Palmitone

Evaluation of BBB permeable nucleolipid (NLDPU): A di-C15-ketalised palmitone appended uridine as neuro-tracer for SPECT.[Pubmed:31047994]

Int J Pharm. 2019 Jun 30;565:269-282.

Despite being in routine for onco-diagnostics for years, the applicability of nucleosidic molecular imaging probes is severely restricted in neurological applications due to their low permeability across blood-brain-barrier (BBB). For extending nucleoside tracers utility for neuro-onco early diagnostics, suitable modification which enhances their BBB permeation needs investigation. Among various modifications, lipidization of nucleosides has been reported to enhance cellular permeability. Extending the concept, the aim was to exemplify the possibility of lipidized nucleosides as potential brain tracer with capability to cross intact BBB and evaluate as metal based neuro-imaging SPECT agent. Uridine based non-lipidic (NSDAU) and di-C15-ketal appended lipidic (NLDPU) ligands were conjugated to chelator, DTPA (DTPA-NSDAU and DTPA-NLDPU) using multi-step chemistry. The ligands were evaluated in parallel for comparative physical and biological parameters. Additionally, effects of enhanced lipophilicity on UV-absorption, acid strength, fluorescence and non-specific protein binding were evaluated. Fluorescence quenching of BSA indicated appreciable interaction of DTPA-NLDPU with protein only above 10mM without inducing conformational changes. In addition, DTPA-NLDPU was found to be haematocompatible and cytocompatible with low dose-dependent toxicity in HEK-cells. The chelator DTPA was used for (99m)Tc-complexation for SPECT imaging. Optimized (99m)Tc-radiolabeling parameters resulted in quantitative (>/=97%) labeling with good stability parameters in in-vitro serum and cysteine challenge studies. We demonstrate that the nucleolipid radiotracer ((99m)Tc-DTPA-NLDPU) was successfully able to permeate the BBB with brain uptake of 0.2% ID/g in normal mice as compared to 0.06% ID/g uptake of (99m)Tc-DTPA-NSDAU at 5min. Blood kinetics indicate biphasic profile and t1/2(distribution) 46min for (99m)Tc-DTPA-NLDPU. The preferential accumulation of (99m)Tc-DTPA-NLDPU in brain tumor intracranial xenograft indicate the targeting capability of the nucleoside. We conclude that as first-of-its-kind, this work presents the potential of the biocompatible nucleolipidic system for brain targeting and early diagnostics.

Chemical Composition, Antiprotozoal and Cytotoxic Activities of Indole Alkaloids and Benzofuran Neolignan of Aristolochia cordigera.[Pubmed:28264205]

Planta Med. 2017 Jul;83(11):912-920.

This is a comparative study on the intraspecific chemical variability of Aristolochia cordigera species, collected in two different regions of Brazil, Biome Cerrado (semiarid) and Biome Amazonia (coastal). The use of GC-MS and statistical methods led to the identification of 56 compounds. A higher percentage of Palmitone and germacrene-D in the hexanes extracts of the leaves of plants from these respective biomes was observed. Phytochemical studies on the extracts led to the isolation and identification of 19 known compounds, including lignans, neolignans, aristolochic acids, indole-beta-carboline, and indole alkaloids. In addition, two new indole alkaloids, 3,4-dihydro-hyrtiosulawesine and 6-O-(beta-glucopyranosyl)hyrtiosulawesine, were isolated and a new neolignan, cis-eupomatenoid-7, was obtained in a mixture with its known isomer eupomatenoid-7. Their structures were determined by spectroscopic methods, mainly by 1D- and 2D-NMR. The occurrence of indole alkaloids is being described for the first time in the Aristolochiaceae family. Moreover, the in vitro susceptibility of intracellular amastigote and promastigote forms of Leishmania amazonensis to the alkaloids and eupomatenoid-7 were evaluated. This neolignan exhibited low activity against promastigotes (IC50 = 46 microM), while the alkaloids did not show inhibitory activity. The new alkaloid 6-O-(beta-glucopyranosyl)hyrtiosulawesine exhibited activity in the low micromolar range against Plasmodium falciparum, with an IC50 value of 5 microM and a selectivity index higher than 50.

In vitro Antigonorrhea Activity of the Aerial Part of Asparagus suaveolens n-Hexane Fraction and Palmitone as a Bioactive Compound.[Pubmed:30807034]

Nat Prod Commun. 2016 Sep;11(9):1319-1321.

Asparagus suaveolens is a medicinal plant used in Lesotho and South Africa to treat epilepsy and gonorrhea. The current investigation identifies the compound responsible for the antiepileptic and antimicrobial properties as Palmitone which showed antigonorrhea activities against WHO 2008 Neisseria gonorrhea F and 0 strains more than the standard used, gentamicin. These results support the traditional use of A. suaveolens for treatment of gonorrhea and epilepsy since Palmitone is known as an anticonvulsant agent. This is the first study indicating the presence of Palmitone in the Asparagus genus and demonstrates the in vitro antigonorrhea activity of Palmitone.

Palmitone prevents pentylenetetrazole-caused neuronal damage in the CA3 hippocampal region of prepubertal rats.[Pubmed:20045039]

Neurosci Lett. 2010 Feb 12;470(2):111-4.

Palmitone is a secondary metabolite of polyketide origin extracted from leaves of Annona diversifolia Saff. (Annonaceae). We found that Palmitone possesses anticonvulsant properties against penicillin-, 4-AP-, and pentylenetetrazole (PTZ)-caused seizure in adult animals. Some convulsants as PTZ cause neuronal damage in different brain regions such as the CA3 hippocampal region. Our objective was to evaluate if Palmitone protects against PTZ-caused seizures and hippocampal neuronal damage in prepubertal rats. We used 32 prepubertal Wistar rats (30-35 days old) divided into four groups of 8 animals; group I was the control group, group II received a single PTZ dose of 50mg/kg ip, group III received a single Palmitone dose of 50mg/kg ip, and group IV received a Palmitone dose of 50mg/kg ip plus a PTZ dose of 50mg/kg ip. Ten days after administration, the animals were killed using pentobarbital anesthesia (35 mg/kg). The brains were removed and were embedded in paraffin. Coronal cuts of 7 microm were obtained from -2.8 to -3.3 from Bregma. Each section was stained with cresyl violet-eosin. We evaluated the number of normal and abnormal neurons in the CA3 hippocampal region in a 10,000 microm(2) section. It was observed that Palmitone did not prevent the PTZ-caused seizure but Palmitone prevents the PTZ-caused neuronal damage in the CA3 hippocampal region.

Antinociceptive activity of Annona diversifolia Saff. leaf extracts and palmitone as a bioactive compound.[Pubmed:19969018]

Pharmacol Biochem Behav. 2010 Mar;95(1):6-12.

Annonas are consumed as fresh fruits, but are also widely used in folk medicine for treating pain and other ailments. Antinociceptive properties of the Annona diversifolia ethanol crude extract were tested using the pain-induced functional impairment model in rat (PIFIR) and the writhing test in mice. The ethanol extract caused a 25% recovery of limb function in rats; this response was significant and dose-dependent. Furthermore, this extract produced a similar antinociceptive response (ED(50)=15.35 mg/kg) to that of the reference drug tramadol (ED(50)=12.42 mg/kg) when evaluated in the writhing test in mice. Bio-guided fractionation yielded hexane and acetone active fractions from which the presence of Palmitone and flavonoids was respectively detected. Palmitone produced an antinociceptive response with an ED(50)=19.57 mg/kg in the writhing test. Antinociceptive responses from ethanol extract and tramadol were inhibited in the presence of either naloxone (1mg/kg, s.c.)--an antagonist of endogenous opioids--or WAY100635 (0.8 mg/kg, s.c.)--a 5-HT(1A) serotonin receptor antagonist. These results provide evidence that A. diversifolia possesses antinociceptive activity, giving support to their traditional use for treatment of spasmodic and arthritic pain. In addition, our results suggest the participation of endogenous opioids and 5-HT(1A) receptors in this antinociceptive response.

Effect of repeated administration of Annona diversifolia Saff. (ilama) extracts and palmitone on rat amygdala kindling.[Pubmed:19836312]

Epilepsy Behav. 2009 Dec;16(4):590-5.

Annonas are consumed as fresh fruits, but, because of their effects on the central nervous system, are also used in folk medicine. The effect on rat amygdala kindling of repeated administration of Annona diversifolia hexane (100mg/kg IP or PO) and ethanol (100mg/kg, PO) leaf extracts and Palmitone (10mg/kg, IP) was determined. Electrographic and/or behavioral changes were monitored during kindling-induced seizures 60minutes after treatments. Antiepileptic efficacy was evaluated with respect to afterdischarge (AD) duration, spike frequency, and/or behavioral seizure activity. Oral administration of both extracts significantly decreased spike frequency, whereas intraperitoneally administered hexane extract and Palmitone only reduced AD duration. Hexane extract and Palmitone exhibited anticonvulsant properties and delayed establishment of a kindling state as observed with diazepam (0.3mg/kg IP). These results reinforce the anticonvulsant properties of this plant, and Palmitone and other constituents are responsible for the pharmacological effects.

Isolation and antimicrobial evaluation of isomeric hydroxy ketones in leaf cuticular waxes of Annona squamosa.[Pubmed:17260693]

Phytochem Anal. 2007 Jan-Feb;18(1):7-12.

A novel natural compound, 11-hydroxy-16-hentriacontanone, has been isolated from the leaf cuticular wax of Annona squamosa along with its known isomer 10-hydroxy-16-hentriacontanone in a ratio of 67:33. This isomeric mixture of hydroxy ketones constituted together 16.5% of the total cuticular waxes. The new compound was characterised using spectral and chromatographic techniques. The major component was found to be 16-hentriacontanone (Palmitone), which constituted up to 48% of the total cuticular wax, together with a homologous series of hydrocarbons, fatty aldehydes, fatty alcohols, fatty acids and sterols as minor components. The antimicrobial activity of the isomeric hydroxy ketones was tested against selected Gram-positive and Gram-negative bacterial strains, and also some selected fungal strains, and compared with Palmitone. The antibacterial activity of Palmitone was significantly higher than that of the isomeric hydroxy ketones, but their antifungal activities were comparable.

Anticonvulsant effect of Annona diversifolia Saff. and palmitone on penicillin-induced convulsive activity. A behavioral and EEG study in rats.[Pubmed:17116019]

Epilepsia. 2006 Nov;47(11):1810-7.

PURPOSE: To evaluate hypnotic and anticonvulsant activities of Annona diversifolia Saff. and Palmitone by using behavior and electroencephalographic (EEG) analysis in an experimental model of focal seizures in rats. METHODS: For hypnotic assessment, EEG analysis of polysomnographic slow-wave sleep (SWS) and rapid eye movement (REM) sleep for a 1 h period were performed after vehicle, A. diversifolia extract or Palmitone, administration. For anticonvulsant effect, 60 minutes after treatments, EEG and behavior were analyzed during penicillin-induced seizures. Latency to the onset of the first paroxystic spike, first seizure and frequency, as well as seizure severity using Racine's scale, were determined. RESULTS: Palmitone, but not A. diversifolia extract, produced a delay in the latency to the SWS phase. In addition, both Palmitone and extract decreased SWS duration and accumulated REM sleep phase. With regard to the seizures, both the extract and Palmitone increased the latency to the onset of spikes and seizures, but also decreased the duration of penicillin-induced seizures. This reduction in the EEG recordings was associated with an attenuation in the severity of behavioral seizures. CONCLUSIONS: A. diversifolia and Palmitone did not produce a sedative-hypnotic effect although both of them were effective in reducing the severity of behavioral and EEG seizures induced by penicillin in rats, suggesting that the diminution in the paroxystic activity by A. diversifolia is likely produced by Palmitone through GABAergic neurotransmission. This study justifies and reinforces the traditional use of this plant in epilepsy.

Palmitone isolated from Annona diversifolia induces an anxiolytic-like effect in mice.[Pubmed:16732521]

Planta Med. 2006 Jun;72(8):703-7.

The aim of this study was to investigate the behavioral effects of Palmitone in the anti-anxiety response in experimental models in mice. In the elevated plus-maze test, Palmitone (0.3, 1, 3, 10 and 30 mg/kg, I. P.) lengthened, from 50 % to 199 %, the time spent in the open arm region of the maze at all doses tested, as compared to the vehicle group ( P < 0.001). In relation to the rearing activity in the exploratory cylinder, Palmitone significantly modified ( P < 0.05), in a dose-dependent manner, this activity by decreasing the number of rearings with an effective dose value (ED (50)) and 95 % confidence limits (CL (50)) of 0.79 (0.23 - 2.68) mg/kg. In addition, in the hole-board test, nose-poking was also significantly decreased ( P < 0.01) in a dose-dependent fashion [ED (50) (CL (50)) = 9.07 (4.51 - 18.26) mg/kg]. Moreover, Palmitone at any dose caused no change in motor activity nor disruption in traction performance. In contrast, diazepam, used as reference drug, produced an anxiolytic effect with a significant and dose-dependent decrease in motor coordination accompanied by disruption of the traction performance. Behavioral studies suggest an anti-anxiety effect produced by Palmitone, but its neuropharmacological profile differs from that observed for benzodiazepines such as diazepam.

Anxiolytic-like actions of the hexane extract from leaves of Annona cherimolia in two anxiety paradigms: possible involvement of the GABA/benzodiazepine receptor complex.[Pubmed:16122763]

Life Sci. 2006 Jan 11;78(7):730-7.

A hexane extract of leaves of Annona cherimolia produced anxiolytic-like actions when administered to mice and tested in two animal models of anxiety: the mouse avoidance exploratory behavior and the burying behavior tests. In order to discard unspecific drug-actions on general activity, all treatments studied in the anxiety paradigms were also analyzed in the open field test. Results showed that A. cherimolia induced anxiolytic-like actions at the doses of 6.25, 12.5, 25.0 and 50.0 mg/kg. Picrotoxin (0.25 mg/kg), a GABA-gated chloride ion channel blocker, antagonized the anxiolytic-like actions of A. cherimolia, while a sub-effective dose of muscimol (0.5 mg/kg), a selective GABA(A) receptor agonist, facilitated the effects of a sub-optimal dose of A. cherimolia (3.12 mg/kg). Thus, the involvement of the GABA(A) receptor complex in the anxiolytic-like actions of A. cherimolia hexane extract is suggested. In addition the extract was also able to enhance the duration of sodium pentobarbital induced sleeping time. Taken together, results indicate that the hexane extract of A. cherimolia has depressant activity on the Central Nervous System and could interact with the GABA(A) receptor complex. On the other hand, the chromatographic separation of this extract led to the isolation of Palmitone, and beta-sitosterol as major constituents. In addition a GC-MS study of some fractions revealed the presence of several compounds such beta-cariophyllene, beta-selinene, alpha-cubebene, and linalool that have been reported to show effects on behavior that could explain some of the extract effects.

Lignans from leaves of Rollinia mucosa.[Pubmed:11926539]

Z Naturforsch C J Biosci. 2002 Jan-Feb;57(1-2):29-32.

A new furofuranic lignan named (+)-epimembrine together with known (+)-epieudesmine and (+)-epimagnoline were isolated from leaves of R. mucosa. Their structures were determined by spectroscopic data. Palmitone and a mixture of beta-sitosterol and stigmasterol were also isolated.

Anticonvulsant properties and bio-guided isolation of palmitone from leaves of Annona diversifolia.[Pubmed:11301859]

Planta Med. 2001 Mar;67(2):136-41.

The activity-guided fractionation of the ethanol extract of leaves of Annona diversifolia Saff., led to the isolation of Palmitone (16-hentriacontanone) as the only anticonvulsant active compound. This aliphatic ketone was highly effective to diminish pentylenetetrazole (PTZ)-induced clonic-tonic seizures and toxicity. Also, it produced a prolongation of the latency for onset of seizures and a reduction of the death rate produced by 4-aminopyridine (4-AP) and bicuculline (BIC). However, it was inactive to inhibit the kainic acid (KA)- and strychnine (STC)-induced seizures. Palmitone did not produce motor incoordination and loss of righting reflex which are used as signs of neurological impairment. Palmitone (ED50 = 1.85 mg/kg) proved to be a more potent antiepileptic drug against the PTZ-induced seizures than etosuximide (ED50 = 59.6 mg/kg), sodium valproate (ED50 = 63 mg/kg), and carbamazepine (ED50 > 300 mg/kg) and it was only four-fold less potent than diazepam (ED50 = 0.48 mg/kg). The pharmacological profile of Palmitone suggests that this compound could be acting on the GABAergic inhibitory system.

Isolation, structural studies and chemical synthesis of a 'palmitone lipid' from Corynebacterium diphtheriae.[Pubmed:102431]

Chem Phys Lipids. 1978 Oct;22(3):185-95.

The isolation of a 'Palmitone lipid' from Corynebacterium diphtheriae is described. The use of a temporary hydrophobic protecting group allows the obtaining of the lipid in free and pure form. Structural studies by chemical degradation and mass spectrometry allow one to propose structure Ic for this compound, namely 6-(2-tetradecyl 3-keto octadecanoyl)-alpha-D-trehalose. This structure was confirmed by chemical synthesis.