Enantioselective synthesis of a costic acid analogue with acaricidal activity against the bee parasite Varroa destructor.

One major disease of the pupae and the adult bee is the so-called Varroosis that is owing to the bee parasite Varroa destructor. It is an ectoparasite of bees, causing significant losses in the bee population needed for honey production as well as for pollination in agriculture. Costic acid is a sesquiterpene-carboxylic acid present in the plant Dittrichia viscosa. Recent studies by our group have shown that costic acid acts as acaricide against V. destructor. Oxalic acid is also an acaricide commonly used against varroa mites. In spite of its structural simplicity-it is the simplest bicarboxlic acid-it is equipotent to costic acid which consists of a trans-decalin system with three chiral centres. The basic goal of this project was to design and synthesize a hybrid entity, incorporating aspects of both oxalic acid and costic acid that would be more active than the parent compounds. This approach introduces a useful strategy for the preparation of congeners of bioactive compounds and proposes a structural framework for a new series of acaricidal agents.

Reporting effectiveness of an extract of three traditional Cretan herbs on upper respiratory tract infection: results from a double-blind randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Observations from the island of Crete, Greece suggest that infusions of traditional Cretan aromatic plants, well known for their ethnopharmacological use in Eastern Mediterranean region and Near East, could be effective in the prevention and treatment of upper respiratory tract infections, including viral-induced infections. The aim of this study was to report the effectiveness of an essential-oil extract of three Cretan aromatic plants in the treatment of cases with an upper respiratory tract infection. MATERIALS AND METHODS: A double blind randomized controlled trial was implemented between October 2013 and February 2014. An essential-oil extract of Cretan aromatic plants in olive oil (total volume of 15ml of essential oil per litre of olive oil) was administered as 0.5ml soft gel capsules, twice a day, for 7 days. Placebo treatment was 0.5ml olive oil in soft gel capsules. Eligible patients were those presenting for clinical examination in the selected setting with signs and symptoms of upper respiratory tract infection that had begun within the previous 24 hours. Real-Time Polymerase Chain Reaction (PCR) was used for the detection of respiratory viruses. The primary outcome was the severity and duration of symptoms of upper respiratory tract infection, assessed using the Wisconsin Upper Respiratory System Survey (WURSS-21) questionnaire. A secondary outcome of interest was the change in C-reactive protein (CRP) status. RESULTS: One hundred and five patients completed the study: 51 in the placebo group, and 54 in the intervention (treated) group. Baseline characteristics were similar in the two groups. No statistically significant differences were found in symptom duration or severity between the two groups, although small and clinically favorable effects were observed. When the analysis was restricted to subjects with a laboratory-documented viral infection, the percentage of patients with cessation of symptoms after 6 days of treatment was 91% in the intervention group and 70% in the control group (p=0.089). At baseline, one third of the patients in each group had elevated CRP levels. At follow-up, the respective proportions were 0% in the intervention group and 15% in the placebo group (p=0.121). The data were also in a favorable direction when 50% and 80% symptom reduction points were considered for specific virus types. CONCLUSIONS: Compared with placebo the essential-oil extract of three Cretan aromatic plants provided no detectable statistically significant benefit or harm in the patients with upper respiratory illness, although descriptive differences were identified in favorable direction mainly in the virus-positive population.

Near-membrane iminocoumarin-based low affinity fluorescent Ca(2+) indicators.

Two new potential near-membrane iminocoumarin-based fluorescent Ca(2+) indicators were synthesized and the spectral profiles of their free and Ca(2+) bound forms were studied. The probes incorporate in their BAPTA-related structures, the 3-(benzimidazolyl)iminocoumarin or the 3-(benzothiazolyl)iminocoumarin moiety, substituted at the imino nitrogen with an n-dodecyl lipophilic chain. The compounds are excited with visible light and have Ca(2+) dissociation constant values of 5.50 and 4.49 microM, respectively, the highest reported to date in the literature. Fluorescence spectra studies indicated a clear shift in their excitation wavelength maxima upon Ca(2+) binding along with changes in fluorescence intensity that enable the compounds to be used as ratiometric near-membrane, low Ca(2+) affinity probes.

Polycarboxylate fluorescent indicators as ion concentration probes in biological systems.

A large number of techniques have been applied to monitor the function of free metal ions in biological systems. Fluorescent ion probes have evolved into an extremely useful tool for contemporary experimentalists. Polycarboxylate indicators are widely used in the determination of metal ion concentrations, especially due to their cell membrane permeability. The design of these probes required detailed knowledge in related fields of medicine, biology, and chemistry, and their preparation demanded the expertise of organic synthesis. In this review, the basic rationale for the selection of particular chemical structures are analyzed, synthetic pathways leading to the desired structures are presented, often via a retrosynthetic approach, and properties and relative advantages of the use of these probes are described. References to specific applications are limited, given the large number of reviews on related subjects. Topics such as those related to dextran conjugates that are broad enough to be the subject of a different review are not included, and leakage resistance and near-membrane probes are mentioned briefly in separate sections, although these are chemically similar to typical polycarboxylate dyes. While reference to topics mentioned in related reviews is unavoidable, presentation of material in this review is from the point of view of a medicinal chemist rather than that of the many experts using these pioneering techniques.

Iminocoumarin-based low affinity fluorescent Ca2+ indicators excited with visible light.

A series of iminocoumarin-based fluorescent Ca2+ indicators were synthesized and the spectral profiles of their free and Ca2+ bound forms were studied. The newly-synthesized compounds incorporate the Ca2+ chelating structure of BAPTA. The chromophore moieties are iminocoumarins substituted at the 3-position with benzothiazolyl, benzoxazolyl and benzimidazolyl groups. These compounds are excited with visible light and their Ca2+ dissociation constants range from 5.4 to 27.5 microM. Fluorescence spectra studies of these probes indicated a clear shift in their excitation wavelength maxima upon Ca2+ binding along with changes in fluorescence intensity that enable the compounds to be used as low Ca2+ affinity, visible excitable probes.

Cis- and trans-N-benzyl-octahydrobenzo[g]quinolines. Adrenergic and dopaminergic activity studies.

In vitro assays on a series of cis- and trans-octahydrobenzo[g]quinolines indicated an unusual trend of affinities at the dopaminergic receptors and alpha adrenoceptors. The trans N-benzyl analogues exhibited affinity at the alpha2 as well as the D1-like receptors whereas their N-unsubstituted congeners showed a distinct preference for the alpha2 adrenoceptor. Enhanced activity for the alpha2 receptors was also exhibited by the cis N-benzylated isomers. These observations are interpreted by theoretical calculations.

N-(Iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines: synthesis and adrenergic and dopaminergic activity studies.

A series of N-(iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines was synthesized and assayed in vitro for their dopaminergic and alpha-adrenergic activity. Structure-activity relationship (SAR) analysis revealed that the tested benzoquinolines exhibited activity at the D1 rather than the D2 receptor sites in contrast to the D2 receptor subfamily activity reported for their aminotetralin congeners. N-Iodopropenyl substitution was apparently a decisive factor for D1 activity independent of ring substitution pattern. Considering the structural factors influencing alpha-adrenergic activity, in a general trend, N-iodopropenyl analogues were alpha1-active, with the ring-hydroxylated congeners exhibiting the highest affinity. Affinity to the alpha2 receptor was even higher with no detectable trend of SAR. However, a combination of the linear arrangement of the [g]-ring system, combined with the ring hydroxyl and the N-iodopropenyl substitution in compound 5c, resulted in a significant enhancement of alpha2 activity in this series as demonstrated by an IC50 value of 0.5 nM. A new synthetic approach to the [g]benzoquinoline system is also described.

Detection of cardiovascular calcified deposits via tetracarboxylate ion dye (BTC) probing and laser-induced fluorescence spectroscopy.

In order to develop a reliable, laser-induced, fluorescence-guided, angioplasty system, fluorescence spectra were recorded during exposure of normal and atherosclerotic cadaveric aortic tissue to argon ion laser irradiation. A characteristic increase in the fluorescence signal in the 520-560 nm spectral region for atheromatous tissue was observed after treatment of the samples with a tetracarboxylate ion dye (BTC). This allowed the development of a simple algorithm (based on the intensity difference) and a subsequent index of discrimination between normal and atheromatous tissue. Our results suggest that monitoring of this index through the catheter could enhance selective ablation.

The development of a new family of intracellular calcium probes.

Four new potential fluorescent probes for Ca2+ using the coumarin moiety as a fluorophore have been synthesized and their spectral properties and binding affinities for Ca2+ determined. The most promising derivative for intracellular use, BTC, exhibits an excitation wavelength shift from 462 nm to 401 nm on binding Ca2+, with an emission wavelength of 530 nm. The quantum yield of this probe increases from 0.07 as the free indicator to 0.12 on binding Ca2+. BTC, loaded as its tetraacetoxymethyl ester (AM ester) into mouse myeloma P3X cells, responded only when cytoplasmic Ca2+ exceeded typical intracellular calcium concentrations. The dye, therefore, appears to be useful in excitatory cells or extracellular spaces with intracellular calcium concentrations high enough to saturate typical excitation ratio Ca2+ indicators such as Fura-2.

Striatally-mediated response of some structurally rigid analogues of dopamine.

The potency of structurally rigid analogues of dopamine (DA) at striatal dopamine receptors was evaluated in rats using three types of assessments: (a) effectiveness in producing rotational and sniffing behaviors by intrastriatal injections (b) inhibition of [3H]-spiroperidol binding and (c) stimulation of adenylate cyclase activity. The compounds included apomorphine (APO) and its analogues, (R)-2,10,11-trihydroxyaporphine (R-THA) and (R)-2-hydroxy-10,11-methylenedioxyaporphine (MDO-APO), 2-amino-6,7-dihydroxyaminotetraline (ADTN) and its analogue, exo-2-amino-6,7-dihydroxybenzonorbornene (exo-amine). (R)-THA produced no stereotypy yet it was a potent inhibitor of [3H]-spiroperidol binding and adenylate cyclase activity. MDO-APO was quite active in inducing stereotypy and stimulating cyclase activity, but it showed low potency in displacing [3H]-spiroperidol. The exo-amine and ADTN were equally potent in enhancing rotation and sniffing intensity, however, the former was completely inactive in biochemical assessments. Except for (R)-THA, all DA analogues studied elicited dopaminomimetic behavioral activities of circling and sniffing. Relationships between the actions of these drugs in the behavioral and biochemical assessments are discussed.

Synthesis and dopamine receptor binding of exo- and endo-2-amino-6,7-dihydroxybenzonorbornene, rigid analogues of 2-amino-6,7-dihydroxytetrahydronaphthalene.

Two bridged tricyclic analogues of 2-amino-6,7-dihydroxytetrahydronaphthalene (ADTN) in which the amino group is held rigidly in an equatorial and axial conformation, respectively, and in which the catechol ring is twisted out of the plane of the ethylamine chain have been synthesized and assayed for their effects on the binding of [3H]dopamine, [3H]apomorphine, and [3H]spiperone to calf and rat striatal homogenates. Up to concentrations of 2000 nM, these exo- and endo-2-amino-6,7-dihydroxybenzonorbornenes displayed no ability to displace any of the radioligands from their receptor sites in the calf and rat brain homogenates, in contrast to measured IC50 values of 6 and 3.1 nM for racemic ADTN vs. [3H]dopamine in the two preparations, respectively. The enantiomers of the exo amine showed no specific activity vs. [3H]dopamine in the two preparations, respectively. The enantiomers of the exo amine showed no specific activity vs [3H]dopamine. Although negative, these data are informative in molecular modeling of dopaminergic receptor interactions.