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Diastereoselective synthesis and biological evaluation of enantiomerically pure tricyclic indolines.

ABSTRACT: Tricyclic indolines are common in both natural products and synthetic chemical probes. In this study we demonstrated that enantiomerically pure tricyclic indolines can be prepared from an inexpensive commercially available chiral starting material, pyroglutamic acid. The synthesis features a highly diastereoselective gold-catalyzed cyclization of alkyne-tethered indoles and subsequent diastereoselective reductive ring-opening reaction. Using this approach, we synthesized analogs of our previously discovered tricyclic indoline probes that possess antibacterial and resistance-modifying activity. The biological activity against methicillin-resistant Staphylococcus aureus (MRSA) of these analogues was evaluated and reported. The synthetic approach reported may be leveraged in the future to prepare diastereopure chemical probes for the determination of biological targets for drug discovery.

SUBMITTER: He W

PROVIDER: S-EPMC5518930 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Diastereoselective synthesis and biological evaluation of enantiomerically pure tricyclic indolines.

He W W Griffiths B M BM Wang W W Wang X X

Organic & biomolecular chemistry 20170501 19

Tricyclic indolines are common in both natural products and synthetic chemical probes. In this study we demonstrated that enantiomerically pure tricyclic indolines can be prepared from an inexpensive commercially available chiral starting material, pyroglutamic acid. The synthesis features a highly diastereoselective gold-catalyzed cyclization of alkyne-tethered indoles and subsequent diastereoselective reductive ring-opening reaction. Using this approach, we synthesized analogs of our previousl ...[more]

PMID: 28466945

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Project description:GluN2B subunit-containing N-methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. As part of our PET ligand development program, we have recently reported on the preclinical evaluation of [18F]OF-NB1 - a GluN2B PET ligand with promising attributes for potential clinical translation. However, the further development of [18F]OF-NB1 is currently precluded by major limitations in the radiolabeling procedure. These limitations include the use of highly corrosive reactants and racemization during the radiosynthesis. As such, the aim of this study was to develop a synthetic approach that allows an enantiomerically pure radiosynthesis of (R)-[18F]OF-NB1 and (S)-[18F]OF-NB1, as well as to assess their in vitro and in vivo performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents. A two-step radiosynthesis involving radiofluorination of the boronic acid pinacol ester, followed by coupling to the 3-benzazepine core structure via reductive amination was employed. The new synthetic approach yielded enantiomerically pure (R)-[18F]OF-NB1 and (S)-[18F]OF-NB1, while concurrently circumventing the use of corrosive reactants. In vitro autoradiograms with mouse and rat brain sections revealed a higher selectivity of (R)-[18F]OF-NB1 over (S)-[18F]OFNB1 for GluN2B-rich brain regions. In concert with these observations, blockade studies with commercially available GluN2B antagonist, CP101606, showed a significant signal reduction, which was more pronounced for (R)-[18F]OF-NB1 than for (S)-[18F]OF-NB1. Conversely, blockade experiments with sigma2 ligand, FA10, did not result in a significant reduction of tracer binding for both enantiomers. PET imaging experiments with CD1 mice revealed a higher brain uptake and retention for (R)-[18F]OF-NB1, as assessed by visual inspection and volumes of distribution from Logan graphical analyses. In vivo blocking experiments with sigma2 ligand, FA10, did not result in a significant reduction of the brain signal for both enantiomers, thus corroborating the selectivity over sigma2 receptors. In conclusion, we have developed a novel synthetic approach that is suitable for upscale to human use and allows the enantiomerically pure radiosynthesis of (R)-[18F]OF-NB1 and (S)-[18F]OF-NB1. While both enantiomers were selective over sigma2 receptors in vitro and in vivo, (R)-[18F]OF-NB1 showed superior GluN2B subunit specificity by in vitro autoradiography and higher volumes of distribution in small animal PET studies.

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Diastereoselective synthesis and biological evaluation of enantiomerically pure tricyclic indolines.

Publications

Diastereoselective synthesis and biological evaluation of enantiomerically pure tricyclic indolines.

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