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Molecules (Basel, Switzerland) Sep 2018Six new cyclodiprenyl phenols were synthesized by direct coupling of perillyl alcohol and the appropriate phenol. Their structures were established by IR, HRMS and...
Six new cyclodiprenyl phenols were synthesized by direct coupling of perillyl alcohol and the appropriate phenol. Their structures were established by IR, HRMS and mainly NMR. Three human cancer cell lines-breast (MCF-7), prostate (PC-3) and colon (HT-29)-were used in antiproliferative assays, with daunorubicin and dunnione as positive controls. Results described in the article suggest that dihydroxylated compounds ⁻ and monohydroxylated compound display selectivity against cancer cell lines, cytotoxicity, apoptosis induction, and mitochondrial membrane impairment capacity. Compound was identified as the most effective of the series by displaying against all cancer cell lines a cytotoxicity close to dunnione antineoplastic agent, suggesting that the cyclodiprenyl phenols from perillyl alcohol deserve more extensive investigation of their potential medicinal applications.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HT29 Cells; Humans; MCF-7 Cells; Mitochondrial Membranes; Molecular Structure; Phenols; Structure-Activity Relationship
PubMed: 30213053
DOI: 10.3390/molecules23092323 -
Neuro-oncology Advances 2021Better treatments for glioblastoma (GBM) patients, in particular in the recurrent setting, are urgently needed. Clinical trials performed in Brazil indicated that...
BACKGROUND
Better treatments for glioblastoma (GBM) patients, in particular in the recurrent setting, are urgently needed. Clinical trials performed in Brazil indicated that intranasal delivery of perillyl alcohol (POH) might be effective in this patient group. NEO100, a highly purified version of POH, was current good manufacturing practice (cGMP) manufactured to evaluate the safety and efficacy of this novel approach in a Phase I/IIa clinical trial in the United States.
METHODS
A total of 12 patients with recurrent GBM were enrolled into Phase I of this trial. NEO100 was administered by intranasal delivery using a nebulizer and nasal mask. Dosing was 4 times a day, every day. Four cohorts of 3 patients received the following dosages: 96 mg/dose (384 mg/day), 144 mg/dose (576 mg/day), 192 mg/dose (768 mg/day), and 288 mg/dose (1152 mg/day). Completion of 28 days of treatment was recorded as 1 cycle. Adverse events were documented, and radiographic response Response Assessment in Neuro-Oncology (RANO) criteria was evaluated every 2 months. Progression-free and overall survival were determined after 6 and 12 months, respectively (progression-free survival-6 [PFS-6], overall survival-12 [OS-12]).
RESULTS
Intranasal NEO100 was well tolerated at all dose levels and no severe adverse events were reported. PFS-6 was 33%, OS-12 was 55%, and median OS was 15 months. Four patients (33%), all of them with isocitrate dehydrogenase 1 (IDH1)-mutant tumors, survived >24 months.
CONCLUSION
Intranasal glioma therapy with NEO100 was well tolerated. It correlated with improved survival when compared to historical controls, pointing to the possibility that this novel intranasal approach could become useful for the treatment of recurrent GBM.
PubMed: 33604574
DOI: 10.1093/noajnl/vdab005 -
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 Experimental & Clinical... Jun 2019Temozolomide-perillyl alcohol conjugate (NEO212), a novel temozolomide (TMZ) analog, was previously reported to exert its anti-cancer effect in non-small cell lung...
BACKGROUND
Temozolomide-perillyl alcohol conjugate (NEO212), a novel temozolomide (TMZ) analog, was previously reported to exert its anti-cancer effect in non-small cell lung cancer (NSCLC), and human nasopharyngeal carcinoma (NPC), etc.. In the current study, we intend to illuminate the potential anticancer property and the underly mechanisms of NEO212 in ovarian cancer cells.
METHODS
The cytotoxicity of NEO212 was detected by MTT, colony formation analysis and xenograft model. The proteins involved in cell proliferation, DNA damage, autophagy and lysosomal function were detected by western blots; mitochondria, lysosome and autophagosome were visualized by TEM and/or immunofluorescence; Apoptosis, cell cycle analysis and mitochondrial transmembrane potential were detected by flow cytometry. TFEB translocation was detected by immunofluorescence and western blot.
RESULTS
NEO212 has the potential anticancer property in ovarian cancer cells, as evidence from cell proliferation inhibition, G/M arrest, DNA damage, xenograft, mitochondrial dysfunction and apoptosis. Importantly, we observed that although it induced significant accumulation of autophagosomes, NEO212 quenched GFP-LC3 degradation, down-regulated a series of lysosome related gene expression and blocked the autophagic flux, which significantly facilitated it induced apoptosis and was largely because it inhibited the nuclear translocation of transcription factor EB (EB).
CONCLUSIONS
NEO212 inhibited TFEB translocation, and impaired the lysosomal function, implying NEO212 might avoid from autophagy mediated chemo-resistance, thus proposing NEO212 as a potential therapeutic candidate for ovarian cancer.
Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagosomes; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Damage; Dacarbazine; Disease Models, Animal; Female; Humans; Membrane Potential, Mitochondrial; Mice; Mitochondria; Ovarian Neoplasms; Protein Transport; Xenograft Model Antitumor Assays
PubMed: 31174569
DOI: 10.1186/s13046-019-1249-1 -
Journal of Natural Medicines Jan 2020The essential oil of perilla (Perilla frutescens) contains volatile low molecular weight compounds such as monoterpenes and phenylpropenes. The composition of the...
The essential oil of perilla (Perilla frutescens) contains volatile low molecular weight compounds such as monoterpenes and phenylpropenes. The composition of the essential oil is classified into about ten chemotypes. The biosynthesis of these constituents is strictly controlled genetically. Among the compounds contained in perilla essential oil, the bioconversion of pure compounds such as perillaldehyde, limonene, and citral has been reported, but that of many other components has not. In addition, changes in the volatile components of raw plant material during brewing have also been investigated for wine and beer. In this study, we examined the bioconversion of perilla essential oil components by Saccharomyces cerevisiae during the brewing of liquor with perilla leaves. S. cerevisiae was added to the ethanol-water extract of dried leaves of P. frutescens and P. citriodora for seven essential oil types: perillaldehyde type, piperitenone type, perillene type, perillaketone type, elsholtziaketone type, citral type, and phenylpropanoid type. Volatile compounds in the reaction mixtures were analyzed by solid-phase microextraction (SPME)-GC-MS, revealing bioconversion of perillaldehyde, isoegomaketone, neral, and geranial by S. cerevisiae. Analysis of the conversion products suggests that they were formed by the reduction of C=C bonds and aldehydes, as well as by esterification and dehydration reactions.
Topics: Acyclic Monoterpenes; Alcoholic Beverages; Furans; Gas Chromatography-Mass Spectrometry; Ketones; Monoterpenes; Oils, Volatile; Perilla frutescens; Plant Leaves; Plant Oils; Saccharomyces cerevisiae; alpha-Linolenic Acid
PubMed: 31576496
DOI: 10.1007/s11418-019-01363-y -
Molecules (Basel, Switzerland) Jul 2015Compounds isolated from essential oils play an important role in the prevention and treatment of cancer. Monoterpenes are natural products, and the principal...
Compounds isolated from essential oils play an important role in the prevention and treatment of cancer. Monoterpenes are natural products, and the principal constituents of many essential oils. The aim of this study was to investigate the cytotoxic potential of p-menthane derivatives. Additionally, analogues of perillyl alcohol, a monoterpene with known anticancer activity, were evaluated to identify the molecular characteristics which contribute to their cytotoxicity, which was tested against OVCAR-8, HCT-116, and SF-295 human tumor cell lines, using the MTT assay. The results of this study showed that (-)-perillaldehyde 8,9-epoxide exhibited the highest percentage inhibition of cell proliferation (GI = 96.32%-99.89%). Perillyl alcohol exhibited high cytotoxic activity (90.92%-95.82%), while (+)-limonene 1,2-epoxide (GI = 58.48%-93.10%), (-)-perillaldehyde (GI = 59.28%-83.03%), and (-)-8-hydroxycarvotanacetone (GI = 61.59%-94.01%) showed intermediate activity. All of the compounds tested were less cytotoxic than perillyl alcohol, except (-)-perillaldehyde 8,9-epoxide (IC50 = 1.75-1.03 µL/mg). In general, replacement of C-C double bonds by epoxide groups in addition to the aldehyde group increases cytotoxicity. Furthermore, stereochemistry seems to play an important role in cytotoxicity. We have demonstrated the cytotoxic influence of chemical substituents on the p-menthane structure, and analogues of perillyl alcohol.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cytotoxins; Drug Screening Assays, Antitumor; Humans; Neoplasms; Terpenes
PubMed: 26197313
DOI: 10.3390/molecules200713264