluorescence quantum yield measurements (Φf ∼ 0.07–0.08) and by the Krasnovsky Reaction (a photosynthetic-like process). The constituents of the Krasnovsky Reaction employed here are methyl red, ascorbic acid, and 2,6-dichlorophenolindophenol. Illumination of the two porphyrin-containing samples (aqueous phase or vesicles) in the presence of the Krasnovsky constituents results in the reduction of methyl red and oxidation of ascorbic acid. Thus, the overall process transforms a colorless aqueous suspension via four stages (two Combinatorial Reactions, oxidation, physical partitioning) to photoactive porphyrins in distinct venues. The process may provide a model for the origin of pigments that enable proto-photosynthesis.
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A tandem Combinatorial model for the prebiogenesis of diverse tetrapyrrole macrocycles
New Journal of Chemistry, 2012Co-Authors: Masahiko Taniguchi, Ana R. M. Soares, Vanampally Chandrashaker, Jonathan S. LindseyAbstract:The extant biosynthesis of tetrapyrrole macrocycles has been considered a paradigm for the prebiotic formation of such molecules, yet only a few analogous non-enzymic Reactions along the overall process have been demonstrated. In a prior study, the aqueous non-enzymic Reaction of a dione and an aminoketone (δ-aminolevulinic acid) afforded uroporphyrinogen, Nature's last universal precursor to all extant tetrapyrroles. Here, in one flask the non-enzymic Combinatorial Reaction of two diones (substituents = acetic acid and methyl) and two aminoketones (substituents = propionic acid and ethyl) yields four pyrroles, which upon subsequent Combinatorial Reaction afford a distribution of porphyrinogens. A software program for virtual library generation predicts 538 porphyrinogens from this [2 × 2] Reaction (owing to combinations and permutations) of which there are 25 sets of isomers based on condensed formulas of substituents. The collection spans the entire range of polarity enabled by the biosynthesis including uro- (number of carboxylic acids = 8), copro- (4), meso- (2), and etio-porphyrinogen (0). The first two are successive intermediates in the extant biosynthesis, the latter two resemble in polarity the advanced biosynthetic products protoporphyrin and chlorophyll. Upon consideration of substituent patterns, the porphyrins (obtained by oxidation of the porphyrinogens) can be grouped into one of four polarity categories (predicted percentage): hydrophilic (0.4%), uncertain (83.6%), amphiphilic (15.6%), and hydrophobic (0.4%). HPLC and mass spectrometry data are consistent with expectations to the limit of analytical capabilities. Thus, in terms of the polarity of the tetrapyrrole macrocycles formed, an all-at-once non-enzymic Combinatorial process recapitulates features of the stepwise biosynthetic pathway.
Arasu Ganesan - One of the best experts on this subject based on the ideXlab platform.
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the n acyliminium pictet spengler condensation as a multicomponent Combinatorial Reaction on solid phase and its application to the synthesis of demethoxyfumitremorgin c analogues
Organic Letters, 1999Co-Authors: Haishan Wang And, Arasu GanesanAbstract:l-Tryptophan immobilized on polystyrene−Wang resin was sequentially reacted with an aldehyde and Fmoc-amino acid chloride. This generates a transient N-acyliminium species which undergoes Pictet−Spengler condensation to give a mixture of cis and trans tetrahydro-β-carbolines. Removal of the Fmoc protecting group, with concomitant diketopiperazine formation, results in cyclative cleavage of the desired products from the resin.
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The N-Acyliminium Pictet−Spengler Condensation as a Multicomponent Combinatorial Reaction on Solid Phase and Its Application to the Synthesis of Demethoxyfumitremorgin C Analogues
Organic Letters, 1999Co-Authors: Haishan Wang And, Arasu GanesanAbstract:l-Tryptophan immobilized on polystyrene−Wang resin was sequentially reacted with an aldehyde and Fmoc-amino acid chloride. This generates a transient N-acyliminium species which undergoes Pictet−Spengler condensation to give a mixture of cis and trans tetrahydro-β-carbolines. Removal of the Fmoc protecting group, with concomitant diketopiperazine formation, results in cyclative cleavage of the desired products from the resin.