3-Fluoro-2<i>H</i>-azirine: Generation, Characterization, and Photochemistry

Zhu, Bifeng; Zeng, Xiaoqing

doi:10.1021/acs.jpca.3c06076

Cited by 3 publications

(1 citation statement)

References 77 publications

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“…Most computational modeling of this moiety has been performed using electronic structure methods where force fields are not needed, but which cannot characterize the processes at question in this work. [29][30][31][32][33][34] Some studies have used automatic parameter generation without adjustment. 17,[34][35][36] We hope to address the limitations of these studies by avoiding parameter assignment by pure analogy since there are few wellcharacterized and analogous moieties to carboxy-2H-azirines.…”

Section: Figure 2: Two Examples Of Potent Natural Product Antimicrobi...mentioning

confidence: 99%

Employing Metadynamics to Predict the Membrane Partitioning of Carboxy-2H-Azirine Natural Products

Daly,

Seebald,

Wolk

2024

Preprint

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Natural products have diverse chemical structures and biological activities which often serve as sources of new therapeutic agents. Those containing a carboxy-2H-azirine moiety are an exciting target for investigation due in part to the broad-spectrum antimicrobial activity these compounds have and the significant chemical space for novel therapeutic development offered by this unique scaffold. The carboxy-2H-azirine moiety, including those appended to well-characterized chemical scaffolds, is understudied, which creates a challenge for understanding potential modes of inhibition. In particular, some known natural product carboxy-2H-azirines have long hydrophobic tails, which might lead to amphipathicity and implicate them in membrane associated processes. Metadynamics is an effective method for calculating the free energy changes associated with membrane embedding processes. In this study, we examined a small set of carboxy-2H-azirine natural products, including analogs with long alkyl chains, geometric isomers, and one comprising the simple carboxy-2H-azirine core. We compared the physiochemical properties of these compounds to those of established membrane embedders with similar chemical scaffolds. This was intended to isolate the physiochemical properties of the carboxy-2H-azirine group and understand molecular influences of this moiety on membrane partitioning. To accomplish this, we developed a force field for the 2H-azirine functional group and performed metadynamics simulations of the partitioning into a model membrane (75 % POPE, 25 % POPG) from aqueous solution. We determine that the carboxy-2H-azirine functional group is likely hydrophilic, imbuing the long chain analogs with amphipathicity similar to the known membrane binding molecules to which they were compared. For the long chain analogs, the carboxy-2H-azirine headgroup stays within 1 nm of the phosphate layer, while the carboxy-2H-azirines lacking the long alkyl chain partitions completely into aqueous solution.

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Section: Figure 2: Two Examples Of Potent Natural Product Antimicrobi...mentioning

confidence: 99%

Employing Metadynamics to Predict the Membrane Partitioning of Carboxy-2H-Azirine Natural Products

Daly,

Seebald,

Wolk

2024

Preprint

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Flash Vacuum Pyrolysis: Principles, Instrumentation, and Applications

Mahadevan,

Venkataramani

2024

Reson

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Employing Metadynamics to Predict the Membrane Partitioning of Carboxy-2H-Azirine Natural Products

Daly,

Seebald,

Wolk

2024

J. Phys. Chem. B

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Natural products containing the carboxy-2H-azirine moiety are an exciting target for investigation due to their broad-spectrum antimicrobial activity and new chemical space they afford for novel therapeutic development. The carboxy-2H-azirine moiety, including those appended to well-characterized chemical scaffolds, is understudied, which creates a challenge for understanding potential modes of inhibition. In particular, some known natural product carboxy-2H-azirines have long hydrophobic tails, which could implicate them in membrane-associated processes. In this study, we examined a small set of carboxy-2H-azirine natural products with varied structural features that could alter membrane partitioning. We compared the predicted membrane partitioning and alignment of these compounds to those of established membrane embedders with similar chemical scaffolds. To accomplish this, we developed parameters within the framework of the CHARMM36 force field for the 2H-azirine functional group and performed metadynamics simulations of the partitioning into a model bacterial membrane from aqueous solution. We determined that the carboxy-2H-azirine functional group is strongly hydrophilic, imbuing the long-chain natural products with amphipathicity similar to the known membrane-embedding molecules to which they were compared. For the long-chain analogs, the carboxy-2H-azirine head group stays within 1 nm of the phosphate layer, while the hydrophobic tail sits within the membrane. The carboxy-2H-azirine lacking the long alkyl chain instead partitions completely into aqueous solution.

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3-Fluoro-2H-azirine: Generation, Characterization, and Photochemistry

Cited by 3 publications

References 77 publications

Employing Metadynamics to Predict the Membrane Partitioning of Carboxy-2H-Azirine Natural Products

Employing Metadynamics to Predict the Membrane Partitioning of Carboxy-2H-Azirine Natural Products

Flash Vacuum Pyrolysis: Principles, Instrumentation, and Applications

Employing Metadynamics to Predict the Membrane Partitioning of Carboxy-2H-Azirine Natural Products

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