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The Journal of Physical Chemistry. A May 2020The reaction mechanism of the isomerization of α and β-pinene epoxides with Fe species as catalysts was studied with density functional theory (DFT) calculations and...
The reaction mechanism of the isomerization of α and β-pinene epoxides with Fe species as catalysts was studied with density functional theory (DFT) calculations and an experimental methodology. β-pinene epoxide can be isomerized into myrtanal and myrtenol in four steps, while in the case of perillyl alcohol, two additional steps are necessary. On the other hand, high selectivity to myrtanal obtained experimentally can be explained by the number of steps and the kind of the hydrogen transference that is easier for this compound in comparison with myrtenol and perillyl alcohol. A thermodynamic analysis showed that transformation into myrtenol, myrtanal, and perillyl alcohol is spontaneous but transformation into myrtanal is the most favorable. In the case of α-pinene epoxide rearrangement, a mechanistic study was carried out toward the optimization of the possible intermediates. Synthesis of campholenic aldehyde and carveol from α-pinene epoxide was carried out through three steps after the coordination of oxygen to iron, showing that in contrast to carveol formation, campholenic aldehyde synthesis is spontaneous. Analysis of ∇ρ, the total energy density ( = + ), and the ||/ ratio evaluated at the bond critical point of the Fe-O bond showed for both epoxides that such interaction is closed shell instead of covalent. Apparently, α-pinene epoxide can be isomerized faster that β-pinene epoxide with Fe, which is in agreement with previous experimental results. This is the first report where a reaction mechanism of isomerization of monoterpenes epoxides is studied based on very detailed experimental and computational methodologies.
PubMed: 32023051
DOI: 10.1021/acs.jpca.9b09622 -
Journal of Neurosurgery Jun 2024Malignancies of the CNS are difficult to treat because the blood-brain barrier (BBB) prevents most therapeutics from reaching the intracranial lesions at sufficiently...
OBJECTIVE
Malignancies of the CNS are difficult to treat because the blood-brain barrier (BBB) prevents most therapeutics from reaching the intracranial lesions at sufficiently high concentrations. This also applies to chimeric antigen receptor (CAR) T cells, for which systemic delivery is inferior to direct intratumoral or intraventricular injection of the cells. The authors previously reported on a novel approach to safely and reversibly open the BBB of mice by applying intra-arterial (IA) injections of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol. The authors hypothesized that this method would enable enhanced brain entry and therapeutic activity of intravenously delivered CAR T cells, which the authors tested in a mouse model of CNS lymphoma.
METHODS
Human Raji lymphoma cells were implanted into the brains of immune-deficient mice. After tumor uptake was confirmed with bioluminescent imaging, 0.3% NEO100 was injected intra-arterially, which was followed by intravenous (IV) delivery of CD19-targeted CAR T cells. After this single intervention, tumor growth was monitored with imaging, long-term survival of mice was recorded, and select mice were euthanized to analyze the distribution of CAR T cells in brain tissue.
RESULTS
Intravenously injected CAR T cells could be readily detected in brain tumor areas after IA injection of NEO100 but not after IA injection of the vehicle (without NEO100). Although all untreated control animals died within 3 weeks, all mice that received IA NEO100 followed by IV CAR T cells survived and thrived for 200 days, when the experiment was terminated. Of the mice that received IV CAR T cells without prior IA NEO100, 3 died within 3 weeks and 2 survived long-term.
CONCLUSIONS
BBB opening by IA NEO100 facilitates brain entry of intravenously delivered CD19 CAR T cells. The long-term survival of all mice with CNS lymphoma, along with the disappearance of the tumor as determined with imaging, suggests that this one-time therapeutic intervention was curative. BBB opening by IA NEO100 may offer a novel option to increase brain access by CAR T cells.
Topics: Animals; Mice; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Injections, Intra-Arterial; Disease Models, Animal; Blood-Brain Barrier; Humans; Brain Neoplasms; Cell Line, Tumor; Lymphoma; Central Nervous System Neoplasms; T-Lymphocytes; Mice, SCID
PubMed: 38157532
DOI: 10.3171/2023.10.JNS231097 -
Acta Chimica Slovenica Mar 2020A series of new quaternary ammonium salts (QASs) containing a terpenoid moiety derived from perillyl alcohol, citronellol, and geraniol was synthesized. Structures of...
A series of new quaternary ammonium salts (QASs) containing a terpenoid moiety derived from perillyl alcohol, citronellol, and geraniol was synthesized. Structures of all novel compounds were confirmed by spectral methods and elemental analyses. Fungicidal activity of the obtained compounds against six plant pathogens, against four fungi destroying wood and technical materials as well as herbicidal activity against ten species of temperate climate weeds has been examined. Several salts showed a higher antifungal and herbicidal activity than activity of the reference compounds.
Topics: Acyclic Monoterpenes; Antifungal Agents; Fungi; Herbicides; Microbial Sensitivity Tests; Plant Weeds; Quaternary Ammonium Compounds
PubMed: 33558942
DOI: No ID Found