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Wireless sensor networks (WSN) are increasingly requiring directional antennas that not only provide higher capacity, security, transmission range or robustness against interference, but also contribute with smart antenna capabilities such as adaptive beamforming or multi beam radiation patterns. Standard phased arrays provide these features, but employing feeding networks based on digitally controlled variable phase shifters (VPSs) which have the disadvantage of high cost and limited angular resolution. Instead, time-modulated arrays (TMAs) use switched feeding networks governed by digital periodic sequences which allow harmonic patterns to be radiated and endows (TMAs) with attractive multifunctional capabilities. In this paper, we analyze and properly combine (TMA) switched feeding networks capable of time-modulating an antenna array with discretized amplitude modulation (AM) and phase modulation (PM) waveforms. The advantages of the proposed innovative dual-beam (TMA) with respect to the competing architectures are, on the one hand, its power efficiency and beamsteering (BS) phase sensitivity and, on the other, its hardware simplicity, which allows for an excellent relative cost advantage.

In this work, we study and analyze the reconstruction of hyperspectral images that are sampled with a CASSI device. The sensing procedure was modeled with the help of the CS theory, which enabled efficient mechanisms for the reconstruction of the hyperspectral images from their compressive measurements. In particular, we considered and compared four different type of estimation algorithms: OMP, GPSR, LASSO, and IST. Furthermore, the large dimensions of hyperspectral images required the implementation of a practical block CASSI model to reconstruct the images with an acceptable delay and affordable computational cost. In order to consider the particularities of the block model and the dispersive effects in the CASSI-like sensing procedure, the problem was reformulated, as well as the construction of the variables involved. For this practical CASSI setup, we evaluated the performance of the overall system by considering the aforementioned algorithms and the different factors that impacted the reconstruction procedure. Finally, the obtained results were analyzed and discussed from a practical perspective.

This work considers the design and practical implementation of JSCC-Cast, a comprehensive analog video encoding and transmission system requiring a reduced amount of digital metadata. Suitable applications for JSCC-Cast are multicast transmissions over time-varying channels and Internet of Things wireless connectivity of end devices having severe constraints on their computational capabilities. The proposed system exhibits a similar image quality compared to existing analog and hybrid encoding alternatives such as Softcast. Its design is based on the use of linear transforms that exploit the spatial and temporal redundancy and the analog encoding of the transformed coefficients with different protection levels depending on their relevance. JSCC-Cast is compared to Softcast, which is considered the benchmark for analog and hybrid video coding, and with an all-digital H.265-based encoder. The results show that, depending on the scenario and considering image quality metrics such as the structural similarity index measure, the peak signal-to-noise ratio, and the perceived quality of the video, JSCC-Cast exhibits a performance close to that of Softcast but with less metadata and not requiring a feedback channel in order to track channel variations. Moreover, in some circumstances, the JSCC-Cast obtains a perceived quality for the frames comparable to those displayed by the digital one.

Objective: This study was designed to search for ancient parasites in abdominal content and coprolites from Bolivian mummies., Materials: Twelve mummified individuals from the Andean highlands, housed at the National Museum of Archaeology (MUNARQ) in La Paz, Bolivia., Methods: Microscopic analysis of rehydrated samples (coprolites and abdominal content), following Lutz's spontaneous sedimentation technique., Results: Eggs of Enterobius vermicularis were identified in coprolites from one mummy, and capillariid eggs in the organic abdominal content from another individual., Conclusions: This is the first evidence of ancient intestinal parasites in Bolivian mummies., Significance: This pioneering study focused on the search of ancient intestinal parasites in human remains of the Bolivian Andes and contributes to greater knowledge of paleoparasitology in South America., Limitations: All mummies in the MUNARQ belonged to the Andean Bolivian highlands (post-Tiwanaku era or Late Intermediate Period), although the exact provenance of the material and the associated contexts are not well recorded., Suggestions for Further Research: Considering the great number of well-known archaeological sites and other unexplored sites in Bolivia, in addition to large collections in museums, further paleopathological and paleoparasitological molecular studies in mummies and skeletons are called for., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A method for channel estimation in wideband massive MIMO systems using hybrid digital analog architectures is developed. The proposed method is useful for FDD at either sub-6 GHz or mmWave frequency bands and takes into account the beam squint effect caused by the large bandwidth of the signals. To circumvent the estimation of large channel vectors, the posed algorithm relies on the slow time variation of the channel spatial covariance matrix, thus allowing for the utilization of very short training sequences. This is possibledue to the exploitation of the channel structure. After identifying the channel covariance matrix, the channel is estimated on the basis of the recovered information. To that end, we propose a novel method that relies on estimating the tap delays and the gains as sociated with each path. As a consequence, the proposed channel estimator achieves low computational complexity and significantly reduces the training overhead. Moreover, our numerical simulations show better performance results compared to the minimum mean-squared error solution.

A smart campus is an intelligent infrastructure where smart sensors and actuators collaborate to collect information and interact with the machines, tools, and users of a university campus. As in a smart city, a smart campus represents a challenging scenario for Internet of Things (IoT) networks, especially in terms of cost, coverage, availability, latency, power consumption, and scalability. The technologies employed so far to cope with such a scenario are not yet able to manage simultaneously all the previously mentioned demanding requirements. Nevertheless, recent paradigms such as fog computing, which extends cloud computing to the edge of a network, make possible low-latency and location-aware IoT applications. Moreover, technologies such as Low-Power Wide-Area Networks (LPWANs) have emerged as a promising solution to provide low-cost and low-power consumption connectivity to nodes spread throughout a wide area. Specifically, the Long-Range Wide-Area Network (LoRaWAN) standard is one of the most recent developments, receiving attention both from industry and academia. In this article, the use of a LoRaWAN fog computing-based architecture is proposed for providing connectivity to IoT nodes deployed in a campus of the University of A Coruña (UDC), Spain. To validate the proposed system, the smart campus has been recreated realistically through an in-house developed 3D Ray-Launching radio-planning simulator that is able to take into consideration even small details, such as traffic lights, vehicles, people, buildings, urban furniture, or vegetation. The developed tool can provide accurate radio propagation estimations within the smart campus scenario in terms of coverage, capacity, and energy efficiency of the network. The results obtained with the planning simulator can then be compared with empirical measurements to assess the operating conditions and the system accuracy. Specifically, this article presents experiments that show the accurate results obtained by the planning simulator in the largest scenario ever built for it (a campus that covers an area of 26,000 m 2 ), which are corroborated with empirical measurements. Then, how the tool can be used to design the deployment of LoRaWAN infrastructure for three smart campus outdoor applications is explained: a mobility pattern detection system, a smart irrigation solution, and a smart traffic-monitoring deployment. Consequently, the presented results provide guidelines to smart campus designers and developers, and for easing LoRaWAN network deployment and research in other smart campuses and large environments such as smart cities.

An analog joint source-channel coding (JSCC) system designed for the transmission of still images is proposed and its performance is compared to that of two digital alternatives which differ in the source encoding operation: Joint Photographic Experts Group (JPEG) and JPEG without entropy coding (JPEGw/oEC), respectively, both relying on an optimized channel encoder-modulator tandem. Apart from a visual comparison, the figures of merit considered in the assessment are the structural similarity (SSIM) index and the time required to transmit an image through additive white Gaussian noise (AWGN) and Rayleigh channels. This work shows that the proposed analog system exhibits a performance similar to that of the digital scheme based on JPEG compression with a noticeable better visual degradation to the human eye, a lower computational complexity, and a negligible delay. These results confirm the suitability of analog JSCC for the transmission of still images in scenarios with severe constraints on power consumption, computational capabilities, and for real-time applications. For these reasons the proposed system is a good candidate for surveillance systems, low-constrained devices, Internet of things (IoT) applications, etc.

Modern Internet of Things (IoT) systems have to be able to provide high-security levels, but it is difficult to accommodate computationally-intensive cryptographic algorithms on the resource-constrained hardware used to deploy IoT end nodes. Although this scenario brings the opportunity for using advanced security mechanisms such as Transport Layer Security (TLS), several configuration factors impact both the performance and the energy consumption of IoT systems. In this study, two of the most used TLS authentication algorithms (ECDSA and RSA) were compared when executed on a resource-constrained IoT node based on the ESP32 System-on-Chip (SoC), which was tested at different clock frequencies (80, 160 and 240 MHz) when providing different security levels (from 80 to 192 bits). With every tested configuration, energy consumption and average time per transaction were measured. The results show that ECDSA outperforms RSA in all performed tests and that certain software implementations may lead to scenarios where higher security-level alternatives outperform cryptosystems that are theoretically simpler and lighter in terms of energy consumption and data throughput. Moreover, the performed experiments allow for concluding that higher clock frequencies provide better performance in terms of throughput and, in contrast to what may be expected, less energy consumption.

In recent years, the improvement of wireless protocols, the development of cloud services and the lower cost of hardware have started a new era for smart homes. One such enabling technologies is fog computing, which extends cloud computing to the edge of a network allowing for developing novel Internet of Things (IoT) applications and services. Under the IoT fog computing paradigm, IoT gateways are usually utilized to exchange messages with IoT nodes and a cloud. WiFi and ZigBee stand out as preferred communication technologies for smart homes. WiFi has become very popular, but it has a limited application due to its high energy consumption and the lack of standard mesh networking capabilities for low-power devices. For such reasons, ZigBee was selected by many manufacturers for developing wireless home automation devices. As a consequence, these technologies may coexist in the 2.4 GHz band, which leads to collisions, lower speed rates and increased communications latencies. This article presents ZiWi, a distributed fog computing Home Automation System (HAS) that allows for carrying out seamless communications among ZigBee and WiFi devices. This approach diverges from traditional home automation systems, which often rely on expensive central controllers. In addition, to ease the platform's building process, whenever possible, the system makes use of open-source software (all the code of the nodes is available on GitHub) and Commercial Off-The-Shelf (COTS) hardware. The initial results, which were obtained in a number of representative home scenarios, show that the developed fog services respond several times faster than the evaluated cloud services, and that cross-interference has to be taken seriously to prevent collisions. In addition, the current consumption of ZiWi's nodes was measured, showing the impact of encryption mechanisms.

Radon is a noble gas originating from the radioactive decay chain of uranium or thorium. Most radon emanates naturally from the soil and from some building materials, so it can be found in many places around the world, in particular in regions with soils containing granite or slate. It is almost impossible for a person to detect radon gas without proper tools, since it is invisible, odorless, tasteless and colorless. The problem is that a correlation has been established between the presence of high radon gas concentrations and the incidence of lung cancer. In fact, the World Health Organization (WHO) has stated that the exposure to radon is the second most common cause of lung cancer after smoking, and it is the primary cause of lung cancer among people who have never smoked. Although there are commercial radon detectors, most of them are either expensive or provide very limited monitoring capabilities. To tackle such an issue, this article presents a cost-effective IoT radon gas remote monitoring system able to obtain accurate concentration measurements. It can also trigger events to prevent dangerous situations and to warn users about them. Moreover, the proposed solution can activate mitigation devices (e.g., forced ventilation) to decrease radon gas concentration. In order to show its performance, the system was evaluated in three different scenarios corresponding to representative buildings in Galicia (Spain), a region where high radon gas concentrations are common due to the composition of the soil. In addition, the influence of using external hardware (i.e., WiFi transceivers and an embedded System-on-Chip (SoC)) next to the radon gas sensor is studied, concluding that, in the tested scenarios, they do not interfere with the measurements., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; nor in the decision to publish the results.

Fog computing extends cloud computing to the edge of a network enabling new Internet of Things (IoT) applications and services, which may involve critical data that require privacy and security. In an IoT fog computing system, three elements can be distinguished: IoT nodes that collect data, the cloud, and interconnected IoT gateways that exchange messages with the IoT nodes and with the cloud. This article focuses on securing IoT gateways, which are assumed to be constrained in terms of computational resources, but that are able to offload some processing from the cloud and to reduce the latency in the responses to the IoT nodes. However, it is usually taken for granted that IoT gateways have direct access to the electrical grid, which is not always the case: in mission-critical applications like natural disaster relief or environmental monitoring, it is common to deploy IoT nodes and gateways in large areas where electricity comes from solar or wind energy that charge the batteries that power every device. In this article, how to secure IoT gateway communications while minimizing power consumption is analyzed. The throughput and power consumption of Rivest-Shamir-Adleman (RSA) and Elliptic Curve Cryptography (ECC) are considered, since they are really popular, but have not been thoroughly analyzed when applied to IoT scenarios. Moreover, the most widespread Transport Layer Security (TLS) cipher suites use RSA as the main public key-exchange algorithm, but the key sizes needed are not practical for most IoT devices and cannot be scaled to high security levels. In contrast, ECC represents a much lighter and scalable alternative. Thus, RSA and ECC are compared for equivalent security levels, and power consumption and data throughput are measured using a testbed of IoT gateways. The measurements obtained indicate that, in the specific fog computing scenario proposed, ECC is clearly a much better alternative than RSA, obtaining energy consumption reductions of up to 50% and a data throughput that doubles RSA in most scenarios. These conclusions are then corroborated by a frame temporal analysis of Ethernet packets. In addition, current data compression algorithms are evaluated, concluding that, when dealing with the small payloads related to IoT applications, they do not pay off in terms of real data throughput and power consumption., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Nowadays, the railway industry is in a position where it is able to exploit the opportunities created by the IIoT (Industrial Internet of Things) and enabling communication technologies under the paradigm of Internet of Trains. This review details the evolution of communication technologies since the deployment of GSM-R, describing the main alternatives and how railway requirements, specifications and recommendations have evolved over time. The advantages of the latest generation of broadband communication systems (e.g., LTE, 5G, IEEE 802.11ad) and the emergence of Wireless Sensor Networks (WSNs) for the railway environment are also explained together with the strategic roadmap to ensure a smooth migration from GSM-R. Furthermore, this survey focuses on providing a holistic approach, identifying scenarios and architectures where railways could leverage better commercial IIoT capabilities. After reviewing the main industrial developments, short and medium-term IIoT-enabled services for smart railways are evaluated. Then, it is analyzed the latest research on predictive maintenance, smart infrastructure, advanced monitoring of assets, video surveillance systems, railway operations, Passenger and Freight Information Systems (PIS/FIS), train control systems, safety assurance, signaling systems, cyber security and energy efficiency. Overall, it can be stated that the aim of this article is to provide a detailed examination of the state-of-the-art of different technologies and services that will revolutionize the railway industry and will allow for confronting today challenges., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

The Internet of Energy (IoE) represents a novel paradigm where electrical power systems work cooperatively with smart devices to increase the visibility of energy consumption and create safer, cleaner and sustainable energy systems. The implementation of IoE services involves the use of multiple components, like embedded systems, power electronics or sensors, which are an essential part of the infrastructure dedicated to the generation and distribution energy and the one required by the final consumer. This article focuses on the latter and presents a smart socket system that collects the information about energy price and makes use of sensors and actuators to optimize home energy consumption according to the user preferences. Specifically, this article provides three main novel contributions. First, what to our knowledge is the first hardware prototype that manages in a practical real-world scenario the price values obtained from a public electricity operator is presented. The second contribution is related to the definition of a novel wireless sensor network communications protocol based on Wi-Fi that allows for creating an easy-to-deploy smart plug system that self-organizes and auto-configures to collect the sensed data, minimizing user intervention. Third, it is provided a thorough description of the design of one of the few open-source smart plug systems, including its communications architecture, the protocols implemented, the main sensing and actuation components and the most relevant pieces of the software. Moreover, with the aim of illustrating the capabilities of the smart plug system, the results of different experiments performed are shown. Such experiments evaluate in real-world scenarios the system's ease of use, its communications range and its performance when using HTTPS. Finally, the economic savings are estimated for different appliances, concluding that, in the practical situation proposed, the smart plug system allows certain energy-demanding appliances to save almost €70 per year.

Time-modulated arrays (TMAs) are electromagnetic systems whose radiated power pattern is controlled by the application of variable-width periodical pulses to the individual elements. The nonlinear nature of the array operation causes the appearance of radiation patterns at the harmonic frequencies of such periodic pulses. The technique can be used for improving the side-lobe level (SLL) topology of the radiation pattern at the central frequency and/or to profitably exploit the harmonic patterns in order to supply smart antenna capabilities. Among the latter features, the TMA harmonic beamforming takes on special importance due to its attractive trade-off performance-hardware complexity. From this perspective, TMAs are sensors capable of transforming the spatial diversity of a communication channel into frequency diversity, thus improving the performance of a wireless communication. In addition to a walk through the origins of the concept, and a brief analysis of the mathematical fundamentals, this paper organizes the prolific state of the art of TMAs in two major thematic blocks: (1) TMA design from an antenna perspective; and (2) TMA design from a signal processing perspective.

This article presents VineSens, a hardware and software platform for supporting the decision-making of the vine grower. VineSens is based on a wireless sensor network system composed by autonomous and self-powered nodes that are deployed throughout a vineyard. Such nodes include sensors that allow us to obtain detailed knowledge on different viticulture processes. Thanks to the use of epidemiological models, VineSens is able to propose a custom control plan to prevent diseases like one of the most feared by vine growers: downy mildew. VineSens generates alerts that warn farmers about the measures that have to be taken and stores the historical weather data collected from different spots of the vineyard. Such data can then be accessed through a user-friendly web-based interface that can be accessed through the Internet by using desktop or mobile devices. VineSens was deployed at the beginning in 2016 in a vineyard in the Ribeira Sacra area (Galicia, Spain) and, since then, its hardware and software have been tested to prevent the development of downy mildew, showing during its first season that the system can led to substantial savings, to decrease the amount of phytosanitary products applied, and, as a consequence, to obtain a more ecologically sustainable and healthy wine.

The Internet of Things (IoT) is a distributed system of physical objects that requires the seamless integration of hardware (e.g., sensors, actuators, electronics) and network communications in order to collect and exchange data. IoT smart objects need to be somehow identified to determine the origin of the data and to automatically detect the elements around us. One of the best positioned technologies to perform identification is RFID (Radio Frequency Identification), which in the last years has gained a lot of popularity in applications like access control, payment cards or logistics. Despite its popularity, RFID security has not been properly handled in numerous applications. To foster security in such applications, this article includes three main contributions. First, in order to establish the basics, a detailed review of the most common flaws found in RFID-based IoT systems is provided, including the latest attacks described in the literature. Second, a novel methodology that eases the detection and mitigation of such flaws is presented. Third, the latest RFID security tools are analyzed and the methodology proposed is applied through one of them (Proxmark 3) to validate it. Thus, the methodology is tested in different scenarios where tags are commonly used for identification. In such systems it was possible to clone transponders, extract information, and even emulate both tags and readers. Therefore, it is shown that the methodology proposed is useful for auditing security and reverse engineering RFID communications in IoT applications. It must be noted that, although this paper is aimed at fostering RFID communications security in IoT applications, the methodology can be applied to any RFID communications protocol., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

The Internet of Things (IoT) is undeniably transforming the way that organizations communicate and organize everyday businesses and industrial procedures. Its adoption has proven well suited for sectors that manage a large number of assets and coordinate complex and distributed processes. This survey analyzes the great potential for applying IoT technologies (i.e., data-driven applications or embedded automation and intelligent adaptive systems) to revolutionize modern warfare and provide benefits similar to those in industry. It identifies scenarios where Defense and Public Safety (PS) could leverage better commercial IoT capabilities to deliver greater survivability to the warfighter or first responders, while reducing costs and increasing operation efficiency and effectiveness. This article reviews the main tactical requirements and the architecture, examining gaps and shortcomings in existing IoT systems across the military field and mission-critical scenarios. The review characterizes the open challenges for a broad deployment and presents a research roadmap for enabling an affordable IoT for defense and PS., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

A Rh-catalyzed intramolecular [3+2+2] cycloaddition is reported. The cycloaddition affords synthetically relevant 5,7,5-fused tricyclic systems of type 2 from readily available dienyne precursors. The transformation takes place with moderate or good yields, high diastereoselectivity, and total chemoselectivity., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Metal-directed supramolecular construction represents one of the most powerful tools to prepare a large variety of structures and functions. The ability of metals to organize different numbers and types of ligands with a variety of geometries (linear, trigonal, octahedral, etc.) expands the supramolecular synthetic architecture. We describe here the precise construction of homo- and heterodimeric cyclic peptide entities through coordination of a metal (Pd, Au) and to β-sheet-type hydrogen-bonding interactions. The selective coordination properties of the appropriate metal allow control over the cross-strand interaction between the two-peptide strands., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this study, a novel dimer-forming cyclic peptide composed exclusively by cyclic γ-amino acids with a saccharide-like outer surface is described. The antiparallel β-sheet type hydrogen bonding interactions responsible for the large association constant in non-polar solvents constitute a suitable model for a novel class of self-assembling peptide nanotubes.

Several 3-alkylaryl mimics of the enol intermediate in the reaction catalyzed by type II dehydroquinase were synthesized to investigate the effect on the inhibition potency of replacing the oxygen atom in the side chain by a carbon atom. The length and the rigidity of the spacer was also studied. The inhibitory properties of the reported compounds against type II dehydroquinase from Mycobacterium tuberculosis and Helicobacter pylori are also reported. The binding modes of these analogs in the active site of both enzymes were studied by molecular docking using GOLD 5.0 and dynamic simulations studies.

The synthesis of high-affinity reversible competitive inhibitors of Mycobacterium tuberculosis type II dehydroquinase, an essential enzyme in Mycobacterium tuberculosis bacteria, is reported. The inhibitors reported here are mimics of the enol intermediate and the effect of substitution on C2 was studied. The crystal structures of Mycobacterium tuberculosis type II dehydroquinase in complex with three of the reported inhibitors are also described. The results show that an aromatic substituent on C2 prevents the closure of the active site by impeding the hydrogen-bonding interaction of Arg108 with the essential Tyr24 of the flexible loop, the residue that initiates catalysis. Chemical modifications of the reported acids were also carried out to improve internalization into Mycobacterium tuberculosis through an ester prodrug approach. Propyl esters proved to be the most efficient in achieving optimal in vitro activities.

A dimer-forming self-assembling cyclic hexapeptide with a control register and a large association constant in water is described. The self-assembly process is followed by pyrene-excimer emission and the main diastereomeric dimer present in solution is switched by controlled addition of divalent cations (e.g., Ca, Mg) or oxalic acid.

The design and synthesis of two α,γ-cyclic octapeptides decorated with one and two Zn-porphyrin units in their periphery is described. In nonpolar organic solvents the α,γ-cyclic octapeptides quantitatively self-assemble into Zn-bis- or -tetraporphyrin architectures that could act as molecular tweezers. The self-assembly process, however, is not regioselective and affords a mixture of different regioisomers that are involved in chemical exchange processes. The regioisomers with the Zn-porphyrin units positioned in register with respect to each other are proposed to be the less abundant species in the solution mixture. It has been demonstrated that the coordination of 1,4-diazabicyclo[2.2.2]octane (DABCO) to the supramolecular bis- or tetraporphyrin tweezers is an effective way to achieve regioisomeric control of the self-assembled mixture of dimers. Thus, DABCO functions as an external molecular trigger and, when used under strict stoichiometric control with respect to the Zn-porphyrin units, provokes the exclusive formation of self-assembled dimers with a cofacial arrangement of Zn-porphyrin units through the formation of sandwich-type complexes. The use of excess DABCO fragments the sandwich complexes and affords open dimers of high stoichiometry with DABCO molecules axially monocoordinated to the Zn-porphyrin units, probably as a regioisomeric mixture. In the case of Zn-tetraporphyrin tweezers, the ditopic coordination of DABCO at the two binding sites shows a moderate positive cooperativity factor, αP=5. These assemblies have potential applications as light-induced energy and electron-transfer switches regulated by DABCO coordination; such applications would require the introduction of additional chromophores in the cyclic peptide scaffold., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cyclic octapeptides composed of α-amino acids alternated with cis-3-aminocycloalkanecarboxylic acids, self-assemble as drumlike dimers through β-sheet-like, backbone-to-backbone hydrogen bonding. Heterodimerization appears to be significantly more favored than homodimerization, and this represents a novel approach for the design and fabrication of highly stable heterodimeric assemblies. A multicomponent equilibrium network based on fluorescently derivatized self-assembling α,γ-cyclic octapeptides has been successfully used to form light-harvesting/light-converting ensembles with a distinctive organization of donor and acceptor units able to act as efficient artificial photosystems.

We have developed a useful modification of the classical preparation of phenanthrenes by UV irradiation of stilbenes in the presence of an oxidant. This modification involves the irradiation, in the presence of base, of stilbenes possessing a sulfonyl group linked to the central double bond. We have proved that this protocol can be successfully applied for the synthesis of diverse phenanthrenes and phenanthrenoids.

The binding mode of several substrate analogues, (2R)-2-benzyl-3-dehydroquinic acids 4, which are potent reversible competitive inhibitors of type II dehydroquinase (DHQ2), the third enzyme of the shikimic acid pathway, has been investigated by structural and computational studies. The crystal structures of Mycobacterium tuberculosis and Helicobacter pylori DHQ2 in complex with one of the most potent inhibitor, p-methoxybenzyl derivative 4 a, have been solved at 2.40 Å and 2.75 Å, respectively. This has allowed the resolution of the M. tuberculosis DHQ2 loop containing residues 20-25 for the first time. These structures show the key interactions of the aromatic ring in the active site of both enzymes and additionally reveal an important change in the conformation and flexibility of the loop that closes over substrate binding. The loop conformation and the binding mode of compounds 4 b-d has been also studied by molecular dynamics simulations, which suggest that the benzyl group of inhibitors 4 prevent appropriate orientation of the catalytic tyrosine of the loop for proton abstraction and disrupts its basicity.

The building blocks of a promising class of peptide nanotubes composed of alternating D-alpha-amino acids and (1R,3S)-3-aminocyclohexane (or cyclopentane) carboxylic acid (D-gamma-Ach or D-gamma-Acp) were explored by computational methods. Specifically, density functional theory (DFT) calculations on monomers and dimers of gamma-Ach-based and gamma-Acp-based alpha,gamma-cyclo-hexapeptides and cyclo-octapeptides were carried out to investigate the experimentally observed preference for alpha-alpha over gamma-gamma dimerization, associated with the two types of stacking patterns present in these peptide nanotubes, as well as the preference for heterodimerization versus homodimerization. Full geometry optimizations were performed at the B3LYP/6-31G(d) level, and single point calculations were subsequently carried out with the B3LYP and M05-2X functionals and the 6-31+G(d,p) basis set. The calculations predict that the interaction energies in the alpha-alpha species are quite similar to those in the gamma-gamma dimers. However, a comparison of dimerization energies (i.e., interaction energies plus deformation energies of monomers) shows that alpha-alpha dimerization is energetically favored over gamma-gamma dimerization. The calculations strongly suggest that the preference for alpha-alpha binding is governed by differences between the deformation energies in the alpha and gamma monomers, rather than by differences between the relative strengths of the alpha-alpha and gamma-gamma hydrogen-bonding patterns. Calculations based on local properties of the electron density support the previous suggestion that the H-N bonds of the alpha-amino acids are more polarized than those of the gamma-amino acids.

The shikimic acid pathway is essential to many pathogens but absent in mammals. Enzymes in its pathway are therefore appropriate targets for the development of novel antibiotics. Dehydroquinase is the third enzyme of the pathway, catalyzing the reversible dehydratation of 3-dehydroquinic acid to form 3-dehydroshikimic acid. Here we present the synthesis of novel inhibitors with high affinity for Helicobacter pylori type II dehydroquinase and efficient inhibition characteristics. The structure of Helicobacter pylori type II dehydroquinase in complex with the most potent inhibitor shows that the aromatic functional group interacts with the catalytic Tyr22 by pi-stacking, expelling the Arg17 side chain, which is essential for catalysis, from the active site. The structure therefore explains the favorable properties of the inhibitor and will aid in design of improved antibiotics.

We report a Pd-catalyzed intramolecular [3C + 2C + 2C] cycloaddition between alkylidenecyclopropanes, alkynes and alkenes. The method provides synthetically relevant 5-7-5 tricyclic structures, with good chemoselectivity and complete diastereoselectivity.

Ru-catalyzed cycloisomerizations of aromatic homo- and bis-homopropargylic alcohols effectively afford benzofurans and isochromenes. These processes proved to be chemo- and regioselective (5-, and 6-endo cyclizations) derived from key Ru vinylidene intermediates. The presence of an amine/ammonium base-acid pair is crucial for the catalytic cycle.

Here we describe a self-assembling alpha,gamma-cyclic tetrapeptide that contains the 4-amino-3-hydroxytetrahydrofuran-2-carboxylic acid, in which the hydroxy group is pointing towards the inner cavity of the resulting dimers.

Gold(I) complexes featuring electron acceptor ligands such as phosphites and phosphoramidites catalyze the [4C+2C] intramolecular cycloaddition of allenedienes. The reaction is chemo- and stereoselective, and provides trans-fused bicyclic cycloadducts in good yields. Moreover, using novel chiral phosphoramidite-based gold catalysts it is possible to perform the reaction with excellent enantioselectivity. Experimental and theoretical data dismiss a cationic mechanism involving intermediate II and suggest that the formation of the [4C+2C] cycloadducts might arise from a 1,2-alkyl migration (ring contraction) in a cycloheptenyl Au-carbene intermediate (IV), itself arising from a [4C+3C] concerted cycloaddition of the allenediene. Therefore, these [4C+2C] allenediene cycloadditions and the previously reported [4C+3C] counterparts most likely share such cycloaddition step, differing in the final 1,2-migration step.

The formation and full characterization of single self-assembling alpha,gamma-peptide nanotubes (alpha,gamma-SPNs) is described. The introduction of C(60) into cyclic peptides allows the preparation of supramolecular 1D fullerene arrangements induced by peptide nanotube formation under appropriate conditions.

A photocyclization of tosylstilbenes in the presence of base is used as a key reaction in the synthesis of the CC-1065 analogue 5.

TFA-promoted exo carbocyclizations of nonterminal 7-alkynals gave good to excellent yields of seven-membered cycloalkenones, a medium-sized functionalized ring present in natural products with relevant pharmacological properties. Nonterminal 5- and 6-alkynals also gave very good yields of the corresponding exo cyclopentenones and cyclohexenones. On the other hand, terminal 5-alkynals gave endo carbocyclizations to cyclohexenones. These carbocyclizations can be considered as tandem alkyne hydration/aldol condensation processes.

Peri selectivity of the electrocyclization of 1-aryl- and heteroaryl-substituted (1Z,3Z)-1,3,5-hexatrienes, obtained by Ru-catalyzed linear coupling of 1,6-diynes to Z-propenyl(hetero)arenes, can be efficiently modulated depending on the aromaticity of the (hetero)arene: 1,3,5-hexatrienyl(hetero)arenes give 8pi e- electrocyclization with the exception of 1,3,5-hexatrienylbenzenes, which give 6pi e- electrocyclization.

Taxing taxanes: A new method for the preparation of alk-2-ene-1,4-diols from 1,3-dienes, especially for geometrical constrained derivatives, via dioxirane derivative formation followed by Ti(III)-induced oxirane ring opening, is described. The strategy has been very efficiently implemented to the construction of the 11-ene-10,13-diol moiety present in taxol derivatives.

Efficient at room temperature: The Au complex generated in situ from [(IPr)AuCl] and AgSbF(6) promotes the [4C+3C] intramolecular cycloaddition of allenes and dienes at room temperature, and in a particularly efficient and versatile manner. A DFT study on dimethylallenyl precursors agreed with the formation and cycloaddition of a metal-allyl cation intermediate, and points to the 1,2-hydride shift as the key rate-limiting step.

Efficient targeting of DNA by designed molecules requires not only careful fine-tuning of their DNA-recognition properties, but also appropriate cell internalization of the compounds so that they can reach the cell nucleus in a short period of time. Previous observations in our group on the relatively high affinity displayed by conjugates between distamycin derivatives and bZIP basic regions for A-rich DNA sites, led us to investigate whether the covalent attachment of a positively charged cell-penetrating peptide to a distamycin-like tripyrrole might yield high affinity DNA binders with improved cell internalization properties. Our work has led to the discovery of synthetic tripyrrole-octa-arginine conjugates that are capable of targeting specific DNA sites that contain A-rich tracts with low nanomolar affinity; they simultaneously exhibit excellent membrane and nuclear translocation properties in living HeLa cells.

An efficient tandem ring-closing dienyne metathesis of dienynes derived from cyclohex-2-enone affords the [5.3.1] carbon framework characteristic of taxanes in a single-step process. Further stereoselective functionalizations of the resulting [5.3.1] carbon framework lead to an advanced intermediate in a novel synthetic strategy for taxane analogs.

Butane-1,2-diacetals are selective protecting groups for trans-diequatorial-1,2-diols and have been widely used in carbohydrate chemistry. The scope of diacetal protection has been extended more recently to include other important hydroxylated chiral templates containing trans-1,2-diols, such as quinic and shikimic acids, the protection of which as diacetals leads to a strong conformational rigidity that induces excellent diastereoselectivity control. In addition, the chiral information stored in the diacetal backbone has also been exploited in the synthesis of important building blocks, such as glycerate, glycolate and tartrate diacetal derivatives. In this critical review, the synthetic power of the conformational rigidity and the chirality stored in the diacetal backbone is described. This phenomenon will be illustrated with recent examples of applications in the synthesis of natural products or biologically interesting compounds (80 references).

Intermolecular sensitization of lanthanide ions was effectively implemented in the development of fluorescent sensors targeting cyclin A. A chelating unit has been conjugated to peptides containing a known cyclin A binding motif (CBM). Upon interaction of the modified terbium-chelating peptides with the cyclin A substrate recruitment groove, the Tb3+ ion is placed in the vicinity of the Trp217 side chain, which results in efficient intermolecular terbium sensitization and specific long wavelength fluorescent emission from the metal center.

Several 3-heteroaryl analogs of the known dehydroquinase inhibitor (1R,4R,5R)-1,4,5-trihydroxy-2-cyclohexene-1-carboxylic acid (4) were synthesized and tested as inhibitors of Helicobacter pylori type II dehydroquinase, the third enzyme of the shikimic acid pathway. All of these compounds proved to be reversible competitive inhibitiors of this enzyme and proved to be, with the exception of nitrile 8 e, more potent than the parent inhibitor 4 (K(i)=370 microM). The 2-thienyl derivative 8 b was found to be the most potent inhibitor of the series and has a K(i) value of 540 nM, which is almost seven hundred times lower than that of the parent inhibitor. The 3-nitrothienyl derivative 8 d and 2-furanyl derivative 8 a also had a good affinity of 1 microM. The conformation of the potent competitive inhibitor 8 b, when bound in the active site of the H. pylori enzyme, was elucidated by 1D-selective inversion NOE, Saturation Transfer Difference (STD) and transferred NOESY NMR experiments. One of the conformations that exists in solution for the potent competitive inhibitor 2-thienyl derivative 8 b is selected when it is bound to the active site of the enzyme. In the bound conformation derivative 8 b has the sulfur atom of its thienyl group oriented towards the double bond of the cyclohexene moiety. The large STD effects observed for the aromatic protons of 8 b show that it is the thiophene side of the ligand that makes closest contact with enzyme protons. Docking studies using GOLD3.0.1 suggest that the conformation determined by NMR allows strong lipophilic interactions with the enzyme residues Pro9, Asn10, Ile11, Gly78 and Ala 79. Competitive STD experiments carried out with high-, medium- and low-affinity ligands 8 b, 5 d and 5 f show that they all bind in the same site of Helicobacter pylori dehydroquinase.

"Formal" and standard Ru(II)-catalyzed [2 + 2 + 2] cycloaddition of 1,6-diynes 1 to alkenes gave bicyclic 1,3-cyclohexadienes in relatively good yields. The neutral Ru(II) catalyst was formed in situ by mixing equimolecular amounts of [Cp*Ru(CH3CN)3]PF6 and Et4NCl. Two isomeric bicyclic 1,3-cyclohexadienes 3 and 8 were obtained depending on the cyclic or acyclic nature of the alkene partner. Mechanistic studies on the Ru catalytic cycle revealed a clue for this difference: (a) when acyclic alkenes were used, linear coupling of 1,6-diynes with alkenes was observed giving 1,3,5-trienes 6 as the only initial reaction products, which after a thermal disrotatory 6e-pi electrocyclization led to the final 1,3-cyclohexadienes 3 as probed by NMR studies. This cascade process behaved as a formal Ru-catalyzed [2 + 2 + 2] cycloaddition. (b) With cyclic alkenes, the standard Ru-catalyzed [2 + 2 + 2] cycloaddition occurred, giving the bicyclic 1,3-cyclohexadienes 8 as reaction products. A complete catalytic cycle for the formal and standard Ru-catalyzed [2 + 2 + 2] cycloaddition of acetylene and cyclic and acyclic alkenes with the Cp*RuCl fragment has been proposed and discussed based on DFT/B3LYP calculations. The most likely mechanism for these processes would involve the formation of ruthenacycloheptadiene intermediates XXIII or XXVII depending on the alkene nature. From these complexes, two alternatives could be envisioned: (a) a reductive elimination in the case of cyclic alkenes 7 and (b) a beta-elimination followed by reductive elimination to give 1,3,5-hexatrienes 6 in the case of acyclic alkenes. Final 6e-pi electrocyclization of 6 gave 1,3-cyclohexadienes 3.

We report here the preparation and structural characteristics of a novel self-assembling peptide composed of alternating alpha,alpha-dialkylated alpha-amino and cis-4-aminocyclopent-2-enecarboxylic acids. The use of alpha,alpha-dialkylated amino acids represents a novel method to prevent the formation of extensive beta-sheet-like hydrogen-bonding networks that are characteristic of peptide nanotubes.