Natural spirocyclic alkaloids and polyphenols as multi target dementia leads.

The U rhynchophylla, U tomentosa, Isatis indigotica Fortune, Voacanga Africana, herbal constituents, fungal extracts from Aspergillus duricaulis culture media, include spirooxindoles, polyphenols or bridged spirocyclic alkaloids. Their constituents exhibit specific and synergistic multiple neuroprotective properties including inhibiting of Aß fibril induced cytotoxicity, NMDA receptor inhibition in mice models of Alzheimer's disease (AD). The pioneering research from Woodward to Waldmann has advanced the synthesis of spirocyclic alkaloids. Furthermore, the elucidation of the genetic analysis, biochemical pathways that links strictosidine to the alkaloids akuammicine, stemmadenine, tabersonine, catharanthine, will now enable the biotechnological generation, also stimulate synthesis of related bridged spirocyclic alkaloids for medicinal investigations. From the value of spirocyclic structures as multi target dementia leads, we hypothesise that simpler Lipinski-like natural/synthetic alkaloid analogues may likewise be discovered that provide neurocognitive enhancing activities against dementia and AD.

Microwave-assisted rapid synthesis of spirooxindole-pyrrolizidine analogues and their activity as anti-amyloidogenic agents.

A library of Sox-pyrrolizidines was rapidly prepared by microwave-assisted, one-pot, three-component, 1,3-dipolar cycloaddition of azomethine ylides from l-proline and isatin, with various ß-nitrostyrenes. Nitro-Sox compounds, 4b, 4d and 4e inhibit HEWL amyloid fibril formation by ThT studies with percentages of fluorescence intensity of 55.4, 42.9 and 40.3%, respectively. Further studies with MTT assay, Raman spectroscopy, TEM and molecular docking supported these promising candidates for activity against amyloid misfolding, a phenomenon leading to Alzheimer's disease pathology.

Fenugreek increases insulin-stimulated creatine content in L6C11 muscle myotubes.

PURPOSE: Creatine uptake by muscle cells is increased in the presence of insulin. Accordingly, compounds with insulin-like actions may also augment creatine uptake. The aim of this study was to investigate whether Trigonella foenum-graecum (fenugreek), an insulin mimetic, increases total intracellular creatine levels in vitro. METHODS: Total cellular creatine content was measured fluorometrically in L6C11 muscle myotubes treated for 1, 4, and 24 h with 0.5 mM creatine (CR), CR and 20 µg/mL fenugreek seed extract (CR + FEN), CR and 100 nM insulin (CR + INS), and CR + INS + FEN (n = 6 per treatment group). Alterations in the expression of the sodium- and chloride-dependent creatine transporter, SLC6A8, and key signaling proteins in the PI3-K/Akt pathway were determined. RESULTS: Compared to control (CON), CR + INS + FEN increased total creatine content after 4 h (P < 0.05), whereas all conditions increased SLC6A8 protein expression above CON at this time (P < 0.05). Changes in insulin signaling were demonstrated via increases in AktThr308 phosphorylation, with CR + INS > CON and CR at 1 h (P < 0.05) and with CR + INS + FEN > CON, CR, and CR + INS at 4 h (P < 0.05). In contrast, no changes in PKCζ/λ or GLUT4 phosphorylation were detected. CONCLUSION: Fenugreek, when combined with insulin, modulates creatine content via a mechanism which is independent of the activity of SLC6A8, suggesting that an alternative mechanism is responsible for the regulation and facilitation of insulin-mediated creatine uptake in skeletal muscle cells.

Macrolactam analogues of macrolide natural products.

The chemical modification of macrolide natural products into aza- or lactam analogues is a strategy employed to improve their metabolic stability and biological activity. The methods for the synthesis of several lactam analogues of macrolide natural products are highlighted and aspects of their biological properties presented.

Brain Food for Alzheimer-Free Ageing: Focus on Herbal Medicines.

Healthy brain aging and the problems of dementia and Alzheimer's disease (AD) are a global concern. Beyond 60 years of age, most, if not everyone, will experience a decline in cognitive skills, memory capacity and changes in brain structure. Longevity eventually leads to an accumulation of amyloid plaques and/or tau tangles, including some vascular dementia damage. Therefore, lifestyle choices are paramount to leading either a brain-derived or a brain-deprived life. The focus of this review is to critically examine the evidence, impact, influence and mechanisms of natural products as chemopreventive agents which induce therapeutic outcomes that modulate the aggregation process of beta-amyloid (Aß), providing measureable cognitive benefits in the aging process. Plants can be considered as chemical factories that manufacture huge numbers of diverse bioactive substances, many of which have the potential to provide substantial neuroprotective benefits. Medicinal herbs and health food supplements have been widely used in Asia since over 2,000 years. The phytochemicals utilized in traditional Chinese medicine have demonstrated safety profiles for human consumption. Many herbs with anti-amyloidogenic activity, including those containing polyphenolic constituents such as green tea, turmeric, Salvia miltiorrhiza, and Panax ginseng, are presented. Also covered in this review are extracts from kitchen spices including cinnamon, ginger, rosemary, sage, salvia herbs, Chinese celery and many others some of which are commonly used in herbal combinations and represent highly promising therapeutic natural compounds against AD. A number of clinical trials conducted on herbs to counter dementia and AD are discussed.

Danshen diversity defeating dementia.

Salvia miltiorrhiza (danshen) is widely used for the clinical treatment of cerebral ischemia and cardiovascular diseases. Its diverse molecular makeup of simple and poly hydroxycinnamic acids and diterpenoid quinones are also associated with its beneficial health effects such as improved cognitive deficits in mice, protection of neuronal cells, prevention of amyloid fibril formation and preformed amyloid fibril disaggregation related to Alzheimer's disease. Whilst the in vitro studies have therapeutic promise, the anti-dementia effect/impact of danshen however depends on its absorbed constituents and pharmacokinetic properties. Both the water and lipid danshen fractions have been shown to have low oral bioavailability and at physiological pH, the polyphenolic carboxylate anions are not brain permeable. To tap into the many neuroprotective and other biological benefits of danshen, the key challenge resides in developing danshen nanopharmaceuticals, semi-synthetic pro-drug forms of its constituents to improve its biocompatability, that is, absorption, circulation in bloodstream and optimization of BBB permeability.

A modeling approach for orthogonality of comprehensive two-dimensional separations.

A novel method is developed for orthogonality evaluation of comprehensive two-dimensional separations (C2DS). Utilization of efficiency measures such as peak capacity (n(c)) can be critically evaluated for C2DS analysis to describe an orthogonal separation of the analytes in a 2D plane. Unlike most previous methods focusing on "bin coverage" over 2D space, rather than taking into account the distribution based on accurate peak retention, in the proposed method, the separation orthogonality of C2DS is divided into two parts (i.e., C(pert) and C(peaks)). These correspond to peak coverage percent, and 2D distribution correlation of compounds, respectively. Bin occupation and a simple-linear regression model, on the basis of normalized retention times in 2D separation space ((1)t(R) and (2)t(R)), are further introduced to quantitatively define the two terms. Orthogonality ranges from 0 to 1 correspond to perfectly correlated and orthogonal separations, respectively, which are presented based on both C(pert) and C(peaks) considerations. The advantage of this method is the use of separation properties of C2DS to characterize practical 2D peak distribution and does not rely on assumptions or any imposed limitations. Simulation of comprehensive two-dimensional gas chromatography (GC × GC) was achieved by using the Abraham solvation parameter model, and applied to generate examples for orthogonality assessment. In this work, 225 compounds comprising a range of chemical classes were simulated for separation on two column set pairs comprising low polarity/polar and moderately polar/polar combinations. Results illustrate that the proposed method applied to GC × GC provides a reasonable assessment of 2D separation performance and may be used to derive optimal experimental conditions when used with an experimental design strategy.

Total synthesis of (+)-pentamethylsalvianolic acid C.

The total synthesis of a methylated analogue of (+)-Salvianolic acid C has been achieved. Key aspects of the synthetic route include an economical Cu(I) acetylide coupling, unique carboxyl activation conditions via microwave irradiation and a novel lipase catalysed kinetic resolution of a racemic mixture of secondary alcohol Danshensu. The preparation of this methylated analogue will not only improve the bioavailability, but also enable access to new and wider bioactivity applications for (+)-Salvianolic acid C.

Tandem nucleophilic addition-Oppenauer oxidation of aromatic aldehydes to aryl ketones with triorganoaluminium reagents.

In the presence of pinacolone, the in situ prepared triorganoaluminium reagents reacted with aromatic aldehydes to give ketones in moderate to high yield. We propose that the products are formed via a tandem organoaluminium reagents addition-Oppenauer oxidation sequence.

Simultaneous estimation of retention times of overlapping primary peaks in comprehensive two-dimensional GC.

A general approach is developed to estimate the retention time (t(R)) of overlapping primary peaks in comprehensive 2D GC without assumptions such as the limitation of modulation ratio or symmetry of the target primary peak. Accurate determination of t(R) can recover the original peak profile by using mathematical fitting. First, the modulation pattern of the first-dimension peak in the second dimension is summarized with the number of major modulation fractions equal to or less than four. A novel formula to derive t(R) is defined and separately investigated for cases of modulation number for 1-4, on the basis of the center of gravity of all fractions of the primary peak, in the second dimension. A moving-window search strategy is further developed for peak clusters overlapping in both separation dimensions, to extract first dimension tR of pure components with the same second dimension time after data pretreatment (background subtraction; time shift correction). Results are very close to the times of simulated comprehensive 2D GC separations. Compared to methods such as reconstruction of original chromatographic profiles to derive t(R), the proposed approach balances the precision, and ease of adaption to real applications.

Evaluating the traditional Chinese literature for herbal formulae and individual herbs used for age-related dementia and memory impairment.

Natural products are the basis of many systems of traditional medicine and continue to provide sources for new drugs. Ethnobiological approaches to drug discovery that have proven productive in the past include the investigation of traditional medical literatures. This study describes a broadly applicable method for locating, selecting and evaluating citations in the traditional Chinese herbal medicine literature of the dynastic period (until 1911) for specific symptoms or disorders. This methodology is applied to evaluate multi-herb formulae for age-related dementia and memory impairment. Of the 174 multi-herb formulae located in the searches, 19 were for disorders broadly consistent with amnestic Mild Cognitive Impairment (MCI) and/or Age Associated Memory Impairment (AAMI). These appeared in books written between c. 650 to 1911. Of the 176 herbs that appeared in these 19 formulae, those with the highest frequencies were tabulated and hierarchical cluster analysis was undertaken. Chinese pharmacopoeias were consulted to determine the botanical identity of the herbs and also which herbs within the formulas were specific for memory disorders. This study found that the top ten herbs, in terms of frequency of inclusion in multi-herb formulae specific for age-related memory disorders, were all listed in the pharmacopoeias for memory disorders and these formed three clusters. The herbs identified in this study may warrant further experimental and clinical evaluation both individually and in combination.

Trimethylsilyl chloride promoted synthesis of α-branched amines by nucleophilic addition of organozinc halides to nitrones.

A general procedure for the nucleophilic addition of organozinc halides with nitrones in the presence of trimethylsilyl chloride has been developed. Trimethylsilyl chloride was found to be both an indispensable reaction promoter and a ready hydroxylamine protective agent in these reactions. The produced O-(trimethylsilyl)hydroxylamines can be easily reduced into corresponding amines just by a zinc-copper couple in saturated aqueous NH(4)Cl solution.

Regioselective pyrrolizidine bis-spirooxindoles as efficient anti-amyloidogenic agents.

Here, we report a microwave-assisted, one-pot, three-component, 1,3-dipolar cycloaddition reaction to produce highly regioselective and stereoselective bis-spirooxindoles as potential inhibitors against amyloid-ß fibrillation. Ease of synthesis, promising anti-amyloidogenic activity, low toxicity, and in vitro blood brain barrier permeability makes these compounds attractive therapeutic leads to treat Alzheimer's disease.

Chemometrics in comprehensive multidimensional separations.

Chemometric methods have critical importance for the discovery of the information/knowledge buried or concealed in high-dimensional datasets acquired from comprehensive multidimensional separations (CMDS), and for interpretation of experiments or chemical processes. In this work, employment of new developments in chemometrics making full use of the data to maximize the potential of CMDS to resolve mathematically a variety of practical problems is reviewed whilst providing the authors' point of view. During the past several years, chemometrics has been successfully applied to many areas of concern to CMDS investigation, including experimental parameter optimization, data quality improvement, identification and quantification of target chemical components, pattern recognition technique for clustering and classification, multivariate model establishment to correlate chromatographic properties and molecular descriptors. On the basis of the high-dimensionality characteristics of CMDS, some special aspects such as evaluation of orthogonality and image processing have also been included in this review. It is expected that an overview of the diverse ways in which chemometrics can aid CMDS investigations will prove valuable to interested users in this area through a comprehensive survey of previous research contributions. Chemometrics lends itself well to the powerful separation capability of CMDS.

Microwave multicomponent synthesis.

In the manner that very important research is often performed by multidisciplinary research teams, the applications of multicomponent reactions involving the combination of multiple starting materials with different functional groups leading to the higher efficiency and environmentally friendly construction of multifunctional/complex target molecules is growing in importance. This review will explore the advances and advantages in microwave multicomponent synthesis (MMS) that have been achieved over the last five years.

Marine fragrance chemistry.

The main marine message in perfumery is projected by Calone 1951 (7-methyl-2H-1,5-benzodioxepin-3(4H)-one). Kraft (Givaudan) and Gaudin (Firmenich) further maximized the marine fragrance molecular membership by extending the carbon chain of the 7-Me group. Our research targeted the polar group of the benzodioxepinone parent compound to investigate how this region of molecular makeup resonates with the dominant marine fragrance of the Calone 1951 structure. The olfactory evaluation of analogues prepared by chemical modification or removal of the CO group resulted in the introduction of aldehydic, sweet and floral-fruity notes with a diluted/diminished potency of the marine odor. To further analyze the olfactory properties of benzodioxepinones containing a diverse range of aromatic ring substituents, a novel synthesis route was developed. We found that a 7-alkyl group in Calone 1951 was essential for the maintenance of the significant marine odor characteristic, and our studies support the concept that the odorant structure occupying the hydrophobic binding pocket adjacent to the aromatic ring-binding site of the olfactory receptor is pivotal in the design and discovery of more potent and characteristic marine fragrances. How the structure of benzodioxepinones connects to marine sea-breeze fragrances is our continuing challenging research focus at the chemistry-biology interface.

Does acupuncture or Chinese herbal medicine have a role in the treatment of allergic rhinitis?

PURPOSE OF REVIEW: Complementary medicines, including acupuncture and Chinese herbal medicine, are being used increasingly for the management of allergies such as allergic rhinitis. Until relatively recently, however, evidence for the efficacy and safety of these therapies in allergic conditions has been lacking. RECENT FINDINGS: A limited number of well conducted studies, all with small sample sizes, have demonstrated the promising therapeutic potential of acupuncture and Chinese herbal medicine for allergic rhinitis. The possible additional benefit of combining the two therapies, however, is yet to be confirmed. There are concerns about the appropriateness of the sham/placebo controls that have been used in acupuncture studies and also about the safety evaluation of individual herbs and herbal formulations. In addition to well established symptom scores and specific quality of life questionnaires, the concurrent use of conventional anti-allergy medications has been utilized as an outcome measure in a number of trials that have evaluated the effectiveness of acupuncture and Chinese herbal medicine for allergic rhinitis. SUMMARY: Tentatively, it appears that acupuncture and Chinese herbal medicine can be effective treatments for allergic rhinitis. Confirmatory evidence, however, is needed from large and, ideally, multi-centre trials.

Polyphenol protection and treatment of hypertension.

INTRODUCTION: High blood pressure is the major risk factor for cardiovascular diseases and the rising prevalence of human hypertension precedes the trend toward a global epidemic of unhealthy ageing. A focus on lifestyle and dietary interventions minimizes dependency on pharmacological antihypertensive therapies. REVIEW: Observational studies indicate that the intake of dietary flavonoids is associated with a decreased risk of cardiovascular disease (CVD). The evidence suggests that the dietary intakes of polyphenol-rich foods, herbs and beverages including flavonols, anthocyanidins, proanthocyanidins, flavones, flavanones, isoflavones and flavan-3-ols, improves vascular health, thereby significantly reducing the risk of hypertension and CVD. Consumption is associated with an improvement in endothelial function via vascular eNOS and Akt activation. Increased NO bioavailability improves vasodilation and blood circulation, effects protein kinases, ion channels and phosphodiesterases, counteracting vascular inflammation and LDL oxidative stress. Importantly, some polyphenols also inhibit the activity of matrix metalloproteinases, inhibit angiotensin converting enzyme activity and thereby improving SBP and DSB. We review the improvement of polyphenol intake on blood pressure and endothelial function for the treatment of hypertension, including not only observational but also RCTs and pre-clinical studies. CONCLUSION: The antihypertensive phytotherapy of polyphenol-rich foods for protection and improving endothelial function with vascular relaxation occurs via the NO-cGMP pathway and ACE inhibition. OPCs stimulate endothelium-dependent vasodilation, suppress vasoconstrictor ET-1 synthesis, activate a laminar shear stress response in endothelial cells and also inhibit the activity of metalloproteinases including ACE lowering blood pressure.

Synthesis and biological evaluation of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one structural derivatives as anti-cancer and apoptosis inducing agents.

A series of thirteen 5H-dibenzo [b,e][1,4]diazepin-11(10H)-one structural derivatives has been synthesized and evaluated for anti-proliferative activity against five human cancer cell lines. Compound 9a exhibited potent tumour growth inhibition in all cell lines with IC50 values in the range of 0.71-7.29 µM. Experiments on lung (A549) and breast (MDAMB-231) cancer cell lines to investigate the mechanisms of growth inhibition and apoptosis inducing effects of 9a showed that it arrested both cancer cell lines in the G2/M phase of cell cycle in a dose dependent manner. Hoechst staining analysis revealed that 9a inhibited tumour cell proliferation through apoptosis induction. Additionally, the mitochondrial membrane potential (ΔΨm) was affected and the levels of reactive oxygen species (ROS) were raised. The simple synthetic preparation and their biological properties make these dibenzodiazepinone-triazole scaffolds promising new entities for the development of cancer therapeutics.

Anti-amyloidogenic properties of some phenolic compounds.

A family of 21 polyphenolic compounds consisting of those found naturally in danshen and their analogues were synthesized and subsequently screened for their anti-amyloidogenic activity against the amyloid beta peptide (Aß42) of Alzheimer's disease. After 24 h incubation with Aß42, five compounds reduced thioflavin T (ThT) fluorescence, indicative of their anti-amyloidogenic propensity (p < 0.001). TEM and immunoblotting analysis also showed that selected compounds were capable of hindering fibril formation even after prolonged incubations. These compounds were also capable of rescuing the yeast cells from toxic changes induced by the chemically synthesized Aß42. In a second assay, a Saccharomyces cerevisiae AHP1 deletant strain transformed with GFP fused to Aß42 was treated with these compounds and analyzed by flow cytometry. There was a significant reduction in the green fluorescence intensity associated with 14 compounds. We interpret this result to mean that the compounds had an anti-amyloid-aggregation propensity in the yeast and GFP-Aß42 was removed by proteolysis. The position and not the number of hydroxyl groups on the aromatic ring was found to be the most important determinant for the anti-amyloidogenic properties.