An Investigation into the In Vitro Metabolic Stability of Aryl Sulfonyl Fluorides for their Application in Medicinal Chemistry and Radiochemistry.

Molecules that feature a sulfonyl fluoride (SOF) moiety have been gaining increasing interest due to their unique reactivity and potential applications in synthetic chemistry, medicinal chemistry, and other biological uses. A particular interest is towards F-radiochemistry where sulfonyl fluorides can be used as a method to radiolabel biomolecules or can be used as radiofluoride relay reagents that facilitate radiolabeling of other molecules. The low metabolic stability of sulfonyl fluoride S-F bonds, however, presents an issue and limits the applicability of sulfonyl fluorides.

Aboriginal medicinal plants of Queensland: ethnopharmacological uses, species diversity, and biodiscovery pathways.

Background: Aboriginal peoples have occupied the island continent of Australia for millennia. Over 500 different clan groups or nations with distinctive cultures, beliefs, and languages have learnt to live sustainably and harmoniously with nature. They have developed an intimate and profound relationship with the environment, and their use of native plants in food and medicine is largely determined by the environment they lived in.

The genus Alphitonia Reissek ex Endl. (Rhamnaceae): A review of its customary uses, phytochemistry and biological activities.

Ethnopharmacological Relevance: Alphitonia Reissek ex Endl. is a relatively small genus of the family Rhamnaceae. Plants of this genus are found predominantly in the tropical regions of Southeast Asia, Australia and the Pacific, with some species being widely distributed and others endemic to a region.

Electrophysiological Responses of (Hardy) (Tephritidae) to Rectal Gland Secretions and Headspace Volatiles Emitted by Conspecific Males and Females.

Pheromones are biologically important in fruit fly mating systems, and also have potential applications as attractants or mating disrupters for pest management. (Hardy) (Diptera: Tephritidae) is a polyphagous pest fruit fly for which the chemical profile of rectal glands is available for males but not for females. There have been no studies of the volatile emissions of either sex or of electrophysiological responses to these compounds.

Sampling technique biases in the analysis of fruit fly volatiles: a case study of Queensland fruit fly.

Diverse methods have been used to sample insect semiochemicals. Sampling methods can differ in efficiency and affinity and this can introduce significant biases when interpreting biological patterns. We compare common methods used to sample tephritid fruit fly rectal gland volatiles ('pheromones'), focusing on Queensland fruit fly, Bactrocera tryoni.

Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals.

The high affinity and specificity of peptides towards biological targets, in addition to their favorable pharmacological properties, has encouraged the development of many peptide-based pharmaceuticals, including peptide-based positron emission tomography (PET) radiopharmaceuticals. However, the poor in vivo stability of unmodified peptides against proteolysis is a major challenge that must be overcome, as it can result in an impractically short in vivo biological half-life and a subsequently poor bioavailability when used in imaging and therapeutic applications. Consequently, many biologically and pharmacologically interesting peptide-based drugs may never see application.

Attraction and Electrophysiological Response to Identified Rectal Gland Volatiles in (Schiner).

(Schiner) (Diptera: Tephritidae) is a polyphagous fruit fly pest species that is endemic to Papua New Guinea and has become established in several Pacific Islands and Australia. Despite its economic importance for many crops and the key role of chemical-mediated sexual communication in the reproductive biology of tephritid fruit flies, as well as the potential application of pheromones as attractants, there have been no studies investigating the identity or activity of rectal gland secretions or emission profiles of this species. The present study (1) identifies the chemical profile of volatile compounds produced in rectal glands and released by , (2) investigates which of the volatile compounds elicit an electroantennographic or electropalpographic response, and (3) investigates the potential function of glandular emissions as mate-attracting sex pheromones.

Rectal Gland Chemistry, Volatile Emissions, and Antennal Responses of Male and Female Banana Fruit Fly, .

The banana fruit fly, (Tryon) (Diptera: Tephritidae), is an economically important pest endemic to Australia and mainland Papua New Guinea. The chemistry of its rectal glands, and the volatiles emitted during periods of sexual activity, has not been previously reported. Using gas chromatography-mass spectrometry (GC-MS), we find that male rectal glands contain ethyl butanoate, -(3-methylbutyl) acetamide, ethyl laurate and ethyl myristate, with ethyl butanoate as the major compound in both rectal gland and headspace volatile emissions.

Systematic Modification of Zingerone Reveals Structural Requirements for Attraction of Jarvis's Fruit Fly.

Tephritid fruit flies are amongst the most significant horticultural pests globally and male chemical lures are important for monitoring and control. Zingerone has emerged as a unique male fruit fly lure that can attract dacine fruit flies that are weakly or non-responsive to methyl eugenol and cuelure. However, the key features of zingerone that mediate this attraction are unknown.

Raspberry Ketone Analogs: Vapour Pressure Measurements and Attractiveness to Queensland Fruit Fly, Bactrocera tryoni (Froggatt) (Diptera: Tephritidae).

The Queensland fruit fly, Bactrocera tryoni (Froggatt) (Q-fly), is a major horticultural pest in Eastern Australia. Effective monitoring, male annihilation technique (MAT) and mass trapping (MT) are all important for control and require strong lures to attract flies to traps or toxicants. Lure strength is thought to be related in part to volatility, but little vapour pressure data are available for most Q-fly lures.

Antimicrobial and antioxidant activity and chemical characterisation of Erythrina stricta Roxb. (Fabaceae).

Ethnopharmacological Relevance: The bark of Erythrina stricta Roxb. (Fabaceae) has been used in Indian indigenous systems as a remedy for rheumatism, stomach-ache, asthma, dysentery, contact dermatitis, eczema and skin infections. However, there have been limited phytochemical or biological studies on the bark of E.

Kynurenine-3-monooxygenase: a review of structure, mechanism, and inhibitors.

Kynurenine monooxygenase (KMO) is an enzyme of the kynurenine (Kyn) pathway (KP), which is the major catabolic route of tryptophan. Kyn represents a branch point of the KP, being converted into the neurotoxin 3-hydroxykynurenine via KMO, neuroprotectant kynurenic acid, and anthranilic acid. As a result of this branch point, KMO is an attractive drug target for several neurodegenerative and/or neuroinflammatory diseases, especially Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) diseases.

Ketimine reductase/CRYM catalyzes reductive alkylamination of α-keto acids, confirming its function as an imine reductase.

Recently, crystalized mouse ketimine reductase/CRYM complexed with NADPH was found to have pyruvate bound in its active site. We demonstrate that the enzyme binds α-keto acids, such as pyruvate, in solution, and catalyzes the formation of N-alkyl-amino acids from alkylamines and α-keto acids (via reduction of imine intermediates), but at concentrations of these compounds not expected to be encountered in vivo. These findings confirm that, mechanistically, ketimine reductase/CRYM acts as a classical imine reductase and may explain the finding of bound pyruvate in the crystallized protein.

Antimicrobial activity of customary medicinal plants of the Yaegl Aboriginal community of northern New South Wales, Australia: a preliminary study.

Background: This study is a collaboration between Macquarie University researchers and the Yaegl Aboriginal Community of northern NSW, Australia to investigate the antimicrobial potential of plants used in the topical treatment of wounds, sores and skin infections. Based on previously documented medicinal applications, aqueous and aqueous ethanolic extracts of Alocasia brisbanensis, Canavalia rosea, Corymbia intermedia, Hibbertia scandens, Ipomoea brasiliensis, Lophostemon suaveolens and Syncarpia glomulifera and the aqueous extracts of Smilax australis and Smilax glyciphylla were tested against common wound pathogens, including antibiotic resistant bacterial strains.

Methods: Plant material was prepared as aqueous extractions modelled on customary preparations and using 80% aqueous ethanol.

Bioactivity and chemical characterisation of Lophostemon suaveolens--an endemic Australian Aboriginal traditional medicinal plant.

Lophostemon suaveolens is a relatively unexplored endemic medicinal plant of Australia. Extracts of fresh leaves of L. suaveolens obtained from sequential extraction with n-hexane and dichloromethane exhibited antibacterial activity in the disc diffusion and MTT microdilution assays against Streptococcus pyogenes and methicillin sensitive and resistant strains of Staphylococcus aureus (minimum bactericidal concentration < 63 μg/mL).

Insights into Enzyme Catalysis and Thyroid Hormone Regulation of Cerebral Ketimine Reductase/μ-Crystallin Under Physiological Conditions.

Mammalian ketimine reductase is identical to μ-crystallin (CRYM)-a protein that is also an important thyroid hormone binding protein. This dual functionality implies a role for thyroid hormones in ketimine reductase regulation and also a reciprocal role for enzyme catalysis in thyroid hormone bioavailability. In this research we demonstrate potent sub-nanomolar inhibition of enzyme catalysis at neutral pH by the thyroid hormones L-thyroxine and 3,5,3'-triiodothyronine, whereas other thyroid hormone analogues were shown to be far weaker inhibitors.

An ethnobotanical study of medicinal plants of Chungtia village, Nagaland, India.

Ethnopharmacological Relevance: Traditional medicinal plant knowledge is an integral and very important part of Indigenous cultures worldwide. For many communities there is a great urgency in recording this knowledge in written form. This is the first ethnobotanical report of medicinal plant knowledge of the Nagaland Ao tribe of Chungtia village and is an important step in the preservation of this culturally and medicinally significant knowledge.

The first indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing carborane.

Indoleamine-2,3-dioxygenase-1 (IDO1) is a critical immunoregulatory enzyme responsible for the metabolism of tryptophan during inflammation and disease. Based upon a pyranonaphthoquinone framework, the first examples of indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing a carborane cage are reported. The novel closo-1,2-carboranyl-N-pyranonaphthoquinone derivatives display low μM binding affinity for the human recombinant enzyme, with IC50 values ranging from 0.

Characterisation of a novel UV filter in the lens of the thirteen-lined ground squirrel (Ictidomys tridecemlineatus).

Structural analysis of a novel UV filter present in the lens of the thirteen-lined ground squirrel has shown that it is related in structure to N-acetyl-3-hydroxykynurenine. This finding is consistent with the fact that the squirrel lenses also contain high levels of this tryptophan metabolite. Analysis of both NMR and mass spectrometric data suggested that the novel UV filter compound forms by condensation of proline with N-acetyl-3-hydroxykynurenine.

Detection, quantification, and total synthesis of novel 3-hydroxykynurenine glucoside-derived metabolites present in human lenses.

Purpose: 3-Hydroxykynurenine O-β-D-glucoside (3OHKG) protects the lens from UV damage, and novel related species may act analogously. The aim of this study was to detect, quantify, and elucidate the structures of novel 3-hydroxykynurenine glucoside-derived metabolites present in the human lens.

Methods: Compounds were detected and quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in 24 human lenses of different ages, of which 22 were normal and two had cataract.

Separate mechanisms for age-related truncation and racemisation of peptide-bound serine.

Some amino acids are particularly susceptible to degradation in long-lived proteins. Foremost among these are asparagine, aspartic acid and serine. In the case of serine residues, cleavage of the peptide bond on the N-terminal side, as well as racemisation, has been observed.

Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1).

Screening of a fragment library identified 2-hydrazinobenzothiazole as a potent inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme expressed by tumours that suppresses the immune system. Spectroscopic studies indicated that 2-hydrazinobenzothiazole interacted with the IDO1 haem and in silico docking predicted that the interaction was through hydrazine. Subsequent studies of hydrazine derivatives identified phenylhydrazine (IC50=0.

Lysine metabolism in mammalian brain: an update on the importance of recent discoveries.

The lysine catabolism pathway differs in adult mammalian brain from that in extracerebral tissues. The saccharopine pathway is the predominant lysine degradative pathway in extracerebral tissues, whereas the pipecolate pathway predominates in adult brain. The two pathways converge at the level of ∆(1)-piperideine-6-carboxylate (P6C), which is in equilibrium with its open-chain aldehyde form, namely, α-aminoadipate δ-semialdehyde (AAS).

Mutation of cysteine residues alters the heme-binding pocket of indoleamine 2,3-dioxygenase-1.

The hemoprotein indoleamine 2,3-dioxygenase-1 (IDO1) is the first and rate-limiting enzyme in mammalian tryptophan metabolism. Interest in IDO1 continues to grow, due to the ever expanding influence IDO1 plays in the immune response. This study examined the contribution of all individual cysteine residues towards the overall catalytic properties and stability of recombinant human IDO1 via mutagenesis studies using a range of biochemical and spectroscopic techniques, including in vitro kinetic assessment, secondary structure identification via circular dichroism spectroscopy and thermal stability assessment.