Margaret A Brimble

University of Auckland · School of Chemical Sciences

Lycibarbarines A–C are spirocyclic alkaloids with a unique tetracyclic framework, consisting of tetrahydroquinoline and spiro-fused oxazine-sugar spiroketal subunits. The first total syntheses of lycibarbarines A–C are reported, achieved over 10 steps (longest linear sequence) each. Through this work, it was discovered that the spiroketal unit of l...

Aim: We have previously reported that polyfunctional T cell responses can be induced to the cancer testis antigen NY-ESO-1 in melanoma patients injected with mature autologous monocyte-derived dendritic cells (DCs) loaded with long NY-ESO-1-derived peptides together with α-galactosylceramide (α-GalCer), an agonist for type 1 Natural Killer T (NKT)...

Azide‐enolate cycloaddition‐rearrangements offer potential for rapid access to diverse molecular frameworks, from simple precursors. We report here that investigations into the cycloadditions of ester or amide enolates with vinyl azides led to the identification of two reaction processes ‐ direct α‐amination of amides and lactams, and synthesis of...

Antimicrobial peptides (AMPs) hold promise as novel therapeutics in the fight against multi-drug-resistant pathogens. Cathelicidin-PY (NH2-RKCNFLCKLKEKLRTVITSHIDKVLRPQG-COOH) is a 29-residue disulfide-cyclised antimicrobial peptide secreted as an innate host defence mechanism by the frog Paa yunnanensis (PY) and reported to possess broad-spectrum a...

Pancreatic ductal adenocarcinoma remains a highly debilitating condition with no effective disease-modifying interventions. In our search for natural products with promising anticancer activity, we identified the aminolipopeptide trichoderin A as a potential candidate. While it was initially isolated as an antitubercular peptide, we provide evidenc...

13-Desmethyl spirolide C is a marine natural product of the cyclic imine class that demonstrates remarkable bioactivity against several biomarkers of Alzheimer's Disease, which renders its [7,6]-spirocyclic imine pharmacophore of significant synthetic interest. This work describes a facile and efficient synthesis of the [7,6]-spirocyclic core of 13...

Depsipeptides are an important class of bioactive natural products, where a growing number of genome-mined structures that display anti-microbial activity are macrocyclic depsipeptides. Chemically, peptide ester (depsipeptide) bond formation often displays low yields, and thereby hampers efforts to access these structures for structure-activity stu...

Over the last few decades, design and discovery of chemical reactions that enable modification of proteins at pre-determined sites have been the focus of synthetic organic chemists. As an invaluable tool, the site-and chemoselective functionalization of peptides and proteins offers an exciting opportunity for creating high-value multicomponent conj...

The related peptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have diverse biological functions in peripheral tissues and the central nervous system. Therefore, these peptides and their three receptors represent potential drug targets for several conditions, including neurological and pain-r...

With the post-antibiotic era rapidly approaching, many have turned their attention to developing new treatments, often by structural modification of existing antibiotics. Polymyxins, a family of lipopeptide antibiotics that are used as a last line of defense in the clinic, have recently developed resistance and exhibit significant nephrotoxicity is...

Marine biofouling is a problem that plagues all maritime industries at vast economic and environmental cost. Previous and current methods to prevent biofouling have employed the use of heavy metals and other toxic or highly persistent chemicals, and these methods are now coming under immense regulatory pressure. Recent studies have illustrated the...

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide expressed in the trigeminal ganglia (TG). The TG conducts nociceptive signals in the head and may play roles in migraine. PACAP infusion provokes headaches in healthy individuals and migraine-like attacks in patients; however, it is not clear whether targeting this system coul...

Peptide5 is a 12–amino acid mimetic peptide that corresponds to a region of the extracellular loop 2 (EL2) of connexin43. Peptide5 regulates both cellular communication with the cytoplasm (hemichannels) and cell-to-cell communication (gap junctions), and both processes are implicated in neurological pathologies. To address the poor in vivo stabilit...

In the current global crisis of antimicrobial resistance, antimicrobial peptides represent a promising source of alternative antibiotics. Recently discovered cadaside B, a novel calcium‐dependent antibiotic, exhibits potent antimicrobial activity towards Gram‐positive pathogens including multi‐drug resistant strains. These properties, coupled with...

Herein we report the first examples of thiol-selective heterobifunctional electrophiles, N-vinyl acrylamides, that enable efficient highly selective thiol-thiol bioconjugations and cysteine modification of peptides. We demonstrate that these new classes of thiol-selective scaffolds can readily undergo a thia-Michael addition and an orthogonal radic...

A20FMDV2 is a 20-mer peptide that exhibits high selectivity and affinity for the tumour-related αvβ6 integrin that can compete with extracellular ligands for the crucial RGD binding site, playing a role as a promising αvβ6-specific inhibitor for anti-cancer therapies. Unfortunately, the clinical value of A20FMDV2 is limited by its poor half-life in...

Objectives: Metastasis is the principal cause of breast cancer mortality. Vaccines targeting breast cancer antigens have yet to demonstrate clinical efficacy, and there remains an unmet need for safe and effective treatment to reduce the risk of metastasis, particularly for people with triple-negative breast cancer (TNBC). Certain glycolipids can...

The drug-likeness and pharmacokinetic properties of 23 dairy-protein-derived opioid peptides were studied using SwissADME and ADMETlab in silico tools. All the opioid peptides had poor drug-like properties based on violations of Lipinski’s rule-of-five. Moreover, prediction of their pharmacokinetic properties showed that the peptides had poor intes...

Vinyl azides have undergone a recent renaissance as versatile synthetic reagents, however their reactivity as 1,3-dipoles in (3+2) cycloadditions remains underexplored. Here the synthesis of ene-gamma-lactam scaffolds via (3+2) cycloaddition of alpha-substituted vinyl azides with ester enolates is established. Mechanistic investigations, including...

Direct alpha-amination of carbonyl compounds remains an important yet synthetically challenging transformation. Here we report a solution for direct alpha-amination of amides and lactams, identified through fundamental exploration of (3+2) vinyl azide-enolate cycloaddition chemistry. Initial cycloadducts undergo rearrangement via 1,2-N-migration to...

Direct alpha-amination of carbonyl compounds remains an important yet synthetically challenging transformation. Here we report a solution for direct alpha-amination of amides and lactams, identified through fundamental exploration of (3+2) vinyl azide-enolate cycloaddition chemistry. Initial cycloadducts undergo rearrangement via 1,2-N-migration to...

Signaling through calcitonin gene-related peptide (CGRP) receptors is associated with pain, migraine, and energy expenditure. Small molecule and monoclonal antibody CGRP receptor antagonists that block endogenous CGRP action are in clinical use as anti-migraine therapies. By comparison, the potential utility of peptide antagonists has received less...

A novel tyrosine hyperoxidation enabling selective peptide cleavage is reported. The scission of the N-terminal amide bond of tyrosine was achieved with Dess-Martin periodinane under mild conditions, generating a C-terminal peptide fragment bearing the unprecedented hyperoxidized tyrosine motif, 4,5,6,7-tetraoxo-1H-indole-2-carboxamide, along with...

Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB, 1), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats, but relatively harmless to other rodents and mammals. As a vasoactive agent, NRB induces a species-specific vasocontractile effect that is restricted t...

Antimicrobial resistance is an ever-increasing global health risk that remains one of the World Health Organisations top priorities. Antimicrobial peptides, the host defence molecules of living organisms, are a rapidly developing class of molecules with promise for the treatment of drug resistant infections. We herein describe the first total synth...

Prostate-specific membrane antigen (PSMA) biomarkers have been recognized as a viable tool for diagnosing prostate cancer (PCa). Herein, we focus on the development of cyclic PSMA inhibitors adopting a urea-based...

The number of donor atoms available on peptides that can competitively coordinate to metal centers renders the site-selective generation of advanced metal-peptide conjugates in high purity a challenging venture. Herein, we present a transmetalation-based synthetic approach on solid support in which an imidazolium proligand can be used to selectivel...

Marine biofouling plagues all maritime industries at vast economic and environmental cost. Previous and most current methods to control biofouling have employed highly persistent toxins and heavy metals, including tin, copper, and zinc. These toxic methods are resulting in unacceptable environmental harm and are coming under immense regulatory pres...

Conjugates comprising a semiconducting dye (Thiophene-diketopyrrolopyrrole, TDPP-dye) attached to a self-assembling peptide (HEFISTAH) assemble into long nanofibers. Well-ordered Langmuir-Blodgett films of these materials can be prepared. Networks of these nanofibres can be deposited to bridge electrodes. Although similar systems have been proposed...

Pancreatic islet-cell function and volume are both key determinants of the maintenance of metabolic health. Insulin resistance and islet-cell dysfunction often occur in the earlier stages of type 2 diabetes (T2D) progression. The ability of the islet cells to respond to insulin resistance by increasing hormone output accompanied by increased islet-...

Background and purpose: The pituitary adenylate cyclase-activating peptide (PACAP) peptide family is of clinical interest for the treatment of migraine. These peptides activate three different PACAP-responsive class B G protein-coupled receptors: the PAC1 , VPAC1 and VPAC2 receptors. The PAC1 receptor may be alternatively spliced, generating varia...

Covering: from 1938 up to March 2021The electron-rich indole side chain of tryptophan is a versatile substrate for peptide modification. Upon the action of various cyclases, the tryptophan side chain may be linked to a nearby amino acid residue, opening the door to a diverse range of cyclic peptide natural products. These compounds exhibit a wide a...

The large number of emerging antibody-drug conjugates (ADCs) for cancer therapy has resulted in a significant market ‘boom’, garnering worldwide attention. Despite ADCs presenting huge challenges to researchers, particularly regarding the identification of a suitable combination of antibody, linker, and payload, as of September 2021, 11 ADCs have b...

Natural products that contain distinctive chemical functionality can serve as useful starting points to develop Nature’s compounds into viable therapeutics. Peptide natural products, an under-represented class of medicines, such as ribosomally synthesized and post-translationally modified peptides (RiPPs), often contain noncanonical amino acids and...

TLR2 agonists are at the forefront of vaccine research for a plethora of diseases, in particular they offer a promising tool for the treatment of cancer. A detailed knowledge of their structure‐activity relationships informs the methodical design of vaccine constructs that include TLR2 agonists. Herein we report the design, synthesis, and biologica...

The NHC-catalysed intermolecular Stetter reaction provides direct access to 1,4-diketones, however current NHC catalysts for this specific transformation remain underdeveloped, significantly limiting the use of this reaction in target-oriented synthesis. Here we report a novel N -mesityl thiazolium NHC as a high-performing catalyst for this reactio...

Lipidation of polypeptides with a fatty acid to form N-linked lipopeptides can be a time consuming process due to the need to mask other reactive function groups present on the side chains of amino acids. Cysteine Lipidation on a Peptide or Amino acid (CLipPA) technology enables the direct lipidation of unprotected peptides containing a free thiol...

The first total synthesis of the benzannulated 5,5-spiroketal natural products paeciloketal B and 1-epi-paeciloketal B has been achieved in 10 linear steps employing a biomimetic spiroketalization. This approach also furnished the related natural product bysspectin A from the same putative biosynthetic precursor as the paeciloketals. Alternatively,...

Antimicrobial resistance is a significant threat to public health systems worldwide, prompting immediate attention to develop new therapeutic agents with novel mechanisms of action. Recently, two new cationic non-ribosomal peptides (CNRPs), laterocidine and brevicidine, were discovered from Brevibacillus laterosporus through a global genome-mining...

Malacidin A is a novel calcium-dependent lipopeptide antibiotic with excellent activity against Gram-positive pathogens. Herein, a concise and robust synthetic route toward malacidin A is reported, employing 9-fluorenylmethoxycarbonyl solid-phase peptide synthesis of a linear precursor, including late-stage incorporation of the lipid tail, followed...

Background and purpose: The calcitonin (CT) receptor family is complex, comprising two receptors (the CT receptor [CTR], and the CTR-like receptor [CLR]), three accessory proteins (RAMPs), and multiple endogenous peptides. This family contains several important drug targets, including CGRP which is targeted by migraine therapeutics. The pharmacolo...

Acute rheumatic fever (ARF) is a serious post-infectious immune sequelae of Group A streptococcus (GAS). Pathogenesis remains poorly understood, including the events associated with collagen autoantibody generation. GAS express streptococcal collagen-like proteins (Scl) that contain a collagenous domain resembling human collagen. Here, the relation...

Fluorescent live imaging on Drosophila melanogaster is a microscopy technique in rapid expansion. The growing number of probes available to detect cellular components and the relatively easy genetic manipulation of fruit fly make this model one of the most used for in vivo analysis of several physiological and/or pathological processes. Here we des...

Preliminary results of the effect of hydrophobicity and halogenation on the cytotoxicity of the anticancer peptaibol culicinin D are reported. Building on previous work, the synthetically challenging (2S,4S,6R)-2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid and (2S,4R)-2-amino-4-methyldecanoic acid building blocks were replaced with derivatives of l...

Transition metal-catalysed C–H activation has emerged as an increasingly powerful platform for molecular syntheses, enabling applications to natural product syntheses, late-stage modification, pharmaceutical industries and material sciences, among others. This Primer summarizes representative best practices for the experimental set-up and data depo...

ERp44, a chaperone of the protein disulfide isomerase (PDI) family cycles between the endoplasmic reticulum (ER) and cis‐Golgi compartments to act on a cohort of disparate proteins either to ensure their proper cellular localization or for the quality control of the correct assembly. This process involves intermolecular disulfide bond formation bet...

In this work we report the synthesis of mono lipidated peptides containing a 3-mercaptopropionate linker in the N-terminus by means of a photoinitiated thiol-ene reaction (S-lipidation). We evaluate the self-assembling and hydrogelation properties of a library of mono S-lipidated peptides containing lipid chains of various lengths and demonstrate t...

In their Review on page 6367 ff., Phillip Grant and Margaret Brimble examine the isolation, bioactivity, and total synthesis of seco‐labdane diterpenoids—a class of diterpenoid arising from C−C bond cleavage events. In doing so, the importance of biosynthetic C−C bond cleavage to the generation of structural diversity is highlighted.

Phytophthora is a genus of microorganisms that cause devastating dieback and root-rot diseases in thousands of plant hosts worldwide. The economic impact of Phytophthora diseases on crops and native ecosystems is estimated to be billions of dollars per annum. These invasive pathogens are extremely difficult to control using existing chemical means,...

ConspectusThe rise of multidrug resistant bacteria has significantly compromised our supply of antibiotics and poses an alarming medical and economic threat to society. To combat this problem, it is imperative that new antibiotics and treatment modalities be developed, especially those toward which bacteria are less capable of developing resistance...

The Maillard Reaction (MR), a condensation reaction between carbonyl-containing and free amino-containing compounds, has attracted the interest of scientists within the food industry, nutrition & health, and materials science. However, due to the complexity of the reaction much remains to be clarified regarding the nature of the reaction products a...

Objective Migraine is a prevalent and disabling neurological disease. Its genesis is poorly understood and there remains unmet clinical need. We aimed to identify mechanisms and thus novel therapeutic targets for migraine using human models of migraine and translational models in animals, with emphasis on amylin, a close relative of calcitonin gene...

While the global market for peptide/protein-based therapeutics is witnessing significant growth, the development of peptide drugs remains challenging due to their low oral bioavailability, poor membrane permeability, and reduced metabolic stability. However, a toolbox of chemical approaches has been explored for peptide modification to overcome the...

Field trials are reported in this paper on a new bait containing 1% norbormide. Two separate field trials were recently completed on commercial chicken farms in South Auckland, New Zealand. Norway rats were abundant both inside the farm sheds and around the surrounding farmland. Monitoring undertaken before toxic baiting recorded high levels of rat...

Parkinson’s disease (PD), as the second most common neurodegenerative disease, is caused by complex pathological processes and currently remains very difficult to treat. PD brings great distress to patients and imposes a heavy economic burden on society. The number of PD patients is growing as the aging population increases worldwide. Therefore, it...

The cleavage of a C−C bond is a complexity generating process, which complements oxidation and cyclisation events in the biosynthesis of terpenoids. This process leads to increased structural diversity in a cluster of related secondary metabolites by modification of the parent carbocyclic core. In this review, we highlight the diversifying effect o...

Covering: 2000 to 2020. trans-Bicyclo[4.4.0]decane/decene (such as trans-decalin and trans-octalin)-containing natural products display a wide range of structural diversity and frequently exhibit potent and selective antibacterial activities. With one of the major factors in combatting antibiotic resistance being the discovery of novel scaffolds, t...

DOI: 10.1002/sscp.202000077 The cover picture shows the collagen structure with several crosslinks then the isolation of the intact GOLD, MOLD and pentosidine advanced glycation end products by acid hydrolysis. The separation was then carried out on a Cogent Diamond Hydride column under isocratic conditions with a short time of 5.5 min. The eluted...

Leonuketal is an 8,9-seco-labdane terpenoid with a unique tetracyclic structure, owing to a diversity-generating biosynthetic C-C bond cleavage event. The first total synthesis of leonuketal is reported, featuring a Ti(III)-mediated reductive cyclization of an epoxy nitrile ether, an unusual ring-opening alkyne formation as part of an auxiliary rin...

Despite significant efforts made towards treatments for Hepatitis B virus (HBV), a long-term curative treatment has thus far eluded scientists. Recently, the Sodium Taurocholate Co-Transporting Polypeptide (NTCP) receptor has been identified as the entry pathway of HBV into hepatocytes. Myrcludex B, an N-terminally myristoylated 47-mer peptide mimi...

A series of C-2 derivatized 8-sulfonamidoquinolines were evaluated for their antibacterial activity against the common mastitis causative pathogens Streptococcus uberis, Staphylococcus aureus and Escherichia coli, both in the presence and absence of supplementary zinc (50 µM ZnSO4). The vast majority of compounds tested were demonstrated to be sign...

Glycation of collagen produces advanced glycation end products including pen-tosidine, glyoxal-lysine dimer, and methylglyoxal-lysine dimer. These products are markers for aging and associated with the development of several diseases. In this study, a rapid and simultaneous analytical method for pentosidine, glyoxal-lysine dimer, and methylglyoxal-...

Chemoselektive Techniken für die Peptidmodifikation sind von Interesse in der medizinischen Chemie. In ihrem Forschungsartikel auf S. 18210 berichten A J. Cameron, P. W. R. Harris und M. A. Brimble über eine Methode für die Herstellung von Allenamid‐modifizierten Peptiden am Harz, was die Konjugation oder intramolekulare Cyclisierung mittels Thia‐M...

The first total synthesis of the allene-containing cyclic tetrapeptide pseudoxylallemycin C is reported. The Tyr(t-Bu)-protected linear peptide was prepared on-resin and cyclized in solution phase to yield the protected cyclic precursor. Upon deprotection of Tyr(t-Bu), the desired phenolic cyclic tetrapeptide was separated by RP-HPLC from its epime...

Chemoselective peptide modification tools are of interest in medicinal chemistry. In their Research Article on page 18054, A. J. Cameron, P. W. R. Harris, and M. A. Brimble report on the on‐resin preparation of allenamide‐modified peptides, enabling conjugation or intramolecular cyclisation via a thia‐Michael addition. The picture illustrates an al...

Callyspongiolide, a macrolide natural product with a conjugated diene-ynic side chain, has garnered significant attention from the synthetic community since its isolation from a sea sponge in 2013. Herein we review the approaches which have been applied to this bioactive natural product to date. These synthetic endeavours have established the absol...