The potential use of plant natural products and plant extracts with antioxidant properties for the prevention/treatment of neurodegenerative diseases: in vitro, in vivo and clinical trials.

Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Huntington's disease, present a major health issue and financial burden for health care systems around the world. The impact of these diseases will further increase over the next decades due to increasing life expectancies. No cure is currently available for the treatment of these conditions; only drugs, which merely alleviate the symptoms. Oxidative stress has long been associated with neurodegeneration, whether as a cause or as part of the downstream results caused by other factors. Thus, the use of antioxidants to counter cellular oxidative stress within the nervous system has been suggested as a potential treatment option for neurological disorders. Over the last decade, significant research has focused on the potential use of natural antioxidants to target oxidative stress. However, clinical trial results have lacked success for the treatment of patients with neurological disorders. The knowledge that natural extracts show other positive molecular activities in addition to antioxidant activity, however, has led to further research of natural extracts for their potential use as prevention or treatment/management of neurodegenerative diseases. This review will cover several in vitro and in vivo research studies, as well as clinical trials, and highlight the potential of natural antioxidants

Two oxazane macrocycles.

The 20-membered ring in 1,7,11,17-tetraoxa-2,6,12,16-tetraazacycloeicosane tetrahydrochloride, C12H32N4O44+·4Cl-, adopts an endo conformation, while the 18-membered ring in 1,6,10,15-tetraoxa-2,5,11,14-tetraazacyclooctadecane tetrahydrochloride, C10H28N4O44+·4Cl-, lies about an inversion centre and adopts a symmetrical conformation. In the crystal structures of both compounds, the cations and chloride anions are linked by N-H...Cl hydrogen bonds into planar sheets of molecules; the sheets are linked into three-dimensional networks via C-H...Cl hydrogen bonds

Morphological changes in MCF-7 human breast cancer cells in response to Bis-Naphthalimidopropylspermidine-treatment.

The effects of bis-naphthalimidopropylspermidine (BNIPSpd), a representative of a novel class of polyamine derivatives with antiproliferative properties on the morphology of MCF-7 human breast cancer cells were studied. BNIPSpd was shown to cause cytoplasmic shrinkage, observed by monitoring the cells by means of phase-contrast microscopy. Chromatin condensation and nucleolar disintegration were also detected by Hoechst 33342 and Giemsa staining the cells, treated with 10 μM BNIPSpd for 8h. Taken together the morhological changes observed strongly suggested that the growth inhibition of MCF- 7 cells in response to BNIPSpd-treatment is realized via an induction of apoptosis. Moreover, nucleolus appears to be an important target in the mode of cytotoxic action of this novel polyamine derivative

Anti-pancreatic cancer potential of secalonic acid derivatives from endophytic fungi isolated from Ocimum basilicum.

The word endophyte means "in the plant" and refers to all microorganisms that live in the intercellular spaces of stems, petioles, roots and leaves of plants causing no apparent symptoms of disease. Seven endophytic fungi were isolated from the medicinal plant of Ocimum basilicum L. The fungal strain, labeled as 2L, was cultivated at large scale on the potato dextrose agar semi solid medium and was extracted with ethyl acetate. Normal phase silica gel column chromatography of the ethyl acetate extract afforded ergosterol (1), secalonic acid A (2) and secalonic acid D (3). The structures of these compounds (1-3) were elucidated unequivocally by UV, IR, MS, a series of 1D & 2D NMR analyses. The cytotoxicity of these compounds was evaluated by the MTT assay against human pancreatic cancer cell line. Secalonic acid A (2) and secalonic acid D (3) exhibited significant anti-pancreatic cancer activity with IC 50 values of 7.3 and 1.6 µM, respectively

The synthesis and reactivity of 7-azaindolizines.

Synthetic routes leading to 7-azaindolizines and the reactivity of this system together with other azaindolizines have been briefly reviewed. A number of simple alkyl, aryl, carboethoxy, methoxy, chloro and amino substituted 7-azaindolizines have been synthesised via the Chichibabin reaction between suitably substituted methylpyrazines and a-bromoketones. The structures of the products obtained have been confirmed spectroscopically (mainly by pmr spectroscopy) and elemental analysis. Examination of the pmr spectra of 7-azaindolizines in trifluoroacetic acid showed solely protonation at the non-bridgehead nitrogen. Similarly quaternisation was found to occur at the non-bridgehead nitrogen. Lithiation of 8-methyl-7-azaindolizine showed the 8-methyl group of 2,8-dimethy1-7-azaindoilzine to be acidic. Reaction between 2,3,8-trimethyl-7-azaindolizine and ethoxalyl chloride gave a diketodipyrrolo[1 ,2-a:2,1-c]pyrazine system. A number of electrophilic substitution reactions occurred at C-3 position. Nucleophilic replacement of chlorine by methoxide and amino from 8-chloro-2-methyl-7-azaindolizine occurred readily. A number of simple alkyl, aryl, and carboethoxy substituted dipyrrolo[1 ,2-a;2,1-c]pyrazines have been obtained by the Chichibabin reaction between appropriate substituted 8-methyl-7-azaindolizines and a-bromoketones. The structures of these products have been established spectroscopically. An examination of the pmr spectra of dipyrrolo-[1,2-a:2,1-c]pyrazines in trifluoroacetic acid showed this system preferentially protonates at C-3 and C-8 postions. When positions 3 and 8 are substituted the C-3 conjugate acid cation predominates together with minor amounts of the C-1 cation. Dipyrrolo[1,2-a:2,1-c]pyrazines undergo electrophilic substitution preferentially at C-3(C-8) and when 3,8-disubstituted, substitution then occurs at C-1(C-10). A brief survey of reaction between relevant nitrogen heteroaromatics and DMAD has been reviewed. The reaction between 7-azaindolizines and DMAD gave products involving bonding at the non-bridgehead nitrogen and the adjacent C-8 position or 8-substituent

Experimental modelling of Alzheimer’s disease for therapeutic screening.

Neurodegenerative diseases, including Alzheimer’s disease (AD), pose a significant and urgent challenge to healthcare systems worldwide. With an increasing life expectancy, these progressive age-related disorders are expected to rise exponentially. No cure currently exists for AD, and the aetiology remains poorly understood. Furthermore, AD drug development faces one of the highest failure rates. Thus, a review of the experimental modelling of the disease is crucial to understanding how the current disease models can be applied to gain useful results while also considering their limitations. Disease models include in vitro, in vivo, ex vivo, and in silico systems as well as clinical trials. These systems are important for testing potential therapeutics to advance drug development, in addition to modelling the pathology of the disease to gain a greater understanding of the cause and progression. This review will discuss the current experimental models employed for the study of AD with the aim of providing an overview of how they are used and discuss their benefits and drawbacks as model systems, as well as highlighting the potential future of the experimental modelling of AD

Novel vanillin derivatives: synthesis, anti-oxidant, DNA and cellular protection properties.

Antioxidants have been the subject of intense research interest mainly due to their beneficial properties associated with human health and wellbeing. Phenolic molecules, such as naturally occurring Resveratrol and Vanillin, are well known for their anti-oxidant properties, providing a starting point for the development of new antioxidants. Here we report, for the first time, the synthesis of a number of new vanillin through the reductive amination reaction between vanillin and a selection of amines. All the compounds synthesised, exhibited strong antioxidant properties in DPPH, FRAP and ORAC assays, with compounds 1b and 2c being the most active. The latter also demonstrated the ability to protect plasmid DNA from oxidative damage in the presence of the radical initiator AAPH. At cellular level, neuroblastoma SH-SY5Y cells were protected from oxidative damage (H2O2, 400 mM) with both 1b and 2c. The presence of a tertiary amino group, along with the number of vanillin moieties in the molecule contribute for the antioxidant activity. Furthermore, the delocalization of the electron pair of the nitrogen and the presence of an electron donating substituent to enhance the antioxidant properties of this new class of compounds. In our opinion, vanillin derivatives 1b and 2c described in this work can provide a viable platform for the development of antioxidant based therapeutics

The use of nano polymeric self-assemblies based on novel amphiphilic polymers for oral hydrophobic drug delivery.

Purpose: To investigate the use of nano self-assemblies formed by polyallylamine (PAA) modified with 5 or 10% mole fluorenylmethoxy carbonyl (Fmoc5/10), dimethylamino-1-naphthalenesulfonyl (Dansyl5/10) and 5% mole cholesteryl group (Ch5) for oral hydrophobic drug delivery. Methods: Propofol, griseofulvin and prednisolone were loaded into amphiphilic PAAs. Particle size and morphology of drug-loaded self-assemblies were determined using photon correlation spectroscopy and transmission electron microscopy. Solubilising capacity, in vitro drug release and formulation stability were analysed by HPLC, and in vitro biocompatibility studies (haemolysis and cytotoxicity) were carried out on bovine erythrocytes and Caco-2 cells, respectively. Dansyl10 and Ch5 griseofulvin formulations were administered intra-gastrically to rats, and drug plasma levels were analysed by HPLC. Results: Drug-encapsulated self-assemblies typically have hydrodynamic size of 300–400 nm. Dansyl10 exhibited universal drug solubiliser property and had significantly improved prednisolone, griseofulvin and propofol solubility by 145, 557 and 224-fold, respectively. Fmoc polymers resulted in modest drug solubility improvement. These polymers were non-haemolytic, did not enhance cytotoxicity compared to unmodified PAA, and demonstrated significant increase in griseofulvin plasma concentration compared to griseofulvin in water after oral administration. Conclusions: Ch5 and Dansyl10 showed promising potential as nano-carriers for oral hydrophobic drug delivery

Synthesis of novel vanillin derivatives: novel multi-targeted scaffold ligands against Alzheimer's disease.

Alzheimer’s Disease (AD) is the most common cause of dementia worldwide, normally affecting people aged over 65. Due to the multifactorial nature of this disease, a “multi-target-directed ligands” (MTDLs) approach for the treatment of this illness has generated intense research interest in the past few years. Vanillin is a natural antioxidant and it provides a good starting point for the synthesis of new compounds with enhanced antioxidant properties, together with many biological activities, including ß-amyloid peptide aggregating and acetylcholinesterase inhibiting properties. Here we report novel vanillin derivatives, bearing a tacrine or a naphthalimido moiety. All compounds exhibited improved antioxidant properties using DPPH assay, with IC50 as low as 19.5 µM, FRAP and ORAC assays, with activities up to 1.54 and 6.4 Trolox equivalents, respectively. In addition, all compounds synthesized showed inhibitory activity toward acetylcholinesterase enzyme at µmolar concentrations using the Ellman assay. Computational docking studies of selected compounds showed interactions with both the catalytic anionic site and the peripheral anionic site of the enzyme. Furthermore, these compounds inhibited Aβ(1-42) amyloid aggregation using the fluorometric ThT assay, with compound 4 showing comparable inhibitory activity to the positive control, curcumin. At cellular level compound 4 (1 µM)showed significant protective effects of neuroblastoma SH-SY5Y cell line when treated with hydrogen peroxide (400 µM). In our opinion, vanillin derivatives could provide a viable platform for future development of multi-targeted ligands against AD

Polymer-drug conjugates as nano-sized multi-targeting systems for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive, neurodegenerative condition. There are clear markers for the presence and progression of the disease, including β-amyloid (Aβ) plaques and Tau tangles, with many potential causes debated in the scientific community. Most existing treatments only provide symptomatic solutions. Due to poor aqueous solubility and possibly limited uptake across the blood–brain barrier (BBB), medications targeting the hallmarks of AD are still under study despite enormous efforts. Recently, nanoparticle-based drug delivery systems have demonstrated remarkable promise as precision medicines that may effectively increase bioavailability, permeate the BBB, and improve the targeting ability of a variety of pharmaceuticals. Polymer therapeutics have made tremendous progress in recent years, particularly in cancer treatment. Polymer–drug conjugates (PDCs) typically have a longer half-life, higher stability, and enhanced water solubility. Polymers serve as carriers for the administration of drugs, proteins, targeting moieties, and imaging agents in polymeric and macromolecular prodrugs. Numerous commercially viable PDCs for the treatment of various diseases have already proved their potential. This paper focuses mainly on the rationale for the design, synthesis, and potential use of PDCs as a multi-target treatment for neurodegenerative diseases