Theoretical Prediction and Explanation of Reaction Site Selectivity in the Addition of a Phenoxy Group to Perfluoropyrimidine, Perfluoropyridazine, and Perfluoropyrazine

Perfluoroaromatics, such as perfluoropyridine and perfluorobenzene, are privileged synthetic scaffolds in organofluorine methodology, undergoing a series of regioselective substitution reactions with a variety of nucleophiles. This unique chemical behavior allows for the synthesis of many perfluoroaromatic derived molecules with unique and diverse architectures. Recently, it has been demonstrated that perfluoropyridine and perfluorobenzene can be utilized as precursors for a variety of materials, ranging from high performance polyaryl ethers to promising drug scaffolds. In this work, using density functional theory, we investigate the possibility of perfluoropyrimidine, perfluoropyridazine, and perfluoropyrazine participating in similar substitution reactions. We have found that the first nucleophilic addition of a phenoxide group substitution on perfluoropyrimidine and on perfluoropyridazine would happen at a site para to one of the nitrogen atoms. While previous literature points to mesomeric effects as the primary cause of this phenomenon, our work demonstrates that this effect is enhanced by the fact that the transition states for these reactions result in bond angles that allow the phenoxide to π-complex with the electron-deficient diazine ring. The second substitution on perfluoropyrimidine and on perfluoropyridazine is most likely to happen at the site para to the other nitrogen. The second substitution on perfluoropyrazine is most likely to happen at the site para to the first substitution. The activation energies for these reactions are in line with those reported for perfluoropyridine and suggest that these platforms may also be worth investigation in the lab as possible monomers for high performance polymers.

Transaminase Catalysis for Enantiopure Saturated Heterocycles as Potential Drug Scaffolds

As efforts in rational drug design are driving the pharmaceutical industry towards more complex molecules, the synthesis and production of these new drugs can benefit from new reaction routes. In addition to the introduction of new centers of asymmetry, complexity can be also increased by ring saturation, which also provides improved developability measures. Therefore, in this report, our aim was to develop transaminase (TA)-catalyzed asymmetric synthesis of a new group of potential chiral drug scaffolds comprising a saturated amine heterocycle backbone and an asymmetric primary amine sidechain (55a–g). We screened the Codex® Amine Transaminase Kit of 24 transaminases with the morpholine containing ketone 57a, resulting in one (R)-selective TA and three (S)-selective TAs operating at 100 mM substrate concentration and 25 v/v% isopropylamine (IPA) content. The optimized reaction conditions were than applied for asymmetric transamination of further six ketones (57b–g) containing various amine heterocycles, in which a strong effect of the substitution pattern of the γ-position relative to the substituted N-atom could be observed. Mediated by the most enantiotope selective (S)-TAs in scaled-up process, the (S)-amines [(S)-55a–g] were isolated with moderate-to-excellent yields (47–94%) in enantiopure form (>99% ee).

Solution NMR and racemic crystallography provide insights into a novel structural class of cyclic plant peptides

Head-to-tail cyclic and disulfide-rich peptides are natural products with applications in drug design. Among these are the PawS-Derived Peptides (PDPs) produced in seeds of the daisy plant family. PDP-23 is a unique member of this class in that it is twice the typical size and adopts two β-hairpins separated by a hinge region. The β-hairpins - both stabilised by a single disulfide bond - fold together into a V-shaped tertiary structure creating a hydrophobic core. In water two PDP-23 molecules merge their hydrophobic cores to form a square prism quaternary structure. Here, we synthesised PDP-23 and its enantiomer comprising all D-amino acids, which allowed us to confirm these solution NMR structural data by racemic crystallography. Furthermore, we discovered the related PDP-24. NMR analysis showed that PDP-24 does not form a dimeric structure and it has poor water solubility, but in less polar solvents adopts near identical secondary and tertiary structure to PDP-23. The natural role of these peptides in plants remains enigmatic, as we did not observe any antimicrobial or insecticidal activity. However, the plasticity of these larger PDPs and their ability to change structure under different conditions makes them appealing peptide drug scaffolds.

Brain-Restricted mTOR Inhibition with Binary Pharmacology

On-target-off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates. In diseases of the central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition of mTOR while sparing mTOR activity elsewhere through the use of a brain-permeable mTOR inhibitor RapaLink-1 and brain-impermeable FKBP12 ligand RapaBlock. We show that this drug combination mitigates the systemic effects of mTOR inhibitors but retains the efficacy of RapaLink-1 in glioblastoma xenografts. We further present a general method to design cell-permeable, FKBP12-dependent kinase inhibitors from known drug scaffolds. These inhibitors are sensitive to deactivation by RapaBlock enabling the brain-restricted inhibition of their respective kinase targets.

Neovascularization Effects of Carbon Monoxide Releasing Drugs Chemisorbed on Coscinodiscus Diatoms Carriers Characterized by Spectromicroscopy Imaging

Silica microparticles made of diatomaceous earth have become particularly attractive materials for designing drug delivery systems. In order to investigate the use of natural diatoms as drug scaffolds for carbon monoxide releasing molecules (CORMs), we evaluated the chemisorption of the cis-[Re(CO)2Br4]2− complex (ReCORM-2) and its vitamin B12 derivative (B12-ReCORM-2) on Coscinodiscus frustules by 3D FT-IR spectroscopic imaging, and the drugs’ neovascularization effects in vivo in the zebrafish (Danio rerio) model. By mapping the symmetric Re-C≡O υ(CO) stretching vibration of the CORMs in the 2000 cm−1 region, we found that the drugs are mostly localized at the girdle band of the diatom frustule. Both ReCORM-2 and B12-ReCORM-2 retain their CO-releasing ability when chemisorbed on the diatoms. When applied in vivo at doses ≥25 µM, the molecules markedly reduced intersegmental and subintestinal vessels development in zebrafish, revealing high anti-angiogenic potential. In addition, diatom frustules did not provoke any toxic in vivo response in the zebrafish embryos, including inflammation. Overall, our results indicate that: (1) CORMs chemisorbed on diatom frustules retain their CO-releasing abilities; (2) both CO-releasing molecules show a concentration-dependent effect on the neovascularization in developing zebrafish; (3) silicate frustules are not toxic and could be used as CORMs drug carriers.