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Mini Reviews in Medicinal Chemistry 2021Limonene and perillyl alcohol are natural monoterpenes that have attracted the attention of medicinal chemists due to their promising anticancer activities. Considering... (Review)
Review
Limonene and perillyl alcohol are natural monoterpenes that have attracted the attention of medicinal chemists due to their promising anticancer activities. Considering this, both compounds were explored as scaffolds to obtain various derivatives with anticancer activity. In this review, the data are organized for the first time, with a focus on the synthetic methods and strategies to obtain the derivatives throughout the period from 2000 to 2020. A brief discussion regarding the structure and activity relationships of the most active derivatives, stereoisomers, and their mechanisms of action is presented. Among the active compounds, a series of limonenes with thiosemicarbazone groups and perillyl alcohol hybrids with glycosides or drugs are illustrated. Taking all of this into account, this review may help researchers develop new promising anticancer candidates based on the structures of limonene and perillyl alcohol.
Topics: Antineoplastic Agents; Carbohydrates; Cell Survival; Humans; Limonene; Monoterpenes; Neoplasms; Structure-Activity Relationship; Thiosemicarbazones
PubMed: 33583370
DOI: 10.2174/1389557521666210212150504 -
Pharmaceutics Feb 2021The low solubility and high volatility of perillyl alcohol (POH) compromise its bioavailability and potential use as chemotherapeutic drug. In this work, we have...
The low solubility and high volatility of perillyl alcohol (POH) compromise its bioavailability and potential use as chemotherapeutic drug. In this work, we have evaluated the anticancer activity of POH complexed with β-cyclodextrin (β-CD) using three complexation approaches. Molecular docking suggests the hydrogen-bond between POH and β-cyclodextrin in molar proportion was 1:1. Thermal analysis and Fourier-transform infrared spectroscopy (FTIR) confirmed that the POH was enclosed in the β-CD cavity. Also, there was a significant reduction of particle size thereof, indicating a modification of the β-cyclodextrin crystals. The complexes were tested against human L929 fibroblasts after 24 h of incubation showing no signs of cytotoxicity. Concerning the histopathological results, the treatment with POH/β-CD at a dose of 50 mg/kg promoted approximately 60% inhibition of tumor growth in a sarcoma S180-induced mice model and the reduction of nuclear immunoexpression of the Ki67 antigen compared to the control group. Obtained data suggest a significant reduction of cycling cells and tumor proliferation. Our results confirm that complexation of POH/β-CD not only solves the problem related to the volatility of the monoterpene but also increases its efficiency as an antitumor agent.
PubMed: 33578857
DOI: 10.3390/pharmaceutics13020245 -
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 -
Naunyn-Schmiedeberg's Archives of... Jun 2021This research aimed to assess the effect of perillyl alcohol (PA) on convulsive behavior in vivo using adult zebrafish (Danio rerio, both sexes). The seizures were... (Comparative Study)
Comparative Study
This research aimed to assess the effect of perillyl alcohol (PA) on convulsive behavior in vivo using adult zebrafish (Danio rerio, both sexes). The seizures were induced with pentylenetetrazole (PTZ) intraperitoneally at 170 mg/kg, and diazepam (DZP) was used as the control anticonvulsant (2 mg/kg, oral); PA was tested at 10, 50, and 100 mg/kg orally. The groups had ten animals per group (total n = 60), observed for 10 minutes after seizure induction. We manually appraised typical seizure phenotypes for quantification and used an animal tracking software (Toxtrac) to assess the motor parameters. Next, we sought to find a mechanism of action for PA anticonvulsant activity in silico using a structure-based activity prediction server and molecular docking. The results show that PTZ induced seizure-like behavior in all untreated animals with hyperlocomotion episodes, seizure itself, posture loss, and immobility. DZP inhibited the seizures in all animals of the positive control group. PA, in turn, inhibited the occurrence of seizures in a dose-dependent manner, with frequencies of 90%, 70%, and 40% (for 10, 50, and 100 mg/kg, respectively). The PA treatments also decreased several seizure endpoints in a dose-dependent manner. Also, the difference of the group treated with highest dose of PA was statistically significant compared with the negative control group for all the endpoints assessed (p < 0.05, Kruskal-Wallis). The in silico analyses suggested that PA can affect the GABAergic system, which might be involved in its anticonvulsant activity, but other mechanisms cannot be ruled out. Overall, our results suggest an anticonvulsant potential in perillyl alcohol.
Topics: Animals; Anticonvulsants; Behavior, Animal; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Molecular Docking Simulation; Monoterpenes; Patient Acuity; Pentylenetetrazole; Seizures; Zebrafish
PubMed: 33515278
DOI: 10.1007/s00210-021-02050-0 -
BMC Biotechnology Jan 2021(R)-(+)-perillyl alcohol is a naturally oxygenated monoterpene widely used as the natural flavor additives, insecticides, jet fuels and anti-cancer therapies. It was...
BACKGROUND
(R)-(+)-perillyl alcohol is a naturally oxygenated monoterpene widely used as the natural flavor additives, insecticides, jet fuels and anti-cancer therapies. It was also readily available monoterpene precursors. However, this natural product is present at low concentrations from plant sources which are not economically viable. Therefore, alternative microbial production methods are rapidly emerging as an attractive alternative to make (R)-(+)-perillyl alcohol production more sustainable and environmentally friendly.
RESULTS
We engineered Escherichia coli to possess a heterologous mevalonate (MVA) pathway, including limonene synthase, P-cymene monoxygenase hydroxylase and P-cymene monoxygenase reductase for the production of (R)-(+)-perillyl alcohol. The concentration of (R)-(+)-limonene (the monoterpene precursor to (R)-(+)-perillyl alcohol) reached 45 mg/L from glucose. Enhanced (R)-(+)-perillyl alcohol production was therefore achieved. The strain produced (R)-(+)-perillyl alcohol at a titer of 87 mg/L and a yield of 1.5 mg/g glucose in a 5 L bioreactor fed batch system.
CONCLUSIONS
These datas highlight the efficient production of (R)-(+)-perillyl alcohol through the mevalonate pathway from glucose. This method serves as a platform for the future production of other monoterpenes.
Topics: Bioreactors; Escherichia coli; Limonene; Metabolic Engineering; Mevalonic Acid; Monoterpenes
PubMed: 33419424
DOI: 10.1186/s12896-020-00662-7 -
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 -
Clinical and Experimental Hypertension... Apr 2021: Pulmonary arterial hypertension (PAH) is a disastrous disease that current treatments cannot prevent its progression. The present study investigated the effects of...
: Pulmonary arterial hypertension (PAH) is a disastrous disease that current treatments cannot prevent its progression. The present study investigated the effects of perillyl alcohol (PA), a natural monoterpene, on the experimental PAH in male Wistar rats. : Rats divided into eight groups of control, Monocrotaline (MCT), MCT+vehicle, and MCT+PA with doses of 20, 30, 40, 50, and 60 mg/kg. PAH was induced by a single injection of monocrotaline (60 mg/kg) on day 0. The animals in the groups of MCT+vehicle and MCT+PA received the vehicle or PA from day 22 to 42 once a day. On day 43, under general anesthesia, right ventricular systolic pressure (RVSP), as an index of pulmonary artery systolic pressure, and the ratio of the right ventricle to the left ventricle plus septum weight, as the right ventricular hypertrophy index (RVHI), were measured. Also, some histological and biochemical indices were assessed in the lung tissue. : MCT significantly ( < .001) enhanced the RVSP and RVHI compared to the control group (89.4 ± 8.2 vs 23 ± 3.3 mmHg & 0.63 ± 0.08 vs 0.26 ± 0.04 respectively). It also increased oxidative stress and inflammatory cytokines and reduced Bax/Bcl2 ratio. Treatment with PA significantly recovered RVSP and hypertrophy index and suppressed vascular cell proliferation, oxidant production, and inflammatory processes. : PA exerted noticeable protective and curative effects against MCT-induced PAH and pulmonary vascular remodeling through inhibiting cellular proliferation, oxidative stress, and inflammation. Therefore, PA can be considered as a new therapeutic goal for the treatment of PAH.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Blood Pressure; Cell Cycle; Disease Models, Animal; Heart Ventricles; Hemodynamics; Hypertrophy, Right Ventricular; Inflammation Mediators; Lung; Male; Monocrotaline; Monoterpenes; Oxidative Stress; Pulmonary Arterial Hypertension; Pulmonary Artery; Pulmonary Fibrosis; Rats, Wistar; Survival Analysis; Systole; Vascular Remodeling; Rats
PubMed: 33322932
DOI: 10.1080/10641963.2020.1860080 -
Surgical Neurology International 2020Standard of care for glioblastoma (GB), consisting of cytotoxic chemotherapy, steroids, and high-dose radiation, induces changes in the tumor microenvironment through...
BACKGROUND
Standard of care for glioblastoma (GB), consisting of cytotoxic chemotherapy, steroids, and high-dose radiation, induces changes in the tumor microenvironment through its effects on glucose availability, which is a determinant for tumor progression (TP). Low-carbohydrate diet (LCD) reduces the glucose levels needed to drive the Warburg effect.
METHODS
To investigate LCD's effect on GB therapy, we have begun a clinical trial using LCD as an addition to intranasal perillyl alcohol (POH) for recurrent GB (rGB) patients. This study involved 29 individuals and evaluated, over a period of 1 year, the adjuvant effect of LCD associated with POH therapy in terms of toxicity, extent of peritumoral edema, reduced corticosteroid use, seizure frequency, and overall survival. POH group ( = 14) received solely intranasal POH without specific diet regimen, whereas POH/LCD group ( = 15) received intranasal POH in combination with nutritional intervention. Patients' assessment was based on clinical reviews and magnetic resonance data.
RESULTS
In the 1-year follow-up, the POH/LCD group showed a 4.4-fold decrease in the proportion of patients who needed treatment with corticosteroids, as well as a reduction in tumor size and peritumoral edema, as compared to the POH group. While 75% of patients undergoing POH treatment experienced seizures, this fraction was reduced to 56% in the POH/LCD group. A 2.07-fold increase in the proportion of patients with stable disease, along with a 2.8-fold decrease in the proportion of patients with TP, was seen in the POH/LCD group.
CONCLUSION
The results presented in this study show that the LCD associated with intranasal POH therapy may represent a viable option as adjunctive therapy for rGB to improve survival without compromising patients' quality of life. Prospective cohort studies are needed to confirm these findings and validate the efficacy of this novel therapeutic strategy.
PubMed: 33282452
DOI: 10.25259/SNI_445_2020 -
Biomedical Chromatography : BMC Apr 2021Perillyl alcohol (POH) is a monocyclic terpene that has strong antitumor activity. Brain tumors are particularly difficult to treat with therapeutic agents, and clinical...
Intranasal administration of perillyl alcohol-loaded nanoemulsion and pharmacokinetic study of its metabolite perillic acid in plasma and brain of rats using ultra-performance liquid chromatography/tandem mass spectrometry.
Perillyl alcohol (POH) is a monocyclic terpene that has strong antitumor activity. Brain tumors are particularly difficult to treat with therapeutic agents, and clinical trials have shown their low tolerance through oral administration. We proposed the entrapment of POH into an oil-in-water chitosan nanoemulsion aiming its intranasal administration for brain targeting. An ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitation of total metabolite perillic acid (PA) in plasma and brain of rats. The rat samples containing the metabolite were treated by liquid-liquid extraction with acetonitrile. The mobile phase was 0.1% formic acid in water (solvent A) and 0.1% formic acid in methanol (solvent B), at a flow rate of 0.3 mL min in gradient elution. The chromatography was run for 10 min, and analytical curves were built in acetonitrile, plasma, and brain. The PA was detected in positive ion mode with multiple reaction monitoring. The method has shown high selectivity, sensitivity, and throughput. The low quantification limits of 162, 178, and 121 ng mL for acetonitrile, brain, and plasma, respectively, indicate a good detectability of the method. The repeatability and precision observed were within the limits recommended in the literature. The accuracy of the method was verified through high recovery rates (106-118%). The validated method was successfully applied to the pharmacokinetic study of the metabolite PA after the intranasal administration of free or POH-loaded nanoemulsion in rats. The results showed that chitosan nanoemulsion improved the plasma and brain bioavailability of POH, representing a promising alternative to free POH treatment.
Topics: Administration, Intranasal; Animals; Brain Chemistry; Chromatography, High Pressure Liquid; Cyclohexenes; Emulsions; Limit of Detection; Linear Models; Monoterpenes; Nanostructures; Rats; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 33238042
DOI: 10.1002/bmc.5037 -
Pharmaceutics Nov 2020Therapeutic deep eutectic systems (THEDES) have dramatically expanded their popularity in the pharmaceutical field due to their ability to increase active pharmaceutical...
Therapeutic deep eutectic systems (THEDES) have dramatically expanded their popularity in the pharmaceutical field due to their ability to increase active pharmaceutical ingredients (APIs) bioavailability. However, their biological performance has not yet been carefully scrutinized. Herein, THEDES based on the binary mixture of perillyl alcohol (POH) and ibuprofen (IBU) were prepared using different molar ratios. Our comprehensive strategy includes the characterization of their thermal and structural behavior to identify the molar ratios that successfully form deep eutectic systems. The in vitro solubility of the different systems prepared has demonstrated that, unlike other reported examples, the presence of the terpene did not affect the solubility of the anti-inflammatory agent in a physiological simulated media. The biological performance of the systems was studied in terms of their antimicrobial activity against a wide panel of microorganisms. The examined THEDES showed relevant antimicrobial activity against all tested microbial strains, with the exception of . A synergistic effect from the combination of POH and IBU as a eutectic system was verified. Furthermore, the cytotoxic profile of these eutectic systems towards colorectal cancer (CRC) in vitro cell models was also evaluated. The results provide the indication that the cell viability varies in a dose-dependent manner, with a selective THEDES action towards CRC cells. With tunable bioactivities in a ratio-dependent manner, THEDES enhanced the antimicrobial and anticancer properties, representing a possible alternative to conventional therapies. Therefore, this study provides foreseeable indications about the utility of THEDES based on POH and IBU as strong candidates for novel active pharmaceutical systems.
PubMed: 33233659
DOI: 10.3390/pharmaceutics12111121