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Deposition of polydopamine on substrates is a facile and effective method of surface modification and the deposited polydopamine can reduce silver ions to form silver nanoparticles (AgNPs) for antibacterial applications. However, polydopamine deposition is a time-consuming process that usually requires 24 h to produce a dense surface coating. Since oxidation of dopamine is critical for its polymerization, we hypothesize herein that substitution of an electron-donating group on the catechol ring of dopamine can enhance its oxidation potential and subsequently accelerate its polymerization. In this work, dopamine substituted with a 5-methoxy group (OMeDA) was prepared. OMeDA polymerized faster than dopamine under similar reaction conditions, resulting in a polymer coating of 13 nm thickness on a silicon surface after 8 h, compared to the 24 h required for dopamine to form a coating of similar thickness. A polymer layer with AgNPs can be directly formed on the silicon substrate after exposure to a solution containing OMeDA and silver nitrate. After 2 h exposure, the silver content on the modified surfaces prepared with OMeDA was 187% higher than that obtained with dopamine, and the antibacterial efficacy of the former against Staphylococcus aureus was correspondingly higher than that of the latter. This study demonstrates that OMeDA with an electron-donating group in the catechol ring offers improvements over dopamine for surface modification applications.

Elevation of reactive oxygen species (ROS) is both a consequence and driver of the upregulated metabolism and proliferation of transformed cells. The resulting increase in oxidative stress is postulated to saturate the cellular antioxidant machinery, leaving cancer cells susceptible to agents that further elevate their intracellular oxidative stress. Several small molecules, including the marine natural product cribrostatin 6, have been demonstrated to trigger apoptosis in cancer cells by increasing intracellular ROS. Here, we report the modular synthesis of a series of cribrostatin 6 derivatives, and assessment of their activity in a number of cell lines. We establish that placing a phenyl ring on carbon 8 of cribrostatin 6 leads to increased potency, and observe a window of selectivity towards cancer cells. The mechanism of activity of this more potent analogue is assessed and demonstrated to induce apoptosis in cancer cells by increasing ROS. Our results demonstrate the potential for targeting tumors with molecules that enhance intracellular oxidative stress.

Biomimetic poly(catecholamine) coatings have gained much attention in recent years due to their versatility as functional materials. Despite this, only limited methods are available to modify the function and property of poly(catecholamine) coatings, primarily through post-modification methods. Our approach reported herein provides a simple approach to the fabrication of novel functionalized poly(catecholamine) coatings. The strategy employs the copolymerization of N-Ac-3,4-dihydroxyphenylalanine methyl ester (NADOPAMe) with nucleophilic additives, giving rise to nano-coatings on various surfaces including plastic, metal, glass and polymers. With the appropriate choice of nucleophilic additives, coatings with desired properties can be achieved. This is demonstrated through the fabrication of a redox responsive coating based on NADOPAMe with cysteamine as additive, which shows a concentration-dependent glutathione (GSH) responsive behavior. The ability to utilize this as a controlled release system is also demonstrated.

This is the peer reviewed version of the following article: Goh, W. Y. L.; Chai, C. L. L.; Chen, A. Q., Synthesis and biological studies of a triazole analogue of resorcylic acid lactone LL-Z1640-2. European Journal of Organic Chemistry 2014, 2014, (32), p 7239–7244, which has been published in final form at https://dx.doi.org/10.1002/ejoc.201403010. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

Oxidative stress is a much-appreciated phenomenon associated with the progression of neurodegenerative diseases (NDDs) due to imbalances in redox homeostasis. The poor correlations between the in vitro benefits and clinical trials of direct radical scavengers have prompted research into indirect antioxidant enzymes such as Nrf2. Activation of Nrf2 leads to the upregulation of a myriad of cytoprotective and antioxidant enzymes/proteins. Traditionally, early Nrf2-activators were studied as chemoprotective agents. There is a consequential lack of clinical trials testing Nrf2 activation in NDDs. However, there is abundant evidence of their utility in pre-clinical studies. Herein, we review the endogenous Nrf2 regulatory pathway and avenues for targeting this pathway. Furthermore, we provide updated information on pre-clinical studies for natural and synthetic Nrf2 activators. On the basis of our findings, we posit that successful therapeutics for NDDs rely on the design of potent synthetic Nrf2 activators with a careful combination of other neuroprotective activities.

A robust heterogeneous self-supported chiral titanium cluster (SCTC) catalyst and its application in the enantioselective imine-cyanation/Strecker reaction is described under batch and continuous processes. One of the major hurdles in the asymmetric Strecker reaction is the lack of availability of efficient and reusable heterogeneous catalysts that work at room temperature. We exploited the readily hydrolyzable nature of titanium alkoxide to synthesize a self-supported chiral titanium cluster (SCTC) catalyst by the controlled hydrolysis of a preformed chiral titanium-alkoxide complex. The isolated SCTC catalysts were remarkably stable and showed up to 98 % enantioselectivity (ee) with complete conversion of the imine within 2 h for a wide variety of imines at room temperature. The heterogeneous catalysts were recyclable more than 10 times without any loss in activity or selectivity. The robustness, high performance, and recyclability of the catalyst enabled it to be used in a packed-bed reactor to carry out the cyanation under continuous flow. Up to 97 % ee and quantitative conversion with a throughput of 45 mg h(-1) were achieved under optimized flow conditions at room temperature in the case of benzhydryl imine. Furthermore, a three-component Strecker reaction was performed under continuous flow by using the corresponding aldehydes and amines instead of the preformed imines. A good product distribution was obtained for the formation of amino nitriles with ee values of up to 98 %. Synthetically useful ee values were also obtained for challenging α-branched aliphatic aldehyde by using the three-component continuous Strecker reaction.

Despite the large difference in their nucleophilicity, phenoxide and carboxylate anions take part nearly simultaneously in the aliphatic nucleophilic substitution reaction with 1,4-dibromo-2-butene. This leads to the formation of ether (O) and ester (COO) linkages simultaneously under mild reaction conditions when hydroxyl benzoic acids are employed as nucleophiles. The process yields a new class of polymer broadly classified as unsaturated poly(ether ester) which are potentially functionalizable. This methodology has also been extended for preparing networked polymers by making use of 3,5-dihydroxybenzoic acid as A3 type monomer. Copyright © 2011 Society of Chemical Industry

The synthesis of the chiral core structure of the lissoclimide class of anti-tumour agents containing three rings, including a chiral succinimide subunit and an exocyclic double bond, has been investigated. The compound 7 was obtained, without the use of any protecting groups for the alcohol at C-12, via an asymmetric boron-mediated aldol addition as the key step to install the chiral centres of the rare succinimido methanol moiety. This was followed by a sequence of lactonisation, microwave-assisted amidation and imidation reactions.

Iron-catalysed sp 3 -sp 3 Kumada coupling with primary and secondary alkyl halides (RX) and alkyl Grignard reagents has been achieved in low to good yields depending on the nature of the R group.

Several derivatives of the natural scabrosin esters were synthesized in order to elucidate the structural features present, which are responsible for the biological activities. The studies demonstrate that full anti-proliferative activities of the scabrosin esters, both the carboskeleton core as well as the ability to form the dithiol and/or the disulfide linkage of the epidithiopiperazine-2,5-dione are required. The presence of the epoxide rings on the scabrosin esters do not contribute to the observed biological activities.

A series of simplified ring-opened resorcylic acid lactone (RAL) derivatives were conveniently synthesized to target FLT3 and its mutants either irreversibly or reversibly. Our design of covalent FLT3 inhibitors is based on cis-enone RALs (e.g., L-783,277) that have a β-resorcylic acid as the core structure. The designed compounds contain three types of Michael acceptors (acrylamide, vinylsulfonamide and maleimide) as potential covalent traps of a cysteine residue at the binding site of kinases. A variety of functional substitutions were also introduced to maximize the binding interactions. Biological evaluations revealed that compound 17, despite the presence of a highly reactive maleimide Michael acceptor, is a potent covalent FLT3 inhibitor which shows some specificity in cellular assays. On the other hand, compounds 2 and 6 containing acrylamide or vinylsulfonamide groups are reversible towards FLT3 binding, and are potent and selective inhibitors of mutant FLT3-ITD versus wt-FLT3. They also inhibit cell proliferation in FLT3-ITD expressing cell line MV-4-11 as compared to wt-FLT3 expressing cell line THP-1 and non-FLT3 cell lines (K562, HL60 and Hek-293T).

The biological activity of gliotoxin is dependent on the presence of a strained disulfide bond that can react with accessible cysteine residues on proteins. Rabbit muscle creatine kinase contains 4 cysteines per 42-kDa subunit and is active in solution as a dimer. Only Cys-282 has been identified as essential for activity. Modification of this residue results in loss of activity of the enzyme. Treatment of creatine kinase with gliotoxin resulted in a time-dependent loss of activity abrogated in the presence of reducing agents. Activity was restored when the inactivated enzyme was treated with reducing agents. Inactivation of creatine kinase by gliotoxin was accompanied by the formation of a 37-kDa form of the enzyme. This oxidized form of creatine kinase was rapidly reconverted to the 42-kDa species by the addition of reducing agents concomitant with restoration of activity. A 1:1 mixture of the oxidized and reduced monomer forms of creatine kinase as shown on polyacrylamide gel electrophoresis was equivalent to the activity of the fully reduced form of the enzyme consistent with only one reduced monomer of the dimer necessary for complete activity. Conversion of the second monomeric species of the dimer to the oxidized form by gliotoxin correlated with loss of activity. Our data are consistent with gliotoxin inducing the formation of an internal disulfide bond in creatine kinase by initially binding and possibly activating a cysteine residue on the protein, followed by reaction with a second neighboring thiol. The recently published crystal structure of creatine kinase suggests the disulfide is formed between Cys-282 and Cys-73.

The synthesis of polymer-supported N-Fmoc-dehydroalanine starting from S-protected cysteine via an oxidation/elimination strategy is described. Cycloaddition with a range of dienes afforded a range of conformationally constrained amino acids in moderate yields. The potential applications of this methodology to combinatorial libraries is discussed.

The versatile and efficient synthesis of a variety of spiroketal motifs via the double intramolecular hydroalkoxylation of aliphatic and aromatic alkyne diols was achieved using simple and readily accessible Ir(I) and Rh(I) cyclooctadiene complexes as catalysts.

The synthesis and Diels-Alder cycloadditions of a number of polymer bound dehydroalanine derivatives are described. The studies compare methodologies for accessing polymer bound dehydroalanines and establish the versatility and efficiency of solid phase Diels-Alder reactions in the synthesis of carbocyclic amino acids. These studies nicely complement the growing repertoire of methodologies for the functionalisation of amino acid derivatives.

The use of latent amino acid functionalities for the syntheses of methylidenepiperazine-2,5-diones is reported. These piperazinediones are potential chiral templates in the synthesis of functionalised piperazinediones and amino acids. Carbon–carbon bond formation utilising radical addition reactions between the methylidenepiperazinediones and a number of alkyl radicals resulted in good yields of the addition adduct. Moderate to high diastereoselectivities were observed and factors controlling the chiral induction are discussed here.

Methylene piperazine-2,5-diones 5a and 5b are important synthetic intermediates. The preparation as well as the use of these compounds in the synthesis of amino acid derivatives are described. Our studies demonstrate that excellent chiral induction in carbon-carbon bond forming reactions can be obtained with methylene piperazinedione 5b .

The natural product aigialomycin D (1) is a member of the resorcylic acid lactone (RAL) family possessing protein kinase inhibitory activities. This paper describes the synthesis of aigialomycin D and a series of its analogues and their activity for the inhibition of protein kinases related to cancer pathways. A preliminary study of these compounds in the inhibition of CDK2/cyclin A kinase has found that aigialomycin D and analogues 11 and 23 are moderate CDK2/cyclin A inhibitors with IC50 values of ca. 20 μM. Kinase profiling of aigialomycin D against a panel of kinases has led to the identification of MNK2 as a promising target (IC50 = 0.45 μM), and preliminary structure–activity relationship studies have been carried out to identify the essential functional groups for activity.

The radical 3, generated (i) from reactions of 5-substituted 2-tert-butyl-1,3-dioxolan-4-ones with N-bromosuccinimide, (ii) from related bromo compounds by reaction with tributylstannane or with allyltributyltin, and (iii) by radical addition to 5-methylene-1,3-dioxolan-4-one, undergoes carbon-bromine, carbon-hydrogen, and carbon-carbon bond formation trans to the tert-butyl group with moderate to high diastereoselectivity

The cyclic methylene compounds (1)–(3) undergo diastereoselective free radical addition when treated with alkylmercury hydride or alkyl iodide/tributylstannane to give products useful for the enantioselective synthesis of α-amino and α-hydroxy acids.

Methylene piperazine-2,5-diones 5a and 5b are important synthetic intermediates. The preparation as well as the use of these compounds in the synthesis of amino acid derivatives are described. Our studies demonstrate that excellent chiral induction in carbon-carbon bond forming reactions can be obtained with methylene piperazinedione 5b .

Author to whom correspondence should be addressed. The Diels-Alder reactions of some acyclic and cyclic dehydrodipeptides have been investigated. Our studies show that the reactivities of the dehydrodipeptides are sensitive to the environment of the double bond. In addition, theexo / endo selectivity of the cycloaddition is enhanced in the cyclic as compared to the acyclic systems.

The use of latent amino acid functionalities for the syntheses of methylidenepiperazine-2,5-diones is reported. These piperazinediones are potential chiral templates in the synthesis of functionalised piperazinediones and amino acids. Carbon–carbon bond formation utilising radical addition reactions between the methylidenepiperazinediones and a number of alkyl radicals resulted in good yields of the addition adduct. Moderate to high diastereoselectivities were observed and factors controlling the chiral induction are discussed here.

This paper introduces the use of a diallyl dicarboxylate compound, diallyl tartrate, as a monomer in the synthesis of a biodegradable polymer. Although the allyl functional group is generally known for not being able to polymerize to high conversions, it was found in this study that by using photoinitiation instead of thermal initiation, a highly cross-linked polymer could be obtained from the polymerization of diallyl tartrate in a relatively short time. The details of the polymerization reaction were investigated in detail using differential photocalorimetry (DPC). The final thermoset obtained was shown to be completely amorphous and rigid, with a glass transition temperature of approx. 90 degrees C and a storage modulus of approx. 1 GPa at room temperature, via thermal analysis. It was also found to biodegrade in vitro via hydrolysis of its ester groups at a moderate rate, taking nearly 12 weeks to lose 50% of its mass. Both the photo-polymerized material and its water-soluble degradation products were further shown to be non-cytotoxic to fibroblast cells over at least 24 h of exposure. These results aim to initiate the use of this class of monomers in the synthesis of new polymers with tailored properties for biomaterial applications.

Copper(I) or -(II) salts with weakly coordinating anions catalyze the diacetoxylation of olefins efficiently in the presence of PhI(OAc)(2) as the oxidant under mild conditions. The reaction is effective for aryl, aryl alkyl, as well as aliphatic terminal and internal olefins forming the corresponding vicinal diacetoxy compounds in 70-85% yields and dr (syn/anti) of up to 5.2. Under these conditions, homoallylic alcohols formed the corresponding tetrahydrofuran derivatives in high yields.

A novel supramolecular star polymer is reported, which can be prepared either from atom-transfer radical polymerization (ATRP) of a self-assembled initiator or from self-assembly of a guanosine-capped linear polymer.

The versatile and efficient synthesis of a variety of spiroketal motifs via the double intramolecular hydroalkoxylation of aliphatic and aromatic alkyne diols was achieved using simple and readily accessible Ir(I) and Rh(I) cyclooctadiene complexes as catalysts.

The bridged disulfide ring of the fungal metabolite gliotoxin presents both synthetic challenges and confers the molecule with a variety of interesting biological activities. This review summarises recent synthetic strategies used to insert the disulfide and polysulfide bridge across the diketopiperazine ring and briefly describes the limited structure–activity data available for this class of molecule which clearly shows the presence of the disulfide bridge dominates their biological activities. The review also covers possible cellular targets of these toxins, the possible role for the disulfide bridge in toxicity and cellular uptake mechanisms, and the nature of the cell death induced by the epipolythiopiperazinedione toxins. The potential role of this simple molecule as a diagnostic marker for invasive aspergillosis is also discussed.

The growth and proliferation of the human malaria parasite Plasmodium falciparum are dependent on the parasite's ability to obtain essential nutrients. One nutrient for which the parasite has an absolute requirement is the water-soluble vitamin pantothenic acid (vitamin B 5 ). In this study, a series of pantothenic acid analogs which retain the 2,4-dihydroxy-3,3-dimethylbutyramide core of pantothenic acid but deviate in structure from one another and from pantothenic acid in the nature of the substituent attached to the amide nitrogen were synthesized using an efficient single-step synthetic route. Eight of 10 analogs tested inhibited the proliferation of intraerythrocytic P. falciparum parasites in vitro, doing so with 50% inhibitory concentrations between 15 and 200 μM. The compounds were generally selective, inhibiting the proliferation of a human cell line (the Jurkat cell line) only at concentrations severalfold higher than those required for inhibition of parasite growth. It was demonstrated that compounds in this series inhibited the phosphorylation of pantothenic acid by pantothenate kinase, the first step in the parasite's biosynthesis of the essential enzyme cofactor coenzyme A, doing so competitively, with K i values in the nanomolar range.

Inhibitors of proteolytic enzymes (proteases) are emerging as prospective treatments for diseases such as AIDS and viral infections, cancers, inflammatory disorders, and Alzheimer's disease. Generic approaches to the design of protease inhibitors are limited by the unpredictability of interactions between, and structural changes to, inhibitor and protease during binding. A computer analysis of superimposed crystal structures for 266 small molecule inhibitors bound to 48 proteases (16 aspartic, 17 serine, 8 cysteine, and 7 metallo) provides the first conclusive proof that inhibitors, including substrate analogues, commonly bind in an extended beta-strand conformation at the active sites of all these proteases. Representative superimposed structures are shown for (a) multiple inhibitors bound to a protease of each class, (b) single inhibitors each bound to multiple proteases, and (c) conformationally constrained inhibitors bound to proteases. Thus inhibitor/substrate conformation, rather than sequence/composition alone, influences protease recognition, and this has profound implications for inhibitor design. This conclusion is supported by NMR, CD, and binding studies for HIV-1 protease inhibitors/ substrates which, when preorganized in an extended conformation, have significantly higher protease affinity. Recognition is dependent upon conformational equilibria since helical and turn peptide conformations are not processed by proteases. Conformational selection explains the resistance of folded/structured regions of proteins to proteolytic degradation, the susceptibility of denatured proteins to processing, and the higher affinity of conformationally constrained 'extended' inhibitors/substrates for proteases. Other approaches to extended inhibitor conformations should similarly lead to high-affinity binding to a protease.

C 14 H 17 ClO 3 S cristallise dans C2/c avec a = 28,795, b = 8,887 et c = 12,139 A, β = 103,17 °, Z = 8; affinement jusqu'a R = 0,031. Le cycle a 5 membres a une conformation intermediaire entre une forme tordue et une enveloppe avec O1 deviant du plan des quatre autres atomes. Les groupes t-butyl et chlorophenylthio sont du meme cote du cycle.

Well-defined pH-responsive polymer nanoparticles were prepared in water directly after a simple dialysis procedure without the process of self-assembly from branched copolymers. The branched AB diblock copolymers of poly(ethyleneglycol methacrylate/dimethylamino ethyl methacrylate) (P(PEGMA/DMA)) and poly(ethyleneglycol methacrylate)/diethylamino ethyl methacrylate) (P(PEGMA/DEA)) have been synthesized using a one-pot atom-transfer radical polymerization (ATRP) approach in presence of a bifunctional monomer-ethyleneglycol dimethacrylate (EGDMA). Clear polymer nanoparticle (170 nm–244 nm) suspensions were obtained after a dialysis process. The aqueous solution behavior of the branched and linear copolymers at different pH (pH 3.7–12) was investigated using dynamic light scattering (DLS). pH-responsiveness was observed for both branched copolymer systems. As a comparison, branched copolymers of P(PEGMA/DMA) were also synthesized via traditional radical polymerization (TRP) in the presence of EGDMA, followed by similar dialysis. Most TRP branched copolymers could not afford neat particles and polymers precipitated on increasing the pH above 7.5. The controlled branching structure is suggested as the key point for the direct synthesis of pH-responsive branched copolymer nanoparticles.

The preparation of acrylic polymers with predetermined molecular weights using metalloenzymes as catalysts, ascorbic acid as reducing agent and alkyl halides as initiators is reported. The mechanism of polymerization resembles an ARGET ATRP process.

Transparent, flexible, self-standing and highly ion conductive ion gels have been synthesised from novel ionic liquid compatible cyclic carbonate (CC) network polymer. The use of dual functional cyclic carbonate methacrylate (CCMA) monomer for the synthesis has enabled versatile and operationally simple routes to such type of ion gels.

C 21 H 22 ClNO 3 S cristallise dans P2 1 /c avec a=11.419, b=20.749, c=8.946A, β=101.85°, Z=4; affinement jusqu'a R=0.044. Les groupements t-butyl et p-chlorophenylthio occupent des positions cis par rapport a l'heterocycle. Le degre de pyramidalisation de N est faible

The scabrosin esters (1){(4), isolated from the lichen Xanthoparmelia scabrosa, were reanalysed by modern one- and two-dimensional n.m.r. spectroscopic methods, including 15N n.m.r. spectroscopy, and single-crystal X-ray structural analysis. This reinvestigation has resulted in the unambiguous structure elucidation and complete spectral assignment of these metabolites and established them to be a family of epidithiopiperazinedione derivatives. A new scabrosin ester, scabrosin butyrate hexanoate (5), has also been isolated and its structure determined, including assignment of absolute configuration. Several scabrosins were found to exhibit potent cytotoxic activity against the murine P815 mastocytomia cell line (IC50 c. 0·5 µM) and the human breast MCF7 carcinoma cell line (IC50 c. nM). Compounds which contain a dithiopiperazinedione moiety have not previously been identified in lichenized fungi.

Author to whom correspondence should be addressed. The Diels-Alder reactions of some acyclic and cyclic dehydrodipeptides have been investigated. Our studies show that the reactivities of the dehydrodipeptides are sensitive to the environment of the double bond. In addition, theexo / endo selectivity of the cycloaddition is enhanced in the cyclic as compared to the acyclic systems.

A single diastereoisomer of phenyl epiandrosterone sulphite and the single diastereoisomer of benzyl epiandrosterone sulphite derived from it by nucleophilic substitution with benzyl alcohol have both been shown by X-ray crystallographic analysis to have the Rs configuration and hence the reaction proceeds with inversion at sulphur.

The cyclic methylene compounds (1)–(3) undergo diastereoselective free radical addition when treated with alkylmercury hydride or alkyl iodide/tributylstannane to give products useful for the enantioselective synthesis of α-amino and α-hydroxy acids.