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Sobrerol, an oral mucolytic agent, in a recent study showed promise for treating multiple sclerosis. A human equivalent dose of 486 mg of sobrerol administered thrice daily (i.e., 1459 mg of daily dose) demonstrated the highest therapeutic efficacy for repurposing use, which also points out the poor compliance of administration. In this study, oral sustained-release pellets of sobrerol were successfully developed with evaluated manufacturing conditions and drug release kinetics. For design of the target drug product, we used a modeling and simulation approach to establish a predictive model of oral pharmacokinetic profile, by exploring the characteristics and correlations corresponding to the pharmacokinetics and pharmacodynamics of sobrerol, such as absorption lag time (0.18 h), time-scaling in vitro–in vivo correlation (tin-vitro = 0.494 tin-vivo − 0.0904), gastrointestinal transit time (8 h), minimum effective concentration (1.61 μg/mL), and duration of action (12.8 h). Results showed that the frequency of administration and the daily dose remarkably reduced by 33.3% (i.e., from thrice to twice daily) and 22.8%, respectively, which indicates that this prototype approach can be adopted for rapidly developing a modified-release dosage form of sobrerol, with improvement of compliance of administration and therapeutic efficacy.

Sobrerol methacrylate (SobMA) was synthesized and subsequently polymerized using different chemical and enzymatic routes. Sobrerol was enzymatically converted from -pinene in a small model scale by ...

Sobrerol acrylate (SobAcr) and sobrerol methacrylate (SobMet) were synthesized for the first time through the functionalization of sobrerol with double bonds. Sobrerol was obtained by a green route that involved the hydration of α-pinene oxide in the presence of CO2. As unsaturated monomers (UMs) with rigid structures and extremely low volatilities, these new monomers are interesting alternatives for styrene (Sty) replacement in unsaturated polyester resin (UPR) formulations. The impact of the substitution of Sty by the new Sob-based monomers was studied using three different unsaturated polyesters (UPs): one commercially available and two fully bio-based that are synthesized in this work. The Sob-based monomers were able to fully dissolve the three UPs. Although UPRs with SobAcr showed higher thermal stability than SobMet-based materials, SobMet-based formulations presented higher glass transition temperatures (Tg) and storage moduli (E′). Overall, both Sob-based monomers exhibited promising properties to be used as low-volatile, bio-based effective Sty substitutes, and by that means mitigate a serious environmental issue concerning human exposure to toxic, volatile organic compounds (VOCs).

Background: Upper and lower respiratory tract infections are common conditions for which medical advice is sought, and their management relies on the use of prescription and over-the-counter (OTC) medicines. Ambroxol, bromhexine, carbocysteine, erdosteine, N-acetyl cysteine (NAC), and sobrerol are mucoactive agents for which clinical trials have been conducted, have been awarded well-established status by regulatory authorities, and are available as OTC or prescription products. Objective: To briefly review the evidence-based efficacy and safety of these substances in the therapy of upper respiratory airways infections. Methods: We conducted searches in MEDLINE and other databases for clinical trials and reviews done on the efficacy and safety of ambroxol, bromhexine, carbocysteine, erdosteine, NAC, and sobrerol. Results: Clinical trials have shown that these mucolytics have an important place in the relief of cough symptoms by easing the elimination of mucus. All drugs have shown comparable efficacy in the symptomatic treatment of productive cough, with some shared characteristics and some specific features. Conclusions and relevance: All mucolytics reviewed have a good safety profile, although some precautions should be taken when using ambroxol and bromhexine, and the use of NAC and carbocysteine should be monitored in special patient groups. Overall, however, the available evidence from randomised, controlled, and observational trials, as well as pragmatic, real-life experience, suggests that these products are useful in the therapy of upper respiratory airways infections, including bronchitis, sinusitis, and rhinosinusitis.

In this communication, we report the gentle preparation of sobrerol from dihydroxylation of α-pinene synergistically catalyzed by V2O5-H2O2 under benign conditions. It was proposed that a “peroxo vanadium acid”, VVO(OH)(OOH), was formed by HOO− insertion and proton transfer between V2O5 and H2O2. Theoretical DFT calculations that using the dimer‑vanadium peracid as a model of the catalytically active species revealed that peroxo vanadium acid exhibited bifunctional catalytic capabilities resembling epoxidation of α-pinene by peracetic acid and then open-ring hydration with an acetic media.

Vanadium-containing molecular sieves (V-M(x)) were synthetized and applied as heterogeneous catalysts for the liquid phase oxidation of -pinene with hydrogen peroxide at 70 ◦C. It has been found that the vanadium content in V-M(x) materials affected the conversion of -pinene and product distribution. The turnover numbers increased strongly with the decreasing of V content probably caused by a high V dispersion. The major products were verbenone,trans-sobrerol and campholenic aldehyde. The acid–base properties of V-M(x) affected the distribution of products formed via the isomerization of -pinene oxide over Lewis acid sites to campholenic aldehyde while Brønsted acid sites brought about the formation of 1,2 pinanediol and trans-sobrerol by hydrolysis and by the opening of oxirane ring. The increase in V content in V-M(x) led to the increase in campholenic aldehyde, 1,2 pinanediol, trans- sobrerol and over oxidation products. Moreover, the effect of several solvents on the reaction oxidation was studied. The results showed that the highest -pinene conversions are obtained in the following order: acetonitrile > ethanol > isoamyl alcohol > methyl ethyl ketone. Thus, using aprotic solvents, the catalytic activity was increased and the formation of alkyl glycol ethers as by-product was not observed. Fil: Cánepa, Analía Laura. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Cordoba. Centro de Investigacion y Tecnologia Quimica; Argentina. Universidad Tecnologica Nacional. Facultad Regional Cordoba; Argentina Fil: Chanquia, Corina Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina Fil: Vaschetti, Virginia María. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Cordoba. Centro de Investigacion y Tecnologia Quimica; Argentina. Universidad Tecnologica Nacional. Facultad Regional Cordoba; Argentina Fil: Eimer, Griselda Alejandra. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Cordoba. Centro de Investigacion y Tecnologia Quimica; Argentina. Universidad Tecnologica Nacional. Facultad Regional Cordoba; Argentina Fil: Casuscelli, Sandra Graciela. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Cordoba. Centro de Investigacion y Tecnologia Quimica; Argentina. Universidad Tecnologica Nacional. Facultad Regional Cordoba; Argentina

Trans-sobrerol (Sob) and 8-p-menthen-1,2-diol (Limo-diol) are the primary products in the atmospheric oxidation of β-pinene and limonene, respectively. Because of their low volatility, they associate more likely to the liquid particles in the atmosphere, where they are subject to the aqueous phase oxidation by the atmospheric oxidants. In this work, through experimental and theoretical study, we first provide the rate constants of Sob and Limo-diol reacting with hydroxyl radical (·OH) in aqueous solution at room temperature of 304±3 K and 1 atm pressure, which are (3.05±0.5)×109 and (4.57±0.2)×109 L/(mol·s), respectively. Quantum chemistry calculations have also been employed to demonstrate the solvent effect on the rate constants in aqueous phase and the calculated results agree well with the measurements. Some reaction products have been identified based on liquid chromatography combined with mass spectroscopy and theoretical calculations.

A convenient and highly efficient synthesis of optically pure trans-(+)-sobrerol (1), starting from methyl 3,5-dihydroxy-4-methyl benzoate 2 in 8 steps with overall yield 26%, is reported. The key intermediate 4 is prepared in remarkably high yield by selectively esterification of 3 using lipase as catalyst. A critical step to stereoselectively inverse the configuration of 7 is realized under Mistunobu conditions.

To better understand the role of terpenic compounds in atmospheric chemistry the influence of sobrerol, a water-soluble product of photochemical autoxidation or ozonolysis of α -pinene, on the rate of S(IV) autoxidation was studied. Laboratory experiments were performed under heterogeneous conditions, at constant supply with S(IV) by dissolution of CaSO3.1/2 H2O fine particles and with air oxygen by diffusion through a planar gas-liquid interface. The progress of S(IV) autoxidation, uncatalysed or catalysed by Fe2(SO4)3 or CoSO4, was followed conductometrically. The inhibiting effect of sobrerol was discussed in terms of the chain reaction terminated in a step linear with respect to sulphoxy radicals. A method was proposed for quantification of the inhibiting effect and the rate constant (2.0–3.8)108 M−1s−1 was given for the step eliminating sulphate radicals. Further consequences of the inhibition: shifting the reaction locus from the gas-liquid (droplet) interface to the liquid (droplet) bulk and strong oscillations in the rate of S(IV) autoxidation resulting of the activity of sobrerol-derived radicals were also shown.

Pinecones from Pinus koraiensis Siebold & Zucc. (Pinaceae), which have historically been treated as an undesired waste by-product in the processing of seeds, have recently been shown to contain ingredients with potent biological activities, such as polyphenols exhibiting anti-tumor activity. With this study, we seek to broaden our understanding of anti-tumor compounds contained in these pinecones beyond just polyphenols. We found that the water extract of P. koraiensis pinecones exhibits significant anti-cancer activity, with IC50 values ranging from 0.62 to 1.73 mg/mL in four human lung cancer cell lines, A549, H1264, H1299, and Calu-6, irrespective of their p53 status. We also demonstrate that pinecone water extract induces apoptosis associated with caspase-3 activation in the same cancer cell lines. Chemical investigation of the pinecone water extract revealed eight main components (1-8), and their structures were identified as dehydroabietic acid (1), 15-hydroxy-7-oxodehydroabietic acid (2), 7β,15-dihydroxydehydroabietic acid (3), β-D-glucopyranosyl labda-8(17,13)-diene-(15,16)-lactone-19-oate (4), 7α,15-dihydroxydehydroabietic acid (5), (1S,2S,4R)-(+)-limonene-1,2-diol (6), sobrerol (7), and 4-hydroxy-benzoic acid (8). These findings suggest a novel biological application of P. koraiensis pinecones in combatting human lung cancer, and further identify the major compounds that could contribute to this anti-cancer activity. This article is protected by copyright. All rights reserved.

A simple and rapid isocratic HPLC assay is presented for the analysis and quantification of monoterpenes, i.e., carvone, cineole, perillaldehyde, perillyl alcohol and sobrerol in the diet of laboratory animals. The monoterpenes were extracted from the diet using 90% methanol in water. The analysis for the monoterpenes was performed by HPLC using a Whatman PartiSphere C18 column with UV detection. The mobile phase was isocratic methanol-water (72:28, v/v) for carvone, cineole, perillaldehyde and perillyl alcohol and methanol-water (65:35, v/v) for sobrerol. The method was simple with good repeatability (R.S.D. = 4.2-16.1%), reproducibility (R.S.D. = 3.7-19%), and accuracy (R.S.D. = 5.5-23.3%). The detection limit of the monoterpenes extracted from the diet was 2 micrograms/g for carvone, perillaldehyde and sobrerol, 20 micrograms/g for perillyl alcohol and 100 micrograms/g for cineole. Excellent resolution was achieved between the monoterpenes and the constituents of the diet. The method demonstrated applicability to monitoring the formulation of monoterpenes in the diet of laboratory animals.

Resolution of the mucolytic drug (±)- trans -sobrerol ( 1 ) was achieved by transesterification with vinyl acetate in organic media, catalyzed by free or immobilized Lipase PS. The enantioselectivity of the enzyme was markedly influenced by the nature of the organic solvent, but there was no correlation between enantiomeric ratio values (70–500) and either the hydrophobicity or the dielectric constant of the medium. With the enzyme immobilized onto Hyflo Super Cell and t -amyl alcohol as the solvent, the selectivity of Lipase PS for (−)- 1 was extremely high and, at 50 % conversion both (−)- trans -sobrerol and (+)- trans -sobrerol monoacetate were obtained in practically 100 % optical purity

The monoterpene d-limonene has been shown to an effective, non-toxic chemopreventive agent in mammary and other rodent tumor models. The studies reported here investigated structure-activity relationships among limonene and three hydroxylated derivatives in the prevention of dimethylbenz[a]anthracene (DMBA)-induced mammary cancer. Rats were fed control or 1% limonene, carveol, uroterpenol or sobrerol diets from 2 weeks before to one week after carcinogen administration. Carveol, uroterpenol and sobrerol significantly prolonged tumor latency and decreased tumor yield. Sobrerol was the most potent of the monoterpenes tested, decreasing tumor yield to half that of the control, a level previously achieved with 5% limonene diets. Excretion of radioactivity from [3H]DMBA was doubled in rats fed 5% limonene and nearly tripled in rats fed 1% sobrerol. Sobrerol is thus 5-fold more potent than limonene in both enhancing carcinogen excretion and in preventing tumor formation. These data demonstrate that hydroxylation of monoterpenes affects chemopreventive potential, with 2 hydroxyl groups greater than 1 greater than 0. Sobrerol, carveol and uroterpenol are novel cancer chemopreventive agents with little or no toxicity.

We have previously demonstrated the anticarcinogenic effects of monocyclic monoterpenes such as limonene when given during the initiation phase of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary cancer in Wistar-Furth (WF) rats. Here we investigated the possible mechanisms for this chemoprevention activity including limonene's effects on DMBA-DNA adduct formation and hepatic metabolism of DMBA. Twenty-four hours after carcinogen administration, there were approximately 50% of the total DMBA-DNA adducts found in control animals formed in the liver, spleen, kidney and lung of limonene-fed animals. While circulating levels of DMBA and/or its metabolites were not different in control and limonene-fed rats, there was a 2.3-fold increase in DMBA and/or DMBA-derived metabolites in the urine of the limonene-fed animals. Studies of the effects of limonene and sobrerol, a hydroxylated monocyclic monoterpenoid with increased chemoprevention activity, on phase I metabolizing enzymes revealed that these terpenoids modulated cytochrome P450 (CYP) and epoxide hydratase (EH) activity. The 5% limonene diet increased total CYP to the same extent as phenobarbital (PB) treatment when compared to control, while 1% sobrerol (isoeffective in chemoprevention to 5% limonene) did not. However, both 5% limonene and 1% sobrerol diets greatly increased the levels of microsomal EH protein and associated hydrating activities towards benzo[a]pyrene 4,5-oxide when compared to control and PB treatment. These changes also modified the rate and regioselectivity of in vitro microsomal DMBA metabolism when compared to PB treatment or control. Identification of the specific isoforms of CYP induced by these terpenoids was performed using antibodies to CYP isozymes in Western blot analysis and inhibition studies of microsomal DMBA metabolism. Five per cent limonene was more effective than 1% sobrerol at increasing the levels of members of the CYP2B and 2C families but was equally effective at increasing EH. Furthermore, both terpenoid diets caused increased formation of the proximate carcinogen, DMBA 3,4-dihydrodiol. While these terpene-induced changes in hepatic CYP and EH do not explain the anticarcinogenic mechanism of these chemopreventive agents, or the ability of limonene systemically to reduce DMBA-DNA binding, they do reveal novel and selective induction mechanisms of hepatic enzymes.

In a double-blind, randomized, placebo-controlled clinical trial, the safety and efficacy of 900 mg/day sobrerol granules given for up to 10 days was assessed in 40 patients with chronic catarrhal rhinosinusitis. At the beginning of treatment a total of six patients had a fever, whereas body temperature was normal in all patients at the end of the treatment. Treatment with sobrerol significantly ( P < 0.01) reduced frontal headache and rhinorrhoea, efficacy being confirmed by rhinomanometry. Patients treated with placebo experienced an improvement in frontal headache, rhinorrhoea and overall rhinomanometry scores. Treatment with sobrerol was well tolerated but two patients treated with placebo reported adverse reactions (stomach pain and cutaneous rash). These preliminary data suggest that sobrerol could be useful if administered with an anti-inflammatory drug for the treatment of chronic catarrhal rhinosinusitis.

The characterization of the solid state of sobrerol enantiomers and racemates has been accomplished by a number of techniques on solid phase such as thermal analysis (DSC) and spectroscopy (IR, 13C NMR, and X-ray diffraction both on powders and on single crystal). Experimental and theoretical binary phase diagrams of cis- and trans-sobrerol enantiomers and their mixtures have been drawn and are discussed. Thermal analysis allowed, moreover, the detection of cis racemate polymorphism. Finally, the quantitative analysis of the cis racemate as an impurity of the trans racemate by means of microcalorimetric determinations is reported.

This paper describes the separation of the enantiomeric and diastereomeric pairs of sobrerol and CO/1408 by reversed-phase (RP) using β-CDs in the above two approachers

A convenient and highly efficient synthesis of optically pure trans-(+)-sobrerol (1), starting from methyl 3,5-dihydroxy-4-methyl benzoate 2 in 8 steps with overall yield 26%, is reported. The key intermediate 4 is prepared in remarkably high yield by selectively esterification of 3 using lipase as catalyst. A critical step to stereoselectively inverse the configuration of 7 is realized under Mistunobu conditions.

C 10 H 18 O 2 , M r =170.25, monoclinic, P2 1 /c, a=16.955 (1), b=9.313 (1, c=13.380 (1) A, β=111.44 (1) o , V=1966.5 (3) A 3 , Z=8, D m =1.148, D x =1.150 g cm -3 , λMo Kα)=0.7107 A, μ=0.73 cm -1 , F(000)=752, T=296 K, R=0.026 for 1318 unique reflections with I>3σ(I). The asymmetric unit of the crystal contains two molecules joined by O-H...O [2.839 (2) A] hydrogen bonds and C-H...O [3.432 (3) A] weak contacts. The difference in stability of cis- and trans-sobrerol racemic compounds is accounted for in terms of their crystal structures.

The effects of two monocyclic monoterpenes, limonene and sobrerol, known as inhibitors of farnesyltransferase activity, were studied on monocrotaline (MCT)-induced lung injury, pulmonary hypertension and right ventricular hypertrophy in male Wistar rats. After 14 days, pulmonary arterial pressure values and the right ventricle to left ventricle plus septum weight ratios, RV/(LV + S), were markedly increased in rats subcutaneously injected with MCT (60 mg/kg). Limonene and sobrerol, administered daily at the oral dose of 400 mg/rat, markedly decreased the MCT-induced alterations. After treatment for 21 days, limonene still prevented pulmonary hypertension and the increase in RV/(LV + S). Both monoterpenes also reduced the increase in pulmonary arterial media thickness, the development of interstitial fibrosis and the increase in the number of macrophages in intra-alveolar spaces and of lymphocytes around the pulmonary veins. The present data indicate that treatment of rats with inhibitors of farnesyltransferase, like limonene and sobrerol, regulate the development of pulmonary hypertension.

The monocyclic monoterpenoid compounds limonene and sobrerol have anticarcinogenic activity when fed during the initiation stage of dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinogenesis. Here we investigated the potential roles of hepatic glutathione-S-transferase (GST; EC 2.5.1.18) and uridine diphosphoglucuronosyl transferase (UDPGT; EC 2.4.1.17) in monoterpene-mediated chemoprevention. Diets containing the isoeffective anticarcinogenic terpenes, 5% limonene or 1% sobrerol, elevated hepatic GST activity > 2-fold when measured using the general substrate 1-chloro-2,4-dinitrobenzene and 3,4-dichloronitrobenzene for the GST dimer 3-3. However, there were no significant changes in hepatic GST activity when 1,2-epoxy-3-(p-nitrophenoxy)propane was used. We found that both terpene diets increased GST affinity-purified protein 1.5-fold and the HPLC subunit profile. Liver GST subunit 3 had the greatest increase followed by 1 and 4 with no change in subunit 2. Both terpene diets significantly increased the activity of the methylcholanthrene-inducible and the phenobarbital-inducible UDPGT isozymes. We propose that much of the anticarcinogenic activity of these monocyclic monoterpenes during the initiation phase of DMBA carcinogenesis is mediated through the induction of the hepatic detoxification enzymes GST and UDPGT.

Differential Scanning Calorimetry was used to predict the physico-chemical compatibility between clenbuterol and some mucolytic drugs.Mixtures of clenbuterol and ambroxol, bromhexine, tiopronin, sobrerol, eprazinone and carbocysteine were examined. Using this method, only eprazinone and carbocysteine were found to be compatible with clenbuterol.

A sensitive gas—liquid chromatographic assay for sobrerol in biological fluids has been developed. The assay procedure involves esterification of both hydroxyl groups of sobrerol with pentafluoropropionic anhydride to form the diester which can be quantitated using gas—liquid chromatography—electron-capture detection. The detection limit of plasma sobrerol under the conditions described is 5 ng/ml. The assay procedure permits the measurement of unchanged drug in plasma, whole blood or urine in the presence of its metabolites.

The therapeutic activity and tolerability of sobrerol, a muco-active agent, were evaluated in 30 children (aged 5–10 years) with secretory otitis media. The drug was administered once daily by inhalation for 10 days consecutively at a dose of 40 mg/3 ml. Clinical assessments showed a significant improvement in the objective measures together with good tolerability. Moreover, sobrerol was shown to improve impedance values; this is an important aspect of the modifications induced by this drug in diseases involving the ear.

Water loss from frans-sobrerol upon electron impact ionization selectively involves the tertiary OH group, predominantly occurring by a stereocontrolled H-transfer from C(5) position in a rate-determining step process, as proved by 18O and deuterium labelling. Monomethyl ethers behave accordingly. Ionic structures of the water-loss product or products are investigated by metastable ion and collision activation mass-analysed ion kinetic energy spectroscopy, using model ions generated from some substrates, which are chemically related to fralts-sobrerol in condensed phase, i.e. α-pinane epoxide, cis-sobrerol and pinol. A substantial conversion of cis-sobrerol molecular ions to ionized pinol by loss of water has been demonstrated.

The stereoselective synthesis of the major oxygenated metabolites of trans-sobrerol (1) in optically active and/or racemic form is described.

The interaction of both nesosteine and trans-sobrerol with O2•− has been studied by electrogenerating this anion radical in acetonitrile and monitoring voltammetrically its disappearance upon addition of the named mucofluidifier drugs. This approach makes it possible to establish that nesosteine acts as an effective sacrificial superoxide quencher, while trans-sobrerol is unable to react with such a radical species. A reaction pathway is proposed which is consistent with the data and implies that the amidic bond present in nesosteine is involved in the first interaction step. The effect on this reaction caused by the addition of moderate amounts of water to acetonitrile has also been investigated.

1. Metabolism of 14C-trans-sobrerol (I) by Sprague-Dawley rat liver microsomes did not result in covalent binding to proteins, lipid peroxidation or cytochrome P-450 destruction. 2. Subacute and chronic treatment of Sprague-Dawley rats with (I) resulted only in an increase in liver cytosolic GSH-S-transferase. 3. Acute treatment of rats with trans-sobrerol or its metabolite, 8-hydroxycarvotanacetone (II) produced considerable GSH depletion, faster in the case of II, in both liver and lung; the original GSH levels were restored within 24 h. No significant increase in lipid peroxidation was found even when GSH was at its lowest level. 4. UDP-glucuronyltransferase and GSH-S-transferase conjugation occurred with trans-sobrerol and some of its metabolites although at low rates.

1. The urinary metabolites of d, l-trans-sobrerol were investigated after oral administration to rats, dogs and humans.2. Structural analysis of the urinary metabolites indicates that allylic hydroxylation, oxidation and glucuronylation are the common interspecies modes of trans-sobrerol biotransformation.3. Comparison of the findings of trans-sobrerol with previous investigations of cyclic monoterpenes shows similarities in their metabolism in vivo, including the resistence to oxidation of the cyclic trisubstituted double bond.

Some pharmacological properties of Sobrerol have been assessed, in frog palate preparation, by measuring the mucociliary transport velocity due to mucus samples obtained from patients suffering from chronic bronchial inflammatory diseases characterized by dense bronchial secretions. The patients were studied before and after 4 days of treatment with Sobrerol, 600 mg per day per os. The significant increase in the relative ratio of mucociliary transport of mucus of treated patients, together with evidence coming from previous experiments, indicates that this drug is capable of modifying rheological properties of bronchial secretions, in such patients, through an ‘in vivo’ muco-regulating activity, thus facilitating mucociliary clearance.