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Organic chemistry. A data-intensive approach to mechanistic elucidation applied to chiral anion catalysis.

ABSTRACT: Knowledge of chemical reaction mechanisms can facilitate catalyst optimization, but extracting that knowledge from a complex system is often challenging. Here, we present a data-intensive method for deriving and then predictively applying a mechanistic model of an enantioselective organic reaction. As a validating case study, we selected an intramolecular dehydrogenative C-N coupling reaction, catalyzed by chiral phosphoric acid derivatives, in which catalyst-substrate association involves weak, noncovalent interactions. Little was previously understood regarding the structural origin of enantioselectivity in this system. Catalyst and substrate substituent effects were probed by means of systematic physical organic trend analysis. Plausible interactions between the substrate and catalyst that govern enantioselectivity were identified and supported experimentally, indicating that such an approach can afford an efficient means of leveraging mechanistic insight so as to optimize catalyst design.

SUBMITTER: Milo A

PROVIDER: S-EPMC4465137 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Organic chemistry. A data-intensive approach to mechanistic elucidation applied to chiral anion catalysis.

Milo Anat A Neel Andrew J AJ Toste F Dean FD Sigman Matthew S MS

Science (New York, N.Y.) 20150201 6223

Knowledge of chemical reaction mechanisms can facilitate catalyst optimization, but extracting that knowledge from a complex system is often challenging. Here, we present a data-intensive method for deriving and then predictively applying a mechanistic model of an enantioselective organic reaction. As a validating case study, we selected an intramolecular dehydrogenative C-N coupling reaction, catalyzed by chiral phosphoric acid derivatives, in which catalyst-substrate association involves weak, ...[more]

PMID: 25678656

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Project description:OBJECTIVE:Recent innovations in biology are boosting gene and cell therapy, but monitoring the response to these treatments is difficult. The purpose of this study was to find an MRI-reporter gene that can be used to monitor gene or cell therapy and that can be delivered without a viral vector, as viral vector delivery methods can result in long-term complications. MATERIALS AND METHODS:CMV promoter-human organic anion transporting polypeptide 1B3 (CMV-hOATP1B3) cDNA or CMV-blank DNA (control) was transfected into HEK293 cells using Lipofectamine. OATP1B3 expression was confirmed by western blotting and confocal microscopy. In vitro cell phantoms were made using transfected HEK293 cells cultured in various concentrations of gadoxetic acid for 24 hours, and images of the phantoms were made with a 9.4T micro-MRI. In vivo xenograft tumors were made by implanting HEK293 cells transfected with CMV-hOATP1B3 (n = 4) or CMV-blank (n = 4) in 8-week-old male nude mice, and MRI was performed before and after intravenous injection of gadoxetic acid (1.2 ?L/g). RESULTS:Western blot and confocal microscopy after immunofluorescence staining revealed that only CMV-hOATP1B3-transfected HEK293 cells produced abundant OATP1B3, which localized at the cell membrane. OATP1B3 expression levels remained high through the 25th subculture cycle, but decreased substantially by the 50th subculture cycle. MRI of cell phantoms showed that only the CMV-hOATP1B3-transfected cells produced a significant contrast enhancement effect. In vivo MRI of xenograft tumors revealed that only CMV-hOATP1B3-transfected HEK293 tumors demonstrated a T1 contrast effect, which lasted for at least 5 hours. CONCLUSION:The human endogenous OATP1B3 gene can be non-virally delivered into cells to induce transient OATP1B3 expression, leading to gadoxetic acid-mediated enhancement on MRI. These results indicate that hOATP1B3 can serve as an MRI-reporter gene while minimizing the risk of long-term complications.

Dataset Information

Organic chemistry. A data-intensive approach to mechanistic elucidation applied to chiral anion catalysis.

Publications

Organic chemistry. A data-intensive approach to mechanistic elucidation applied to chiral anion catalysis.

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