-
Current Pharmaceutical Biotechnology 2022Gliomas are highly malignant brain tumours with high resistance to chemotherapy. Therefore, investigations of new therapeutic molecules with high anti-glioma activity...
BACKGROUND
Gliomas are highly malignant brain tumours with high resistance to chemotherapy. Therefore, investigations of new therapeutic molecules with high anti-glioma activity are of great importance.
OBJECTIVES
In this work, biocatalytic esterification of terpene alcohols with proven anti-cancer activity was performed to enhance their potency to induce cell death in human glioblastoma multiforme T98G and anaplastic astrocytoma MOGGCCM cell lines in vitro.
METHODS AND RESULTS
We used primary terpene alcohols and carboxylic acids with a length of two to nine carbon atoms. The structure of the alcohols had an influence on the esterification efficiency, which decreased in the following order: monocyclic > linear > bicyclic. Terpene alcohols and their esters only induced apoptotic cell death, which is highly desirable from a therapeutic point of view, but did not induce autophagy and necrosis. The esterification of perillyl alcohol with butyric acid caused a 4-fold increase in cell death induction in the T98G line. Citronellol valerate, caprylate, and pelargonate and myrtenol butyrate, caprylate and pelargonate also showed higher activity than their alcohol precursors.
CONCLUSION
We have herein shown that esterification of natural alcohols by biocatalysis can be used for improving the activity of other compounds investigated for their anti-glioma activity.
Topics: Astrocytoma; Biocatalysis; Esters; Glioblastoma; Glioma; Humans; Terpenes
PubMed: 34254911
DOI: 10.2174/1389201022666210712094925 -
Neuro-oncology Advances 2020NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to the alkylating agent...
BACKGROUND
NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to the alkylating agent temozolomide (TMZ). It is undergoing preclinical development as a therapeutic for brain-localized malignancies. The aim of this study was to characterize metabolism and pharmacokinetic (PK) properties of NEO212 in preclinical models.
METHODS
We used mass spectrometry (MS) and modified high-performance liquid chromatography to identify and quantitate NEO212 and its metabolites in cultured glioblastoma cells, in mouse plasma, brain, and excreta after oral gavage.
RESULTS
Our methods allowed identification and quantitation of NEO212, POH, TMZ, as well as primary metabolites 5-aminoimidazole-4-carboxamide (AIC) and perillic acid (PA). Intracellular concentrations of TMZ were greater after treatment of U251TR cells with NEO212 than after treatment with TMZ. The half-life of NEO212 in mouse plasma was 94 min. In mice harboring syngeneic GL261 brain tumors, the amount of NEO212 was greater in the tumor-bearing hemisphere than in the contralateral normal hemisphere. The brain:plasma ratio of NEO212 was greater than that of TMZ. Excretion of unaltered NEO212 was through feces, whereas its AIC metabolite was excreted via urine.
CONCLUSIONS
NEO212 preferentially concentrates in brain tumor tissue over normal brain tissue, and compared to TMZ has a higher brain:plasma ratio, altogether revealing favorable features to encourage its further development as a brain-targeted therapeutic. Its breakdown into well-characterized, long-lived metabolites, in particular AIC and PA, will provide useful equivalents for PK studies during further drug development and clinical trials with NEO212.
PubMed: 33392507
DOI: 10.1093/noajnl/vdaa160 -
Physical Chemistry Chemical Physics :... Jul 2019The rotational spectrum of perillyl alcohol, a naturally occurring, chiral, dietary monoterpene, was investigated using a chirped pulse Fourier transform microwave...
The rotational spectrum of perillyl alcohol, a naturally occurring, chiral, dietary monoterpene, was investigated using a chirped pulse Fourier transform microwave spectrometer and a cavity-based Fourier transform microwave spectrometer. To aid the assignment of the dense chirped pulse spectrum obtained, extensive theoretical conformational searches were carried out. In one approach, several one and two-dimensional scans along three dihedral angles associated with the rotational motions of the -OH, -CH2OH, and -C(CH2)CH3 groups were performed. These scans, combined with the equatorial and axial positions of the -C(CH2)CH3 group, resulted in 54 conformers. The same conformers were identified in the second approach where a semi-classical conformational search code was used. The relative stabilities of the conformers and the interconversion barriers among them were explored extensively at the DFT B3LYP-D3(BJ)/def2-TZVP and B3LYP-D3(BJ)/6-311++G(2d,p), as well as local MP2/aug-cc-pVQZ levels of theory, and 12 conformers were ultimately identified as possibly observable candidates in a molecular jet expansion. Rotational spectra of eight out of the 12 candidates were observed experimentally and analyzed. The non-observation of the remaining four conformers may be attributed to their low abundances. The study points out the importance of identifying all conformers of relevant abundance, even those which could not be detected experimentally, in order to properly benchmark the theoretical relative stabilities with the experimental ones. A comprehensive study of the conformational distribution of perillyl alcohol contributes to our understanding of its structural properties which may influence its functions.
PubMed: 31287115
DOI: 10.1039/c9cp03028j -
Molecules (Basel, Switzerland) Jun 2020The interaction between a drug molecule and its carrier's components is an important factor which influences the drug release profile. For this purpose, molecular...
The interaction between a drug molecule and its carrier's components is an important factor which influences the drug release profile. For this purpose, molecular dynamics (MD) may be the in silico tool which can help to understand the mechanism of drug loading/release. The aim of this work is to explain the effect of interactions between different types of terpenes, namely perillyl alcohol, forskolin, ursolic acid, and the nanoemulsion droplet core, on the release by means of experimental and theoretical studies. The basic nanoemulsion was composed of caprylic/capric triglyceride as the oil phase, polysorbate 80 as the emulsifier, and water. The in vitro release tests from a terpene-loaded nanoemulsion were carried out to determine the release profiles. The behavior of terpenoids in the nanoemulsion was also theoretically investigated using the molecular dynamics method. The forskolin-loaded nanoemulsion showed the highest percentage of drug release (almost 80% /) in contrast to ursolic acid and perillyl alcohol-loaded nanoemulsions (about 53% / and 19% /, respectively). The results confirmed that the kinetic model of release was terpene-type dependent. The zero-order model was the best to describe the ursolic acid release profile, while the forskolin and the perillyl alcohol followed a first-order and Higuchi model, respectively. Molecular dynamics simulations, especially energetical analysis, confirmed that the driving force of terpenes diffusion from nanoemulsion interior was their interaction energy with a surfactant.
Topics: Emulsifying Agents; Emulsions; Kinetics; Models, Chemical; Nanostructures; Polysorbates; Terpenes
PubMed: 32545817
DOI: 10.3390/molecules25122747 -
Food Chemistry Jun 2024Degradation of trans-cinnamaldehyde and limonene in cucumber was evaluated under laboratory and greenhouse conditions. Two commercial biopesticides, one based on...
Degradation of trans-cinnamaldehyde and limonene in cucumber was evaluated under laboratory and greenhouse conditions. Two commercial biopesticides, one based on cinnamon extract and other from orange oil, were utilized. Compound degradation was monitored using gas chromatography (GC) and ultra-high-performance liquid chromatography (UHPLC) coupled to a quadrupole-high-resolution mass analyzer (Q-Orbitrap). In both studies, trans-cinnamaldehyde followed a second-order degradation kinetics, whereas limonene followed a first-order kinetics. The half-life values (DT or t) for trans-cinnamaldehyde ranged from 2.02 to 2.49 h, while for limonene this value ranged from 0.49 to 6.17 h. Non-targeted analysis (suspect and unknown modes) allowed for the detection of trans-cinnamaldehyde and limonene metabolites. Benzyl alcohol, cinnamyl alcohol, cinnamic acid, p-tolylacetic acid and 4-hydoxycinnamic acid were tentatively identified as trans-cinnamaldehyde metabolites. While three limonene metabolites, carvone, limonene-1,2-epoxide, and perillyl alcohol, were tentatively identified. Greenhouse studies have not revealed any metabolites of these compounds because the parent compounds degrade more quickly.
Topics: Limonene; Cucumis sativus; Chromatography, High Pressure Liquid; Biological Control Agents; Allergens; Chromatography, Gas; Acrolein
PubMed: 38241992
DOI: 10.1016/j.foodchem.2024.138443 -
ChemistryOpen Apr 2021A series of tetraimidazolium salts with different anions was prepared and applied in the isomerization of β-pinene oxide. After examining the activity of different...
A series of tetraimidazolium salts with different anions was prepared and applied in the isomerization of β-pinene oxide. After examining the activity of different catalysts, a remarkable enhancement of the selectivity of perillyl alcohol (47 %) was obtained over [PEimi][HNO ] under mild reaction conditions and using DMSO as the solvent. Furthermore, noncovalent interactions between solvent molecules and the catalyst were found by FT-IR spectroscopy and confirmed by computational chemistry. The homogeneous catalyst showed excellent stability and was reused up to six times without significant loss.
PubMed: 33908700
DOI: 10.1002/open.202000318 -
AMB Express Apr 2022Optimized recombinant whole cells of E. coli bearing CYP153A6 were employed for catalyzing the hydroxylation of different monoterpene derivatives. In most cases, high...
Optimized recombinant whole cells of E. coli bearing CYP153A6 were employed for catalyzing the hydroxylation of different monoterpene derivatives. In most cases, high selectivity was observed with exclusive hydroxylation of the allylic methyl group bound to the aliphatic ring. In the case of (R)- and (S)-carvone, hydroxylation occurred also on the other allylic methyl group, although to a lesser extent. Biotransformations carried out in fed-batch mode on (S)-limonene and α-terpineol showed that recombinant whole cells retained activity for at least 24 h, allowing for the recovery of 3.25 mg mL of (S)-perillyl alcohol and 5.45 mg mL of 7-hydroxy-α-terpineol, respectively.
PubMed: 35478304
DOI: 10.1186/s13568-022-01389-8 -
Scientific Reports Mar 2021Perillyl alcohol (POH) has been extensively studied for the treatment of peripheral and primary brain tumors. The intranasal route of administration has been preferred...
Perillyl alcohol (POH) has been extensively studied for the treatment of peripheral and primary brain tumors. The intranasal route of administration has been preferred for dosing POH in early-stage clinical trials associated with promising outcomes in primary brain cancer. However, it is unclear how intranasal POH targets brain tumors in these patients. Multiple studies indicate that intranasally applied large molecules may enter the brain and cerebrospinal fluid (CSF) through direct olfactory and trigeminal nerve-associated pathways originating in the nasal mucosa that bypass the blood-brain barrier. It is unknown whether POH, a small molecule subject to extensive nasal metabolism and systemic absorption, may also undergo direct transport to brain or CSF from the nasal mucosa. Here, we compared CSF and plasma concentrations of POH and its metabolite, perillic acid (PA), following intranasal or intravascular POH application. Samples were collected over 70 min and assayed by high-performance liquid chromatography. Intranasal administration resulted in tenfold higher CSF-to-plasma ratios for POH and tenfold higher CSF levels for PA compared to equal dose intravascular administration. Our preclinical results demonstrate POH undergoes direct transport from the nasal mucosa to the CSF, a finding with potential significance for its efficacy as an intranasal chemotherapeutic for brain cancer.
Topics: Administration, Intranasal; Animals; Blood-Brain Barrier; Brain; Brain Neoplasms; Chromatography, High Pressure Liquid; Disease Models, Animal; Humans; Monoterpenes; Nasal Mucosa; Rats; Trigeminal Nerve
PubMed: 33737566
DOI: 10.1038/s41598-021-85293-4 -
Journal of Materials Chemistry. B Jun 2022Elemental sulfur (), a by-product of the petroleum refining industries, possesses many favourable properties including photocatalytic activity and antibacterial...
Elemental sulfur (), a by-product of the petroleum refining industries, possesses many favourable properties including photocatalytic activity and antibacterial activity, in addition to being intrinsically hydrophobic. Despite this, there is a relative lack of research employing elemental sulfur and/or sulfur copolymers within superhydrophobic materials design. In this work, we present the use of sulfur copolymers to produce superhydrophobic materials with advanced functionalities. Using inverse vulcanization and the use of a natural organic crosslinker, perillyl alcohol (PER), stable S-PER copolymers were synthesised and later combined with silica (SiO) nanoparticles, to achieve highly water repellent composites that displayed both antimicrobial and photocatalytic properties, in the absence of carcinogenic and/or expensive materials. Here, we investigated the antibacterial performance of coatings against the Staphylococcus aureus bacterial strain, where coatings displayed great promise for use in antifouling applications, as they were found to limit surface adhesion by more than 99%, when compared to uncoated glass samples. Furthermore, UV dye degradation tests were performed, utilizing the commercially available dye resazurin, and it was shown that coatings had the potential to simultaneously exhibit surface hydrophobicity and photoactivity, demonstrating a great advancement in the field of superhydrophobic materials.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Polymers; Silicon Dioxide; Sulfur; Water
PubMed: 35438120
DOI: 10.1039/d2tb00319h -
PloS One 2020The prognosis for patients with glioblastoma (GB) remains grim. Concurrent temozolomide (TMZ) radiation-the cornerstone of glioma control-extends the overall median...
The prognosis for patients with glioblastoma (GB) remains grim. Concurrent temozolomide (TMZ) radiation-the cornerstone of glioma control-extends the overall median survival of GB patients by only a few months over radiotherapy alone. While these survival gains could be partly attributed to radiosensitization, this benefit is greatly minimized in tumors expressing O6-methylguanine DNA methyltransferase (MGMT), which specifically reverses O6-methylguanine lesions. Theoretically, non-O6-methylguanine lesions (i.e., the N-methylpurine adducts), which represent up to 90% of TMZ-generated DNA adducts, could also contribute to radiosensitization. Unfortunately, at concentrations attainable in clinical practice, the alkylation capacity of TMZ cannot overwhelm the repair of N-methylpurine adducts to efficiently exploit these lesions. The current therapeutic application of TMZ therefore faces two main obstacles: (i) the stochastic presence of MGMT and (ii) a blunted radiosensitization potential at physiologic concentrations. To circumvent these limitations, we are developing a novel molecule called NEO212-a derivatization of TMZ generated by coupling TMZ to perillyl alcohol. Based on gas chromatography/mass spectrometry and high-performance liquid chromatography analyses, we determined that NEO212 had greater tumor cell uptake than TMZ. In mouse models, NEO212 was more efficient than TMZ at crossing the blood-brain barrier, preferentially accumulating in tumoral over normal brain tissue. Moreover, in vitro analyses with GB cell lines, including TMZ-resistant isogenic variants, revealed more potent cytotoxic and radiosensitizing activities for NEO212 at physiologic concentrations. Mechanistically, these advantages of NEO212 over TMZ could be attributed to its enhanced tumor uptake presumably leading to more extensive DNA alkylation at equivalent dosages which, ultimately, allows for N-methylpurine lesions to be better exploited for radiosensitization. This effect cannot be achieved with TMZ at clinically relevant concentrations and is independent of MGMT. Our findings establish NEO212 as a superior radiosensitizer and a potentially better alternative to TMZ for newly diagnosed GB patients, irrespective of their MGMT status.
Topics: Animals; Blood-Brain Barrier; Brain; Brain Neoplasms; Cell Line, Tumor; Cell Survival; DNA Damage; Dacarbazine; Drug Resistance, Neoplasm; Gas Chromatography-Mass Spectrometry; Glioma; Humans; Mice; Mice, Inbred C57BL; O(6)-Methylguanine-DNA Methyltransferase; Radiation-Sensitizing Agents; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 32881880
DOI: 10.1371/journal.pone.0238238