Friends or Foes? Emerging Impacts of Biological Toxins.

Toxins are substances produced from biological sources (e.g., animal, plants, microorganisms) that have deleterious effects on a living organism.

Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers.

IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKα in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ.

Synthesis and Evaluation of a New Series of 8-(2-Nitroaryl)Xanthines as Adenosine Receptor Ligands.

Preclinical Research A new series of 1,3-dimethylxanthine derivatives bearing 8-(2-nitroaryl) residue was synthesized and evaluated for affinity for recombinant human adenosine receptors subtypes. Nitrate esters of 7-substituted-1,3-dimethyl-8-phenylxanthines were also synthesized and tested. Introducing a nitro substituent at the 2-position of the 8-substituted phenyl ring resulted in generally low affinity for adenosine receptors (ARs), selectivity toward the A2A subtype was enhanced in some of the compounds.

The re-emergence of natural products for drug discovery in the genomics era.

Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers.

Toxins and drug discovery.

Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine.

Zebrafish bioassay-guided microfractionation identifies anticonvulsant steroid glycosides from the Philippine medicinal plant Solanum torvum.

Medicinal plants used for the treatment of epilepsy are potentially a valuable source of novel antiepileptic small molecules. To identify anticonvulsant secondary metabolites, we performed an in vivo, zebrafish-based screen of medicinal plants used in Southeast Asia for the treatment of seizures. Solanum torvum Sw.

A phenotypic screen in zebrafish identifies a novel small-molecule inducer of ectopic tail formation suggestive of alterations in non-canonical Wnt/PCP signaling.

Zebrafish have recently emerged as an attractive model for the in vivo bioassay-guided isolation and characterization of pharmacologically active small molecules of natural origin. We carried out a zebrafish-based phenotypic screen of over 3000 plant-derived secondary metabolite extracts with the goal of identifying novel small-molecule modulators of the BMP and Wnt signaling pathways. One of the bioactive plant extracts identified in this screen - Jasminum gilgianum, an Oleaceae species native to Papua New Guinea - induced ectopic tails during zebrafish embryonic development.

The effect of temperature on the effects of the phospholipase A₂ neurotoxins β-bungarotoxin and taipoxin at the neuromuscular junction.

Snake venom neurotoxins with phospholipase A₂ affect the neuromuscular junction with three distinct phases. There is a transient decrease in twitch height, followed by a facilitatory phase and finally a progressive blockade. It has been suggested that the initial phase is a direct consequence of the binding of the toxins to nerve terminals.

A novel dihydro-pyrazolo(3,4d)(1,2,4)triazolo(1,5a)pyrimidin-4-one (AJ23) is an antagonist at adenosine A(1) receptors and enhances consolidation of step-down avoidance.

Adenosine A(1) receptor antagonists are of potential value in the treatment of cognitive dysfunction. We have developed compound AJ23 (7-methyl-1-phenyl-1,8-dihydro-pyrazolo-(3,4d)(1,2,4)-triazolo(1,5a)-pyrimidin-4-one) as a novel, non-xanthine based antagonist at A(1) receptors. It has micromolar affinity at human A(1) receptors with a 45-fold selectivity for A(1) over A(2A) receptors and little affinity for many other receptors and transporters tested in a screening panel.

Design, synthesis and evaluation of novel 16-imidazolyl substituted steroidal derivatives possessing potent diversified pharmacological properties.

As a part of our investigations into the structural-activity relationship studies of a novel class of medicinally active 16-substituted steroids, several new 16-imidazolyl substituted steroidal derivatives have been synthesized and pharmacologically evaluated in the current study. The new steroidal analogues 5, 6, 8, 9, 11 and 12 exhibited moderate cytotoxic effects in sixty cancer cell lines derived from nine cancers types. The imidazolyl substituted steroidal derivatives 6 (DPJ-RG-1241) and 7 (RB-401) were obtained as the powerful inhibitors of aromatase with IC50=0.

Snake toxins from mamba venoms: unique tools for the physiologist.

Snake venoms are complex mixtures of small molecules, peptides and proteins. Most of the biologically active toxins are peptides or enzymes. The peptides belong to several structural classes, and they have many different biological actions.

Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids.

Ethnopharmacological Relevance: The South African plant Sceletium tortuosum has been known for centuries for a variety of traditional uses, and, more recently, as a possible source of anti-anxiety or anti-depressant effects. A standardised extract Zembrin(®) was used to test for pharmacological activities that might be relevant to the ethnopharmacological uses, and three of the main alkaloids were also tested.

Materials And Methods: A standardised ethanolic extract was prepared from dried plant material, along with the purified alkaloids mesembrine, mesembrenone and mesembrenol.

Synthesis of a new series of 1H-imidazol-1-yl substituted 8-phenylxanthines as adenosine receptor ligands.

A new series of 1H-imidazol-1-yl substituted 8-phenylxanthine analogs has been synthesized to study the effects of the imidazole group on the binding affinity of compounds for adenosine receptors. Competition binding studies of these compounds were carried out in vitro with human cloned receptors using [(3) H]DPCPX and [(3) H]ZM 241385 as radioligands at A(1) and A(2A) adenosine receptors, respectively. The effect of the substitution pattern of the (imidazolyl)alkoxy group on various positions of the phenyl ring at C(8) was also studied.

Suramin inhibits the early effects of PLA(2) neurotoxins at mouse neuromuscular junctions: A twitch tension study.

Several phospholipase A(2) (PLA(2)) neurotoxins from snake venoms can affect acetylcholine release at the neuromuscular junction. In isolated nerve-muscle preparations three distinct phases have been described for this phenomenon: An initial transient decrease in twitch tension; a second facilitatory phase during which twitch height is greater than control twitch height; and the last phase which causes a reduction in twitch height that finally results in paralysis. Suramin has been reported to inhibit the toxic effects of β-bungarotoxin and another PLA(2) neurotoxin, crotoxin in vitro and in vivo.

Synthesis and biological evaluation of 1,4-benzodiazepin-2-ones with antitrypanosomal activity.

A library of 1,4-benzodiazepines has been synthesized and evaluated against Trypanosoma brucei, a causative parasite of Human African trypanosomiasis. Benzodiazepines possessing a P2- transporter motif were found to have MIC values as low as 0.78 μM.

Memory impairment in rats by hippocampal administration of the serine protease subtilisin.

Since the serine protease subtilisin has been reported to generate a novel form of long-term depression (LTD) in rat hippocampal slices, the present work was designed to determine whether it has any effect on learning and memory processes. Rats were used to examine the effects of subtilisin, injected directly into the dorsal hippocampus, on task performance in a step-through inhibitory avoidance of a mild footshock. The administration of 100 ng of subtilisin into each hippocampus, immediately after training, was sufficient to induce a detectable learning deficit with a footshock stimulus of 0.

Synthesis of quaternary ammonium salts of 16E-[4-(2-alkylaminoethoxy)-3-methoxybenzylidene]androstene derivatives as skeletal muscle relaxants.

Synthesis of eighteen new quaternary ammonium salts of 16E-arylidene androstene derivatives as skeletal muscle relaxants is reported in the present study. The effects of possibly extended interonium distances on muscle relaxant activity are discussed. All the quaternary ammonium steroids produced reduction in the twitch responses, when screened for in vitro neuromuscular blocking activity using isolated chick biventer cervicis muscle preparation.

High-throughput screening of natural products for cancer therapy.

Natural products have been the biggest single source of anticancer drugs and there are continued efforts to explore the chemical diversity provided by nature in order to find new lead compounds. Bioassay test methods have developed into high throughput screening assays using both cell-based and molecular approaches. The various ways to detect effects on cell viability and cell proliferation are summarised and examples are given of developments using three-dimensional cultures and cancer stem cells.

Efficacy of anti-cancer agents in cell lines versus human primary tumour tissue.

The discovery of anti-cancer drugs has become dependent on cell lines, which are used to screen potential compounds for activity as well as to explore cancer biology. Cell lines produce rapid results, but their relevance to patient outcomes is questionable as they undergo selection over many passages to a point where they are no longer representative of their originating tumour. This has led to the increasing use of primary cell cultures, primary tumour cell explants, early passage cell lines, and xenografts to improve the accuracy of results during drug development.

The Drug Discovery Portal: a resource to enhance drug discovery from academia.

Drug discovery in universities is usually associated with research on drug targets and mechanisms, but more recently there have been efforts to progress from target studies to proof of concept by applying commercially focussed medicinal chemistry. This creates more opportunities for novel interactions and partnering models between academic groups and pharmaceutical companies. We present a review of coordinated, multi-institutional drug discovery operations within academia that are engaging with industry nationally and internationally and describe how the Drug Discovery Portal at the University of Strathclyde enhances the possibilities for academic drug discovery.

Current strategies for drug discovery through natural products.

Importance To The Field: Natural products are the most consistently successful source of drug leads, both historically and currently. Despite this, the use of natural products in industrial drug discovery has fallen out of favour. Natural products are likely to continue to be sources of new commercially viable drug leads because the chemical novelty associated with natural products is higher than that of any other source: this is particularly important when searching for lead molecules against newly discovered targets for which there are no known small molecule leads.

Synthesis of 8-(cyclopentyloxy)phenyl substituted xanthine derivatives as adenosine A2A ligands.

The present paper describes the synthesis of a series of 8-(cyclopentyloxy)phenyl-xanthines and their evaluation for affinity for A1 and A2 adenosine receptors using radioligand binding assays. The effects of moving the cyclopentyloxy substituent with or without an ortho methoxy group on the various positions of the 8-phenyl ring have been studied. The vanilloid based xanthines 8-[4-(cyclopentyloxy)-3-methoxyphenyl]-1,3-dimethylxanthine (6a) (K(i)= 100 nM) and 8-[(4-cyclopentyloxy)-3-methoxyphenyl] -3-methyl-1-propylxanthine (12) (K(i) = 150 nM) displayed the highest affinity at A2A receptors as well as over 1000 fold selectivity over the A1 adenosine receptor subtype.

The drug discovery portal: a computational platform for identifying drug leads from academia.

The Drug Discovery Portal (DDP) is a research initiative based at the University of Strathclyde in Glasgow, Scotland. It was initiated in 2007 by a group of researchers with expertise in virtual screening. Academic research groups in the university working in drug discovery programmes estimated there was a historical collection of physical compounds going back 50 years that had never been adequately catalogued.