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The wasp venom‐derived antimicrobial peptide polybia‐CP has been previously shown to exhibit potent antimicrobial activity, but it is also highly toxic. Previously, using a physicochemical‐guided peptide design strategy, we reversed its toxicity while preserving and even enhancing its antibacterial properties. Here, we report on several additional unanticipated biological properties of polybia‐CP and derivatives, namely their ability to target Plasmodium sporozoites and cancer cells. We leverage a physicochemical‐guided approach to identify features that operate as functional hotspots making these peptides viable antiplasmodial and anticancer agents. Helical content and net positive charge are identified as key structural and physicochemical determinants for antiplasmodial activity. In addition to helicity and net charge, hydrophobicity‐related properties of polybia‐CP and derivatives were found to be equally critical to target cancer cells. We demonstrate that by tuning these physicochemical parameters, it is possible to design synthetic peptides with enhanced submicromolar antiplasmodial potency and micromolar anticancer activity. This study reveals novel and previously undescribed functions for Polybia‐CP and analogs. Additionally, we demonstrate that a physicochemical‐guided rational design strategy can be used for identifying functional hotspots in peptide molecules and for tuning structure–function to generate novel and potent new‐to‐nature therapies.

The analgesic, sedative, antidepressant, euphoriant, intoxicating, and addictive properties of opium and its synthetic derivatives are well known and have been known for centuries. Hence, the current major public health problems due to excessive availability should be no surprise. What is unprecedented in the United States, and emerging elsewhere, is the extent of the profound consequences and complexity of addressing this public health crisis.

The discovery of defined peptidoglycan metabolites that activate host immunity and their specific receptors has revealed fundamental insights into host–microbe recognition and afforded new opportunities for therapeutic development against infection and cancer. In this review, we summarise the discovery of two key peptidoglycan metabolites, γ‐d‐glutamyl‐meso‐diaminopimelic acid (iE‐DAP) and muramyl dipeptide and their respective receptors, Nod1 and Nod2, and review progress towards translating these findings into therapeutic agents. Notably, synthetic derivatives of peptidoglycan metabolites have already yielded approved drugs for chemotherapy‐induced leukopenia and paediatric osteosarcoma; however, the broad effects of peptidoglycan metabolites on host immunity suggest additional translational opportunities for new therapeutics towards other cancers, microbial infections and inflammatory diseases., Peptidoglycan metabolites are key microbe‐associated molecular patterns that sensed by pattern recognition receptors. Modification of these microbiota‐derived metabolites is providing new therapeutic leads towards infection, cancer and inflammatory diseases.

Although fungi produce highly structurally diverse metabolites, many of which have served as excellent sources of pharmaceuticals, no fungi-derived agent has been approved as a cancer drug so far. This is despite a tremendous amount of research being aimed at the identification of fungal metabolites with promising anticancer activities. This review discusses the results of clinical testing of fungal metabolites and their synthetic derivatives, with the goal to evaluate how far we are from an approved cancer drug of fungal origin. Also, because in vivo studies in animal models are predictive of the efficacy and toxicity of a given compound in a clinical situation, literature describing animal cancer testing of compounds of fungal origin is reviewed as well. Agents showing the potential to advance to clinical trials are also identified. Finally, the technological challenges involved in the exploitation of fungal biodiversity and procurement of sufficient quantities of clinical candidates are discussed, and potential solutions that could be pursued by researchers are highlighted.

This paper presents a review on kaurane diterpenes, covering various aspects of chemical and microbiological transformations of native ent-kaurenoic acid, namely, its reactions via COOH groups, double bonds and rearrangements of the carbon skeleton that lead to a wide range of natural and synthetic derivatives with potential biologic activities and can present convenient synthons for the syntheses of other native ent-kauranes.

Besides its particular importance as a widely used therapeutic agent, insulin (and its synthetic derivatives) has been suspected, purported, and proven to be a lethal weapon in numerous cases of attempted or successful homicide and suicide. In addition to blood and urine as common matrices for clinical diagnosis and post-mortem analysis, vitreous humour has gained considerable attention in autopsy and follow-up investigations due to its ability to provide valuable information on cause and time of death. However, post-mortem insulin analyses using such specimens have been rare due to the limited penetration of peptide hormones into the vitreous body, and immunoassays were exclusively employed in those studies. In the present communication, the determination of insulin(s) from vitreous humour by means of immunopurification combined with ultrahigh performance liquid chromatography--high resolution/high accuracy (tandem) mass spectrometry is reported. Exploiting the constantly increasing sensitivity and robustness of modern mass-spectrometry-based instruments, the option to identify insulin in post-mortem vitreous samples is demonstrated with a specimen collected from a non-diabetic victim who died from an insulin overdose. This communication represents the first successful mass-spectrometry-based analysis of post-mortem material related to an insulin poisoning case.

Physico-chemical and chemical properties of citric acid and methods of synthesis of its derivatives, namely esters, amides, 1,3-dioxolan-4-ones etc. are presented. The important group of natural derivatives of this acid belonging to the siderophore family, i.e. compounds fulfilling in nature the function of biocarriers of ferric ions, is described in detail. The recent advances in the total synthesis of natural siderophores — citric acid derivatives, its homologues and analogues of the “retro” type are summarized.

Whereas significant knowledge is accumulating on the antibacterial and antifungal properties of host defense peptides (HDPs) and their synthetic mimics, much less is known of their activities against parasites. A variety of in vitro and in vivo antiparasitic assays suggest that these notorious antimicrobial compounds could represent a powerful tool for the development of novel drugs to fight parasites in the vertebrate host or to complement current therapeutic strategies, albeit the fact that HDPs essentially act by nonspecific mechanisms casts serious doubt on their ability to exert sufficient selectivity to be considered ideal candidates for drug development. This minireview summarizes recent efforts to assess the antiparasitic properties of HDPs and their synthetic derivatives, focusing on two of the most used models –Plasmodium and Leishmania species – for antiparasitic assays against the different development stages.

γ-L-Glutamyl derivatives and a β-L-aspartyl derivative of different amines (taurine, nortaurine, N-methyltaurine, taurine amide, tauryl-methylamine, tauryl-piperidine, β-alanine amide, orthanilic acid, 2-aminoethanephosphonic acid, ethanolamine-O-sulfate and ethanolamine-O-phosphate) have been synthesized by mixed anhydride or active ester coupling method. One of the dipeptide analogues, γ-L-glutamyl-(ethanolamine-O-sulfate) was prepared by esterification, too. Syntheses of α,γ-L-glutamyl-bis-taurine and of DL-2-amino-8-sulfo-octanoic acid are also described.

Background Since its isolation in 1970, and discovery of its potent inhibitory activity on T-cell proliferation, cyclosporin A (CsA) has been shown to play a significant role in diverse fields of biology. Furthermore, chemical modification of CsA has led to analogs with distinct biological activities associated with its protein receptor family, cyclophilins. Scope of review This review systematically collates the synthetic chemistry performed at each of the eleven amino acids, and provides examples of the utility of such transformations. The various modifications of CsA are traced from early, modest chemistry performed at the unique Bmt residue, through the remarkable use of a polyanion enolate that can be stereoselectively manipulated, and onto application of more recently developed olefin metathesis chemistry to prepare new CsA derivatives with unexpected biological activity. Major conclusions The myriad biological activities of CsA and its synthetic derivatives have inspired the development of new approaches to modify the CsA ring. In turn, these new CsA derivatives have served as tools in the discovery of new roles for cyclophilins. General significance This review provides information on the types of cyclosporin derivatives that are available to the many biologists working in this field, and should be of value to the medicinal chemist trying to discover drugs based on CsA. This article is part of a Special Issue entitled Proline-directed foldases: Cell signaling catalysts and drug targets.

Naturally occurring aromatic abietane diterpenoids (dehydroabietanes) exhibit a wide range of biological activities. A number of synthetic studies aimed at modifying the abietane skeleton in order to obtain new potential chemotherapeutic agents have been reported. In this study, the biological activities of synthetic derivatives of aromatic abietane diterpenoids are reviewed.

The pyrethroid group of insecticides consists of natural pyrethrins derived from pyrethrum flowers and synthetic derivatives which are similar in chemical structure to the natural compounds. Pyrethroids have been considered to be ideal insecticides because of their rapid knock-down effect against insects in a minimal dose and low mammalian toxicity. © 1999 Society of Chemical Industry

Chiral resolution of atropine, homatropine and eight synthetic tropinyl and piperidinyl esters were studied by capillary zone electrophoresis with cyclodextrin additives. Atropine and eight synthetic derivatives were successfully resolved by heptakis-(2,3,6-tri-O-methyl)-beta-cyclodextrin (TM-beta-CD) at concentrations ranging from 10 to 40 mM. Homatropine was baseline resolved by 10 mM beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin (HP-beta-CD), respectively. The developed method was employed for the determination of atropine enantiomers in human serum.

In recent years, organocatalysis has enhanced its importance as a tool for the synthesis of enantiomerically enriched compounds. Among the candidates for organocatalysis, the construction of asymmetric quaternary carbons is regarded as a challenging problem in organic synthesis. In particular, 3,3′-disubstituted oxindoles have one or more asymmetric quaternary carbon atoms and they represent a large family of bioactive compounds and synthetic derivatives that mimicry natural products. Therefore they are good targets for drug candidates and in the last two years many papers have appeared on organocatalytic methods for the synthesis of 3,3′-disubstituted oxindoles. Moreover, in the last few years 2-substituted and 2,2′-disubtituted 3-indolinones have also attracted the interest of chemists. This review aims to cover the literature on these topics from its origin to the end of 2011.

The total proton and carbon-13 NMR assignments of quinghaosu I, II and V isolated from Artemisia annua cultivated in Brazil and of the synthetic derivatives quinghaosu alkene, ketone and epoxy are reported. The conformations and conformational equilibria of these compounds in solution were obtained from the spectral data and molecular mechanics calculations.

Genistein, the principal isoflavone constituent of soybean, attracts much attention as a natural molecule with significant affinity towards targets of potential medicinal interest, but also as a food supplement or prospective chemopreventive agent. Since its physicochemical properties are considered suboptimal for drug development, much effort has been invested in designing its analogs and conjugates in hope to obtain compounds with improved efficacy and selectivity. The aim of this article is to summarize current knowledge about the properties of synthetic genistein derivatives and to discuss possible clinical application of selected novel compounds. Some basic information concerning chemical reactivity of genistein, relevant to the synthesis of its derivatives, is also presented.

An investigation of metabolites from the soft coral Sarcophyton trocheliophorum collected at North East Reef, Orpheus Island, has yielded three simple cembranoid diterpenes , namely (7R,8R,14S,1E,3E,11E)-7,8-epoxycembra-1,3,11-trien-14-ol (1), (7R,8R,14S,1E,3E,11E)-14-acetoxy-7,8-epoxycembra-1,3,11-triene (2) and (7R,14S,1E,3E,8E,11E)-cembra-1,3,8,11-tetraene-7,14-diol(3), together with the known dihydrofuran sarcophytoxide (4). The diterpenes (2) and (3) were previously reported as synthetic derivatives of sarcophytol A, but this is the first report of their natural occurrence. The three mildly cytotoxic diterpenes (1)-(3) are structural modifications of the antitumour promotor sarcophytol A (5). Structures were established by high-resolution n.m.r. spectroscopy and interconversion. The absolute stereochemistries of the metabolites were determined by use of the Mosher n.m.r. method, and the stereochemistry at C14 was shown to be the same as that of sarcophytol A in each case. These results are in agreement with the published absolute stereochemistries of the metabolites determined by the Horeau method. Full n.m.r. assignments for (11S,12S,14S,1E,3E,7E)-11,12-epoxycembra-1,3,7-trien-14-ol (6) and (11S,12S,14S,1E,3E,7E)-14-acetoxy-11,12-epoxycembra-1,3,7-triene (7) are given.

Publisher Summary This chapter focuses on the structure or property relationships of polystannanes. Distannane, which can be considered a heavy-atom analog of ethane, is the simplest chemical structure that falls under the preceding definition for the class of compounds known as polystannanes. It has long been known that the electronic spectrum of hexaphenyldistannane exhibits a strong absorption maximum, which has been attributed to the presence of the Sn–Sn bond in this compound. Sulfur and selenium can similarly be inserted into the Sn–Sn bond, and while peralkyl distannanes are typically more reactive than peraryl ones, bulky substituents can retard these reactions by raising energy barriers for bimolecular processes. The use of sterically demanding substituents is, in fact, the basis for a strategy known as kinetic stabilization, which has been successfully employed for the synthesis of polystannane frameworks that would normally have highly reactive Sn–Sn bond. Propellanes are a class of nonclassical structures, since they possess bridgehead atoms having formally inverted tetrahedral geometries that force the four bonds from each of the bridgehead atoms to lie within the same hemisphere. Given this configuration, theoretical investigations have long sought to determine the stability and reactivity of these molecular frameworks prior to the availability of representative synthetic derivatives.

Solandelactones A-I(1–9), cyclopropyl and lactone containing novel docosanoids have been isolated from the hydroid Solanderia secunda. The structures of these compounds have been elucidated by combined spectral and chemical studies. Configuration of the cyclopropyl ring has been assigned as the opposite of related oxylipins by NOESY experiments. Absolute stereochemistry has been determined on the basis of chemical transformations and CD measurements of synthetic derivatives. In addition, the biogenetic origin of solandelactones has been discussed. Solandelactones C, D, and G exhibited moderate inhibitory activity against Farnesyl Protein Transferase.

This review discusses recent progress in the synthesis of inositol phosphates and their analogues. Most of the research published prior to 1992 has been extensively reviewed (Potter and Nahorski, 1992; Potter, 1990; Billington, 1989), probably most completely in the book by Billington (1993). Therefore, mainly findings published since then and some of the most important earlier results are covered by this chapter. A brief discussion of the biochemistry of intracellular inositol phosphates in respect to cell signaling is presented, followed by some of the most crucial stereochemical aspects of inositol phosphates. The synthesis of naturally occurring myo-inositol phosphates and their synthetic derivatives is covered. In particular, the efforts to find agonists and antagonists of the most prominent inositol phosphate, myo-inositol-l,4,5-trisphosphate [Ins(1,4,5)P3], are summarized, including some of their biochemical properties. Finally, some of the most widely used techniques for separation and identification of inositol phosphates are presented.

Data on the chemistry of azafluorenes (indenopyridines) for the last two decades are summarised. Methods of synthesis of all isomeric (as regards the position of the nitrogen atom) azafluorenes are considered. The main reactions of azafluorenes are analysed, their reactivity is determined by the presence and mutual influence of two different conjugated fused rings (benzene and pyridine) and the mode of fusion of the indene and pyridine fragments. The principal conversions of substituents at different positions of the azafluorene system are considered. Evidence is presented on the natural occurrence of azafluorenes, the biological activity of their synthetic derivatives, and on the structure and physicochemical properties of azafluorenes and their derivatives. The bibliography includes 204 references.

L'activite inhibitrice in vitro d'une mycotoxine produite par le genre fusarium et de nouveaux analogues synthetiques, vis-a-vis de bacteries Gram + (Staphylococcus aureus 209P) et Gram - (Escherichia coli K12) est reportee.

The enantioselective hydrogenation of methyl or ethyl pyruvate over cinchona-platinum catalyst system (Orito's reaction) is one of the most intensively studied heterogeneous catalytic asymmetric hydrogenation reactions. Studies aiming at systematic changes of the chiral template have played a crucial role in creating hypotheses for the mechanism of Orito's reaction. It is very important to clarify which structural unit of the alkaloid takes part in the enantiodifferentiation, and learn about the role of the different structural units of chiral templates. In this article, we made an attempt to describe the behavior of natural alkaloids, their synthetic derivatives, and analogues as chiral templates in the heterogeneous catalytic asymmetric hydrogenation of activated ketones.

The "mature" status presently enjoyed by polyolefins prepared with homogeneous (soluble) single-site catalysts through the transition-metal-catalyzed coordination polymerization of ethene and 1-alkenes brings with it a common impression that it is now routinely possible to obtain, with a high degree of confidence, any desired stereochemical microstructure or copolymer composition through iterative optimization employing a set of mutationally related synthetic derivatives generated from an initial molecular design. The dominant reliance on this "one catalyst, one material" strategic approach to discovery is intrinsically self-limiting, however, owing to the limited pool of molecular structures that can be reasonably synthesized and drawn upon. Recently, non-chain-terminating, reversible group-transfer processes have been purposefully introduced to olefin coordination polymerization. These processes, which are highly competitive with propagation, can be controlled externally and now provide the basis for new "one catalyst, many materials" paradigms that have the potential to greatly expand the reach of polyolefin materials for the 21st century.

The impact of natural products on the well being of mankind has been enormous, and their study continues to influence research in the fields of chemistry, biology, and ecology. Historically, the majority of our medicines originate from natural products and their synthetic derivatives, many of which have taught us valuable lessons about biology. While advances in synthetic and combinatorial chemistry have given rise to notable successes in the development of new drugs, the perceived value of natural products has not waned when it comes to treating infectious diseases. In this Miniperspective, we review the role natural products have played in the treatment of tuberculosis (TBa), their value and limitations as chemical probes, the challenges associated with TB drug development, and the current status of natural product and synthetic small molecules as new TB drug leads.

We describe herein an evaluation of trypanocidal effects of the natural alkaloid piperine and twelve synthetic derivatives against epimastigote and amastigote forms of the protozoan parasite Trypanosoma cruzi, the causative agent of the incurable human disease, Chagas' disease. The results obtained point to piperine as a suitable template for the development of new drugs with trypanocidal activity.

Molecular self-assembly is central to many processes in both biology and supramolecular chemistry. The G-quartet, a hydrogen-bonded macrocycle formed by cation-templated assembly of guanosine, was first identified in 1962 as the basis for the aggregation of 5'-guanosine monophosphate. We now know that many nucleosides, oligonucleotides, and synthetic derivatives form a rich array of functional G-quartets. The G-quartet surfaces in areas ranging from structural biology and medicinal chemistry to supramolecular chemistry and nanotechnology. This Review integrates and summarizes knowledge gained from these different areas, with emphasis on G-quartet structure, function, and molecular recognition.

Two synthetic derivatives of the flavonol kaempferol were prepared in order to probe the biological mechanism of action of this natural product. Efficient synthetic routes to both a benzophenone-containing derivative and an amine-containing derivative are reported herein.

B-5354c is a new inhibitor of sphingosine kinase from a novel marine bacterium, SANK 71896. Kinetic study revealed that B-5354c inhibits sphingosine kinase with a Ki value of 12μM. The inhibition is noncompetitive with respect to sphingosine. The compound also inhibits sphingosine-1-phosphate formation in human platelets. Experiments using synthetic derivatives of B-5354c indicate that all the three functional groups, i.e., the long unsaturated aliphatic chain, 4-amino and 3-hydroxyl groups are necessary to inhibit sphingosine kinase.

The antimycotic activity of medicagenic acid and of some synthetic derivatives thereof was tested against plant pathogenic fungi. In general they all possess antimycotic activity. Furthermore, in the case of Sclerotium rolfsii, compounds where the hydroxyl functions of the aglycon remained unchanged (medicagenic acid and its dimethyl ester) or could be enzymically released (3-0-β-D-glucoside of medicagenic acid dimethyl ester) were significantly more active than compounds where these functions were modified by acetylation or methylation. Selective 2-0-methylation of medicagenic acid and comparison of the antimycotic activity of the resulting derivative against S. rolfsii to that of other derivatives suggests that a potential free hydroxyl at position 3 is essential to antimycotic activity.

Pyrethroids are a class of lipophilic insecticide very easily degraded in the natural environment. The two main routes of degradation, photo- and biodegradation, are often superimposed. Pyrethroids developed for use in agriculture are much more photostable than the natural pyrethrins or early synthetic derivatives but they are still sensitive to sunlight, which triggers many alterations such as isomerisation or ester cleavage. The basic pathways of pyrethroid metabolism include hydrolysis of the central ester linkage and oxidation of both acid and alcohol moieties. The rate of these metabolic transformations and the nature of the metabolites depend mainly on the organism involved. Birds and mammals metabolise and excrete more rapidly than insects and fishes. In plants, initial metabolic processes are identical to those known in animals. In soil, pyrethroids undergo the same type of transformation, hydrolysis and oxidation. Neither degradation products nor intact parent compounds are leached.

The synthesis of the protected octapeptide N-t-butoxycarbonyl-phenylalanyl-valylasparaginyl-glutaminyl-Nim-tritylhistidyl-leucyl-S-benzhydrylcysteinyl-glycine-hydrazide 1 , corresponding to the amino-terminal sequence of the insulin B-chain, is described. Up to the protected octapeptide all intermediates have greatly improved solubility properties in neutral organic solvents in comparison with other synthetic derivatives of the same sequence.

A series of investigations involving the total syntheses of a variety of indole and dihydroindole alkaloids in the Aspidosperma, Iboga and Vinca families are discussed. In this lecture particular emphasis is placed on studies relating to the synthesis of the clinically important bisindole or "dimeric" alkaloids of the vinblastine-vincristine family. Apart from the activity demonstrated by the natural alkaloids, it is shown that closely related synthetic derivatives can possess interesting anti-tumor activity as well.

Unlike ethylene, 1,1-dimethoxyethene, an electron-rich olefin, has been photocycloadded to a cis-hexahydroindenone to form a norprotoilludane derivative with a correct stereostructure. Methylation and subsequent chemical transformations yielded several oxygenated derivatives, from which the parent hydrocarbon, protoillud-7-ene, was obtained by deoxygenation. Independent evidence for the stereostructures of the synthetic derivatives has been provided by the X-ray crystallographic analysis of a dihydroxy acetal.

Studies involving selective functionalization of the indole unit in a number of bisindole alkaloids and related synthetic derivatives are described. These investigations include such reagents as te...

Physico-chemical and chemical properties of citric acid and methods of synthesis of its derivatives, namely esters, amides, 1,3-dioxolan-4-ones etc. are presented. The important group of natural derivatives of this acid belonging to the siderophore family, i.e. compounds fulfilling in nature the function of biocarriers of ferric ions, is described in detail. The recent advances in the total synthesis of natural siderophores — citric acid derivatives, its homologues and analogues of the “retro” type are summarized.