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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 a novel structure, non‐cytotoxicity, and low likelihood of developing resistance render cadaside B an important synthetic target. Herein, a synthetic strategy towards cadaside B is reported with the key steps involving on‐resin depsipeptide bond formation and solution‐phase macrolactamization. Good agreement of the synthetic cadaside B MS/MS fragmentation pattern was observed with the natural product, but a different 1H NMR spectrum and absence of antimicrobial activity suggest an undetected epimerization event took place during the synthesis. Herein the findings of our synthetic journey and suggestions for future directions are presented. [ABSTRACT FROM AUTHOR]

Covering: from 1938 up to March 2021 The 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 array of biological activity and possess fascinating molecular architectures, which have made them popular targets for total synthesis studies. This review examines the isolation and bioactivity of tryptophan-linked cyclic peptide natural products, along with a discussion of their first total synthesis, and biosynthesis where this has been studied. [ABSTRACT FROM AUTHOR]

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 (2 S ,4 S ,6 R)-2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid and (2 S ,4 R)-2-amino-4-methyldecanoic acid building blocks were replaced with derivatives of l -phenylalanine and 2-aminodecanoic acid, respectively. Substitution of (2 S ,4 S ,6 R)-2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid with l -4,4′-biphenylalanine yielded an analogue that was tenfold more potent than the natural product and was also the most hydrophobic analogue, as judged by an antiproliferative IC50 assay and logD calculations; these results suggest that the potency of culicinin D may be governed by its hydrophobicity. However, the introduction of halogenated moieties into the peptide sequence generated analogues that were similarly potent, although not necessarily hydrophobic. Thus, the parameters regulating the cytotoxicity of culicinin D, and by extension other peptaibols, are multimodal and include both halogenation and hydrophobicity. [ABSTRACT FROM AUTHOR]

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, the efficient construction of these natural products is an attractive pursuit in the development of novel antibiotics. This highlight aims to provide a critical analysis on how the presence of dense architectural and stereochemical complexity necessitated special strategies in the synthetic pursuits of these natural trans-bicyclo[4.4.0]decane/decene antibiotics. [ABSTRACT FROM AUTHOR]

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 of C−C bond cleavage by examining the literature related to seco‐labdanes—a class of diterpenoids arising from such C−C bond cleavage events. [ABSTRACT FROM AUTHOR]

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, the approaches that have been applied to this bioactive natural product to date are reviewed. These synthetic endeavors have established the absolute stereochemistry of this molecule and allowed further investigation into its promising caspase‐independent bioactivity, while also contributing to the wider field of macrolide synthesis. [ABSTRACT FROM AUTHOR]

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 epimer that also formed during the macrocyclisation step. Subsequent alkylation with 4-bromobuta-1,2-diene yielded pseudoxylallemycin C. [ABSTRACT FROM AUTHOR]

An enantioselective synthesis of macrocyclic core of (+)‐callyspongiolide is described, constituting a formal synthesis of this natural product. The synthetic strategy constructs the 14‐membered macrocyclic domain via Yamaguchi esterification followed by a challenging ring‐closing metathesis (RCM) to effect the final formation of the macrolactone. [ABSTRACT FROM AUTHOR]

Asymmetric access to α-hydroxy-1,4-diketones has been achieved by direct ene coupling of silyl enol ethers with glyoxal electrophiles, mediated by a chiral N , N ′-dioxide–nickel(II) complex catalyst. Successful union of a polyketide silyl enol ether with an α-quaternary glyoxal, generated by dioxirane oxidation of an α-diazo ketone, models a proposed C5 –C6 disconnection of the polyketide and spirocyclic imine domains of the marine natural product, portimine. [ABSTRACT FROM AUTHOR]

The biological activity and structural diversity of natural products are unsurpassed by any available synthetic screening libraries. As such, these privileged scaffolds serve as important, biologically prevalidated platforms for the design of compound libraries in the search for new drug candidates. Recent progress has focussed on improving the potency, selectivity and pharmacokinetics of bioactive natural products through structural modification, leading to the emergence of a number of drug-like lead compounds. Here, we review recent advances in the exploitation of terpenoid, polyketide, phenylpropanoid and alkaloid natural product scaffolds for inspiration in the design and development of important new drug candidates. [ABSTRACT FROM AUTHOR]

In this study we investigated the influence of oxygen availability on a phenotypic microtiter screen to identify new, natural product inhibitors of growth for the bovine mastitis-causing microorganisms; Streptococcus uberis , Staphylococcus aureus , and Escherichia coli. Mastitis is a common disease in dairy cattle worldwide and is a major cause of reduced milk yield and antibiotic usage in dairy herds. Prevention of bovine mastitis commonly relies on the application of teat disinfectants that contain either iodine or chlorhexidine. These compounds are used extensively in human clinical settings and increased tolerance to chlorhexidine has been reported in both Gram-positive and Gram-negative microorganisms. As such new, non-human use alternatives are required for the agricultural industry. Our screening was conducted under normoxic (20% oxygen) and hypoxic (<1% oxygen) conditions to mimic the conditions on teat skin and within the mammary gland respectively, against two natural compound libraries. No compounds inhibited E. coli under either oxygen condition. Against the Gram-positive microorganisms, 12 inhibitory compounds were identified under normoxic conditions, and 10 under hypoxic conditions. Data revealed a clear oxygen-dependency amongst compounds inhibiting growth, with only partial overlap between oxygen conditions. The oxygen-dependent inhibitory activity of a naturally occurring quinone, β-lapachone, against S. uberis was subsequently investigated and we demonstrated that this compound is only active under normoxic conditions with a minimum inhibitory concentration and minimum bactericidal concentration of 32 μM and kills via a reactive oxygen species-dependent mechanism as has been demonstrated in other microorganisms. These results demonstrate the importance of considering oxygen-availability in high-throughput inhibitor discovery. [ABSTRACT FROM AUTHOR]

Syn dihydroxyketone motifs are embedded in a wide range of biologically active natural products, however the development of stereoselective synthetic methods to assemble these structures has proven a challenging task. We report a highly diastereoselective method for the synthesis of syn dihydroxyketones from propargylic alcohols, with wide scope for application in natural product synthesis. The reaction sequence involves regioselective cyclisation of propargylic alcohols with incorporation of a triketone to give enol dioxolanes that are then diastereoselectively epoxidised to form unusual spiroepoxide intermediates. Hydrolysis affords syn dihydroxyketones as essentially single diastereisomers. The reaction sequence is operationally simple, of wide substrate scope, and remarkably can be efficiently carried out as a one‐pot process with no loss of overall yield or diastereoselectivity. [ABSTRACT FROM AUTHOR]

The Diels–Alder cycloaddition reaction has become established as a fundamental approach for the preparation of complex natural products; however, successful application of the intermolecular Diels–Alder cycloaddition reaction to the synthesis of particularly congested scaffolds remains surprisingly problematic. Inspired by the terpenoid spiroketal natural product leonuketal, a challenging telescoped reaction sequence has been realized to access the core [2.2.2]‐bicyclic lactone ring system and its [3.2.1] isomer. Our four‐step, protecting‐group‐free process required detailed investigation to circumvent the problems of adduct fragmentation and intermediate instability. Successful solution of these practical issues, along with unambiguous structural determination of the target structures, provide useful insights that will facilitate future applications of the Diels–Alder cycloaddition reaction to challenging, highly congested molecular scaffolds and ongoing synthetic efforts towards this natural product. [ABSTRACT FROM AUTHOR]

Several hundred (396) compounds from New Zealand flora with medicinal properties were analyzed for their physicochemical properties. It was found that approximately 10 % fulfilled all the requirements to be considered to be lead‐like, over half of the compounds were deemed to be in the drug‐like space and ≈75 % were in the known drug space. These results indicate the presence of a significant proportion of compounds that are of particular interest to pursue as potential lead compounds or therapeutics. Additionally, compound classes were analyzed separately—most carbonyl‐containing compounds (aldehydes, ketones, esters and lactones), along with phenols were the most lead‐like compounds, which also displayed very good proportions in the drug‐like and known drug space. The information presented herein can be harnessed and utilized in future work, through focussing on the compounds and compound classes that exhibit high‐levels of lead‐likeness for further development. [ABSTRACT FROM AUTHOR]

The emergence of multidrug-resistant bacteria has necessitated the urgent need for novel antibacterial agents. Antimicrobial peptides (AMPs), the host-defence molecules of most living organisms, have shown great promise as potential antibiotic candidates due to their multiple mechanisms of action which result in very low or negligible induction of resistance. However, the development of AMPs for clinical use has been limited by their potential toxicity to animal cells, low metabolic stability and high manufacturing cost. Extensive efforts have therefore been directed towards the development of enhanced variants of natural AMPs to overcome these aforementioned limitations. In this review, we present our efforts focused on development of efficient strategies to prepare several recently discovered AMPs including antitubercular peptides. The design and synthesis of more potent and stable AMP analogues with synthetic modifications made to the natural peptides containing glycosylated residues or disulfide bridges are described. [ABSTRACT FROM AUTHOR]

Covering: up to April 2018 2-Formylpyrroles are ubiquitous in nature, arising from the non-enzymatic Maillard reactions of amines and sugars. Often confused for secondary metabolites, these Maillard products display interesting biological activities including hepatoprotective, immunostimulatory, antiproliferative and antioxidant effects. This review presents all 2-formylpyrrole natural products reported to date and identifies structural sub-classes for their categorisation. The origin, biological activity and chemical syntheses of these natural products are discussed herein. [ABSTRACT FROM AUTHOR]

Abstract: The first synthesis of the anti‐TB cyclic peptide callyaerin A (1), containing a rare (Z)‐2,3‐diaminoacrylamide bridging motif, is reported. Fmoc‐formylglycine‐diethylacetal was used as a masked equivalent of formylglycine in the synthesis of the linear precursor to 1. Intramolecular cyclization between the formylglycine residue and the N‐terminal amine in the linear peptide precursor afforded the macrocyclic natural product 1. Synthetic 1 possessed potent anti‐TB activity (MIC100=32 μ m) while its all‐amide congener was inactive. Variable‐temperature NMR studies of both the natural product and its all‐amide analogue revealed the extraordinary rigidity imposed by this diaminoacrylamide unit on peptide conformation. The work reported herein pinpoints the intrinsic role that the (Z)‐2,3‐diaminoacrylamide moiety confers on peptide bioactivity. [ABSTRACT FROM AUTHOR]

The facile Fmoc (Fluorenylmethoxycarbonyl) solidphase synthesis of the α-helical-channel-forming peptaibol alamethicin U-22324 is described. A late-stage reduction by using a new double-linker method was used to introduce the C-terminal alcohol. Furthermore, we also report the synthesis of an alamethicin analogue with a C-terminal carboxylic acid. [ABSTRACT FROM AUTHOR]

The cyclization of the linear tetrapeptides sequence H-NMePhe-Xaa¹-NMePhe-Xaa²-OH (for which Xaa¹ = Xaa² = Ile, Val, or Leu; Xaa¹ = Val; Xaa² = Ile or Leu) by using 1-propane-phosphonic acid anhydride was explored. An unanticipated finding is the cyclization towards cyclotetrapeptide conformers (kinetic products) that were highly prone to hydrolysis and that slowly interconvert into the more stable trans, cis, trans, cis (tctc) conformers (thermodynamic products). [ABSTRACT FROM AUTHOR]

Covering: 2008 to 2015. A review on the isolation, biological activity and synthesis of pyranonaphthoquinone natural products from 2008–2015 is provided This review discusses the isolation, biological activity and synthesis of pyranonaphthoquinone natural products, covering the years 2008–2015. The pyranonaphthoquinones are a group of metabolites sharing a common naphtho[2,3-c]pyran-5,10-dione ring system that have been isolated from a wide range of microorganisms, plants and insects. In addition to their synthetically challenging molecular structures, pyranonaphthoquinones exhibit a wide array of biological activity, including anti-bacterial, anti-fungal and anti-cancer properties. The therapeutic potential of these compounds has led to a dynamic interplay between total synthesis and biological evaluation. [ABSTRACT FROM AUTHOR]

A full account of the evolution of a convergent total synthesis of gonytolide C is reported. The assembly of the natural product core relies on a Horner-Wadsworth-Emmons (HWE) olefination followed by an intramolecular oxa-Michael addition. Robust and efficient preparations of both HWE coupling partners were established. The synthesis enabled further investigation of an asymmetric oxa-Michael cyclisation to prepare gonytolide C, demonstrating the utility of this strategy for synthesis of 2,2-disubstituted chromanones. [ABSTRACT FROM AUTHOR]

Synthesis of the benzannulated spiroketal core of the pinnatifinoside family of natural products, via Sonagashira cross-coupling and gold-catalysed spirocyclisation of function-alised flavone derivatives is described. These investigations lay the framework for ongoing synthetic studies towards the pinnatifinoside family, and related biologically active derivatives. [ABSTRACT FROM AUTHOR]

Covering from 1953 to 2014 The rubromycins are an ever growing family of natural products isolated from various Actinomycetes over the last 60 years. Exhibiting a highly attractive array of antimicrobial and enzyme activity, this unique family of compounds have attracted significant attention from many synthetic chemists. Investigations into the synthesis of the densely functionalised hexacyclic ring system have revealed many hidden synthetic challenges. This review covers the isolation, the reported biological activity and the detailed synthetic studies towards these complex natural products. [ABSTRACT FROM AUTHOR]

A novel Maillard-type condensation between a primary amine derived from D-mannitol and a dihydropyranone, was used as a key step to access the unusual morpholine-spiroketal acortatarin A. The synthetic approach also enabled access to a C-2 analogue of acortatarin A, and can be used for the synthesis of related 2-formylpyrrole natural products. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides and proteins represent an important class of plant defensive compounds against pathogens and provide a rich source of lead compounds in the field of drug discovery. We describe the effective preparation of the cysteine-rich snakin-1 and -2 antimicrobial peptides by using a combination of solid-phase synthesis and native chemical ligation. A subsequent cysteine/cystine mediated oxidative folding to form the six internal disulfide bonds concurrently gave the folded proteins in 40-50 % yield. By comparative evaluation of mass spectrometry, HPLC, biological data and trypsin digest mapping of folded synthetic snakin-2 compared to natural snakin-2, we demonstrated that synthetic snakin-2 possesses full antifungal activity and displayed similar chromatographic behaviour to natural snakin-2. Trypsin digest analysis allowed tentative assignment of three of the purported six disulfide bonds. [ABSTRACT FROM AUTHOR]

A convenient synthesis of the traditional medicine constituents magnolamide, lobechine and funebral is described. Construction of the 2-formylpyrrole core of these natural products was achieved by means of a Maillard reaction, involving condensation of the sugar surrogate, dihydropyranone 9, with the requisite primary amines. This approach offers a very direct and general route to the 2-formylpyrrole ring system. [ABSTRACT FROM AUTHOR]

An efficient first synthesis of the cysteine protease inhibitors CPI-2081a and CPI-2081b is described. These naturally occurring penta-peptidesx exhibit extensive amino acid modifications including N-terminal acylation, S-tert-butylation and C-2 p-hydroxybenzyl alkylation of the tryptophan indole ring in CPI-2081b. Both compounds were synthesised by using Fmoc SPPS. In the case of CPI-2081b a SPPS side reaction was optimized to allow straightforward synthetic access to this p-hydroxybenzylated tryptophan-containing natural product. [ABSTRACT FROM AUTHOR]

The first total syntheses of the chromone-containing natural products chaetoquadrins H and I are reported, using an aldol reaction and an acid-catalyzed deprotection/cyclization/elimination sequence. Chaetoquadrin H was isolated from the ascomycete Chaetomium quadrangulatum and exhibits potent mouse liver monoamine oxidase (MAO) inhibitory activity. Chaetoquadrin I was not isolated in sufficient quantity to enable biological evaluation. The synthesis of the title compounds provides a useful starting point for a medicinal chemistry program focused on chaetoquadrin natural products. [ABSTRACT FROM AUTHOR]

Herein we describe the first synthesis of the all-L naturally occurring cyclopentapeptides versicoloritides A, B, and C. We found that the extent of oligomerization and epimerization upon head-to-tail cyclization of the linear pentapeptide precursors could be reduced to acceptable levels by modifying the reaction conditions. [ABSTRACT FROM AUTHOR]

Studies toward the synthesis of three biologically active [5,6]-benzannulated spiroketal natural products are described. The first total synthesis of paecilospirone is reported, employing a late-stage, pH-neutral spiroketalization. A formal synthesis of γ-rubromycin is described, where the spiroketal moiety is formed by delicate manipulation of the electronic properties of the spirocyclization precursor. Finally, model work toward the total synthesis of berkelic acid is summarized, introducing a novel Horner--Wadsworth--Emmons/oxa-Michael (HWE/oxa-M) cascade to access the spiroketal precursor. [ABSTRACT FROM AUTHOR]

Abstract: A short convergent synthesis of the fungal metabolites cephalosporolides E and F is reported. The key step makes use of a chelation-controlled Mukaiyama aldol reaction to access the key acyclic spiroacetal precursor with the required syn stereochemistry. [ABSTRACT FROM AUTHOR]

A new total synthesis of the HRV 3C protease inhibitor (±)-thysanone is described. The synthetic route hinges on an iridium-catalysed borylation to install the resorcinol-derived component of the natural product. [ABSTRACT FROM AUTHOR]

Keywords: biomimetic synthesis; C-C bond cleavage; labdanes; natural products; terpenoids EN biomimetic synthesis C-C bond cleavage labdanes natural products terpenoids 1 1 1 04/16/21 20210412 NES 210412 In their Review on page 6367 ff., Phillip Grant and Margaret Brimble examine the isolation, bioactivity, and total synthesis of I seco i -labdane diterpenoids - a class of diterpenoid arising from C-C bond cleavage events. Biomimetic synthesis, C-C bond cleavage, labdanes, natural products, terpenoids Frontispiece: seco-Labdanes: A Study of Terpenoid Structural Diversity Resulting from Biosynthetic C-C Bond Cleavage. [Extracted from the article]

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, and the effectiveness of the few treatments available is being jeopardized by increasing rates of resistance. There is an urgent need to identify new chemical treatments that are effective against Phytophthora diseases. Natural products have long been regarded as "Nature's medicine chest", providing invaluable leads for developing front-line drugs and agrochemical agents. Here, we have screened a natural product-inspired library of 328 chemicals against two key Phytophthora species: Phytophthora cinnamomi and Phytophthora agathidicida. The library was initially screened for inhibition of zoospore germination. From these screens, we identified twenty-one hits that inhibited germination of one or both species. These hits were further tested in mycelial growth inhibition studies to determine their half-maximal inhibitory concentrations (IC50s). Four compounds had IC50 values of approximately 10 µM or less, and our best hit had IC50s of approximately 3 µM against both Phytophthora species tested. Overall, these hits may serve as promising leads for the development of new anti-Phytophthora agrochemicals [ABSTRACT FROM AUTHOR]

The first synthesis of the cyclic peptides tunicyclins C and D is described. Tunicyclin D is a potent antifungal agent, isolated from a traditional Chinese medicinal herb. [ABSTRACT FROM AUTHOR]

Review: 36 refs. [ABSTRACT FROM AUTHOR]

A robust synthetic approach to cis-γ-hydroxycarvone derivatives has been developed, enabling efficient access to synthetic building blocks for the growing family of bioactive sesterterpenoid natural products. Using this approach, an allyl bromide carvone derivative was used as the key building block for the total synthesis of the natural product phorbin A. This synthetic sequence also demonstrates the utility of benozyl enol ethers as an effective means of masking a β-ketophosphonate and their subsequent application in a one-pot benzoyl transfer-intramolecular Horner-Wadsworth-Emmons reaction. [ABSTRACT FROM AUTHOR]

A synthetic strategy to access the carbon skeleton of the griseorhodin family of natural products has been developed. The key step involved the acid-mediated spirocyclisation of a highly functionalised dihydroxyketone. The delicate electronic balance between the electron rich naphthalene moiety and the electron-withdrawing isocoumarin ring system were finely tuned to facilitate the acid-mediated spirocyclisation reaction. The development of this synthetic strategy provides a basis for further synthetic investigations towards the more structurally complex griseorhodin natural products. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of four possible stereoisomers of the spiroacetal core of the natural products cephalosporolides H and I and penisporolides A and B is described. The key steps involve the use of Sharpless asymmetric dihydroxylation to install the desired stereochemistry of the γ-lactone ring and an oxidative radical cyclisation to form the spiroacetal ring system. [Copyright &y& Elsevier]

Abstract: A series of pyranonaphthoquinone derivatives related to the known topoisomerase II inhibitor eleutherin 1 have been shown to act as specific topoisomerase II catalytic inhibitors, with several analogues displaying greater potency than the natural product itself. Amongst the compounds tested were the natural products ventiloquinone L 4 and thysanone 8 with a diverse range of topoisomerase II inhibition properties being observed. Interestingly, the natural products are generally weaker inhibitors than their synthetic counterparts, emphasising that subtle changes in the basic molecular structure of a natural product led to significant changes in the inhibition profile. It has also been demonstrated for the first time that analogues related to nanaomycin A and cardinalin-type dimeric pyranonaphthoquinones exhibit potent topoisomerase II inhibitory properties. With respect to structural features, it appears that the nature of the substituents at C1 on the pyran ring and oxygenated substituents on the aryl ring are critical for anti-topoII activity. Importantly, the topoisomerase II inhibition strength does not correlate well with the measured cytotoxicity against yeast, indicating that other molecular features in the pyranonaphthoquinone family must be considered for the design and use of this structural class as highly specific topoisomerase II inhibitors. [Copyright &y& Elsevier]

The article focuses on a research titled "Total Synthesis of Virgatolide B (I)" by researchers P.A. Hume and colleagues published in the journal "Organic Letters" in a 2013 issue.

Abstract: We have synthesised a focused library of derivatives of natural products containing the pyranonaphthoquinone moiety including the first report of such a scaffold with an appended tetrazole functionality. Examples include kalafungin derivatives as well as analogues of nanaomycin and eleutherin. These compounds were assessed for cytotoxic activation by breast cancer cell lines engineered to express the prototypic human one- and two-electron quinone bioreductive enzymes, NADPH: cytochrome P450 oxidoreductase (POR) and NAD(P)H: quinoneoxidoreductase 1 (NQO1; DT-diaphorase), respectively. Several compounds were observed to be cytotoxic at sub-micromolar level and a pattern of increased aerobic potency was observed in cells over expressing POR. A subset of analogues was assessed under anoxic conditions, where cytotoxicity was reduced, implicating redox cycling as a major mechanism of toxicity. The substrate specificity for reductive enzymes is relevant to the future design of bioreductive prodrugs to treat cancer. [Copyright &y& Elsevier]

A series of pyranonaphthoquinone derivatives possessing structural features present in both natural products annulin B and exiguamine A have been shown to exhibit low micromolar inhibition of indoleamine 2,3-dioxygenase-1 (IDO-1). These inhibitors retain activity against the enzyme in a cellular context with an approximate one-log loss of dose potency against IDO-1 in cells. One particular analogue, triazole 8 shows good inhibition of IDO-1 along with little loss of cell viability at low drug concentrations. These results have extended the naphthoquinone series of novel IDO-1 inhibitors based on lead compounds from nature. Pyranonaphthoquinones exhibit low micromolar inhibition of indoleamine 2,3-dioxygenase-1 (IDO-1). These inhibitors retain activity against the enzyme in a cellular context with an approximate one-log loss of dose potency against IDO-1 in cells. Triazole 8 shows good inhibition of IDO-1 along with little loss of cell viability at low drug concentrations. [ABSTRACT FROM AUTHOR]

Abstract: Bicyclic analogues of methyllycaconitine (MLA), such as 12, have been synthesised that incorporate the C1–OMe substituent present in the natural product. Electrophysiology experiments using Xenopus oocytes expressing nicotinic acetylcholine receptors (nAChRs) were conducted on these analogues and a related tricyclic analogue 2. The most potent compound, 2, was an antagonist at all receptors studied but displayed different antagonist effects at each receptor subtype. This study more clearly defines the biological effects of MLA analogues at nAChRs and demonstrates that these analogues are not selective ligands for the α7 nAChR subtype. [Copyright &y& Elsevier]

Culicinin D (1), a 10 amino acid peptaibol originally isolated from Culicinomyces clavisporus , exhibits potent activity against a range of cancer cell lines. Building on our previous work exploring the structure–activity relationship (SAR) of the unusual (2 S ,4 S ,6 R)-AHMOD residue, a series of analogues of culicinin D were prepared to further investigate the SAR of these peptaibols. Alanine scanning of a potent and readily accessible analogue 23 revealed the effect of each residue on antiproliferative activity, and a small panel of analogues were prepared to explore the SAR of the non-natural amino acid residue (2 S ,4 R)-AMD. Results from the alanine scan were used to design an expanded library of culicinin D analogues, leading to the discovery of cyclohexylalanine analogue 52 , which exhibited better antiproliferative activity than the natural product 1. [ABSTRACT FROM AUTHOR]

The article presents a chemical formula related to the article "Total Synthesis of Heronapyrrole C." by X.-B. Ding, D. P. Furkert and others, published in the periodical "Organic Letters" in 2014.