In silico Support for Eschenmoser’s Glyoxylate Scenario

A core topic of research in prebiotic chemistry is the search for plausible synthetic routes that connect the building blocks of modern life, such as sugars, nucleotides, amino acids, and lipids to “molecular food sources” that were likely to have been abundant on early Earth. In a recent contribution, Albert Eschenmoser emphasised the importance of catalytic and autocatalytic cycles in establishing such abiotic synthesis pathways. The accumulation of intermediate products furthermore provides additional catalysts that allow pathways to change over time. We show here that generative models of chemical spaces based on graph grammars make it possible to study such phenomena in a systematic manner. In addition to reproducing the key steps of Eschenmoser’s hypothesis paper, we discovered previously unexplored potentially autocatalytic pathways from HCN to glyoxylate. A cascade of autocatalytic cycles could efficiently re-route matter, distributed over the combinatorial complex network of HCN hydrolysation chemistry, towards a potential primordial metabolism. The generative approach also has it intrinsic limitations: the unsupervised expansion of the chemical space remains infeasible due to the exponential growth of possible molecules and reactions between them. Here, in particular, the combinatorial complexity of the HCN polymerisation and hydrolysation networks forms the computational bottleneck. As a consequence, guidance of the computational exploration by chemical experience is indispensable.     

Dynamic deconvolution of a pre-equilibrated dynamic combinatorial library of acetylcholinesterase inhibitors

A dynamic combinatorial library composed of interconverting acylhydrazones has been generated and screened towards inhibition of acetylcholinesterase from the electric ray Torpedo marmorata. Starting from a small set (13) of initial hydrazide and aldehyde building blocks, a library containing possibly 66 different species was obtained in a single operation. Of all possible acylhydrazones formed, active compounds containing two terminal cationic recognition groups separated by an appropriate distance, permitting two-site binding, could be rapidly identified by using a dynamic deconvolution--screening procedure, based on the sequential removal of starting building blocks. A very potent bis-pyridinium inhibitor (K(i)=1.09 nM, alphaK(i)=2.80 nM) was selected from the process and the contribution of various structural features to inhibitory potency was evaluated.     

On the Free Energy That Drove Primordial Anabolism

A key problem in understanding the origin of life is to explain the mechanism(s) that led to the spontaneous assembly of molecular building blocks that ultimately resulted in the appearance of macromolecular structures as they are known in modern biochemistry today. An indispensable thermodynamic prerequisite for such a primordial anabolism is the mechanistic coupling to processes that supplied the free energy required. Here I review different sources of free energy and discuss the potential of each form having been involved in the very first anabolic reactions that were fundamental to increase molecular complexity and thus were essential for life.     

Combinatorial-designed multifunctional polymeric nanosystems for tumor-targeted therapeutic delivery

By definition, multifunctional nanosystems include several features within a single construct so that these devices can target tumors or other disease tissue, facilitate in vivo imaging, and deliver a therapeutic agent. Investigations of these nanosystems are rapidly progressing and provide new opportunities in the management of cancer. Tumor-targeted nanosystems are currently designed based primarily on the intrinsic physico-chemical properties of off-the-shelf polymers. Following fabrication, the surfaces of these nanoscale structures are functionalized for passive or active targeted delivery to the tumors. In this Account, we describe a novel approach for the construction of multifunctional polymeric nanosystems based on combinatorial design principles. Combinatorial approaches offer several advantages over conventional methods because they allow for the integration of multiple components with varied properties into a nanosystem via self-assembly or chemical conjugation. High-throughput synthesis and screening is required in polymer design because polymer composition directly affects properties including drug loading, retention in circulation, and targeting of the nanosystems. The first approach relies on the self-assembly of macromolecular building blocks with specific functionalities in aqueous media to yield a large variety of nanoparticle systems. These self-assembled nanosystems with diverse functionalities can then be rapidly screened in a high-throughput fashion for selection of ideal formulations, or hits, which are further evaluated for safety and efficacy. In another approach, a library of a large number of polymeric materials is synthesized using different monomers. Each of the formed polymers is screened for the selection of the best candidates for nanoparticle fabrication. The combinatorial design principles allow for the selection of those nanosystems with the most favorable properties based on the type of payload, route of administration, and the desired target for imaging and delivery.     

New approaches to producing polyols from biomass

Polyols are polymers that contain multiple hydroxyl groups in their structure. They are generally produced from petroleum derivatives and have a relevant commercial value as building blocks, intermediates in organic synthesis, or precursors for production of polyurethanes. New alternatives for green synthesis of polyols involve the substitution of some hazardous petrochemical derivatives by others based on biomass and which are safer and environmentally more benign. This mini‐review assesses the synthesis processes of some relevant biomass polyols, products that are becoming a commercial reality. © 2016 Society of Chemical Industry     

Peptide-Based Nanoarchitectonics for the Treatment of Liver Fibrosis

Liver fibrosis is a process of excessive accumulation of extracellular matrix caused by liver injury. Liver fibrosis can progress to cirrhosis or even liver cancer without proper intervention. Until now, no effective therapeutic drugs have been clinically approved for treating liver fibrosis. Hence, the development of safe and effective antifibrotic drugs is particularly important. As a representative biomaterial, peptides have been investigated as key components for constructing antifibrotic nanomaterials given their advantages of biological origination, synthetic availability, and good biocompatibility. Peptides serve as multifunctional motifs in antifibrotic nanomaterials, such as liver-targeting molecules, antifibrotic molecules, and self-assembling building blocks for the formation of the nanomaterials. In this review, we focus on peptide-based nanoarchitectonics for treating liver fibrosis, including nanomaterials modified with liver-targeting peptides, nanomaterials for the efficient delivery of antifibrotic peptides, and self-assembled peptide nanomaterials for the delivery of antifibrotic drugs. The design rules of these peptide-based nanomaterials are described. The antifibrotic mechanisms and effects of these peptide-based nanomaterials in treating liver fibrosis and related diseases are highlighted. The challenges and future perspectives of using peptide-based nanoarchitectonics for the treatment of liver fibrosis are discussed. These results are expected to accelerate the rational design and clinical translation of antifibrotic nanomaterials.     

Targeted synthesis and environmental applications of oxide nanomaterials

Oxide nanomaterials are indispensable building blocks for a future nanotechnology, because they offer an infinite variety of structural motifs that lead to their widespread technical application. Therefore, flexible and tunable preparative strategies are required to convert this large family of materials onto the nanoscale. Although hydrothermal syntheses have proven especially suitable for this purpose, their reaction pathways and mechanisms often remain unknown so that they can be difficult to control. In the following, we summarize our comprehensive approach towards nanostructured functional oxides that is based on synthetic parameter optimizations, mechanistic in situ investigations and the characterization of environmentally relevant properties, e.g. in photocatalysis or sensor technology. The connection between preparative morphology control and the resulting materials properties is demonstrated for selected tungstate systems and bismuth-containing oxides. Furthermore, different methods for the in situ monitoring of hydrothermal processes are discussed.     

Supramolecular Self-Assembled Ligands in Asymmetric Transition Metal Catalysis

The design of novel chiral ligands is at the core of asymmetric catalysis. The catalytic characteristics of a transition metal catalyst such as activity, selectivity and stability can be fine-tuned by optimization of the steric and electronic properties of the coordinating ligands. In asymmetric transformations, catalyst optimization still relies to a large extent on trial-and-error and educated guesses. New strategies based on combinatorial screening and high-throughput experimentation have been introduced for the design and optimization of new ligands and catalytic systems. Supramolecular bidentate ligands that form by self-assembly of building blocks are particularly suited for this combinatorial approach as the potential number of catalysts grows exponentially with the number of building blocks synthesized. Catalytic systems based on supramolecular interactions have proven to be highly advantageous in creating large ligand libraries for high-throughput screening, which allows optimization of activity and selectivity for a variety of reactions. In this review we describe the progress in this field.     

Effect of network mesh size and swelling to the drug delivery from pH responsive hydrogels

pH responsive hydrogels are ideal platforms for numerous therapeutic delivery applications, including oral delivery, as they are capable of overcoming the many barriers that must be considered when creating an effective drug delivery system. Understanding of the innate hydrogel network structure and its swelling behavior at environmentally relevant conditions is vital for designing hydrogel network capable of effective controlled drug release. Herein, we explored how to expand traditional techniques of swelling and pore characterization to gain better insight into the performance of anionic microparticles composed of the poly(methyl methacrylate-co-acrylic acid) with varying molar percentage of 10, 20, and 30 mol% of MMA, for controlled release of low-molecular-weight drugs. By evaluating these carrier systems at environmental conditions, we can observe changes in swelling and pore size of the anionic hydrogel networks as a function of MMA, which was then correlated with the release profiles of the small-molecular-weight drug sodium nitrate. With the correlation of the swelling behavior of the networks and the release profiles, we demonstrated how the expansion of swelling parameters at relevant pH values provides further incite for evaluating for the optimal blend for controlled release. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48767.     

Simultaneous Disulfide and Boronic Acid Ester Exchange in Dynamic Combinatorial Libraries

Dynamic combinatorial chemistry has emerged as a promising tool for the discovery of complex receptors in supramolecular chemistry. At the heart of dynamic combinatorial chemistry are the reversible reactions that enable the exchange of building blocks between library members in dynamic combinatorial libraries (DCLs) ensuring thermodynamic control over the system. If more than one reversible reaction operates in a single dynamic combinatorial library, the complexity of the system increases dramatically, and so does its possible applications. One can imagine two reversible reactions that operate simultaneously or two reversible reactions that operate independently. Both these scenarios have advantages and disadvantages. In this contribution, we show how disulfide exchange and boronic ester transesterification can function simultaneous in dynamic combinatorial libraries under appropriate conditions. We describe the detailed studies necessary to establish suitable reaction conditions and highlight the analytical techniques appropriate to study this type of system.     

Viruses as self-assembled nanocontainers for encapsulation of functional cargoes

Viruses naturally exhibit an incredible variety of sophisticated nanostructures, which makes them ideal biological building blocks for nanoengineered material research. By mimicking their spontaneous assembly process, tremendous advances have been made towards utilizing virus and virus-like particles (VLPs) as protein cages, scaffolds, and templates for nanomaterials in the last few years. This review outlines recent progress in the field of bionanotechnology in which viruses are introduced to encapsulate various functional cargoes in a precise and controlled fashion. The encapsulation mechanisms are summarized into three main strategies: electrostatic interaction, chemical conjugation, and covalent attachment by genetic manipulation. The combination with chemical modification and genetic engineering heralds a brilliant future for fabrication of functional nanomaterials. These well-defined architectures will find attractive applications in biosensing, drug delivery, enzyme confinement, light-harvesting system, and pharmaceutical therapy.     

Repertoires of aggregation-resistant human antibody domains

We recently described a method for the generation of a large human domain antibody repertoire involving combinatorial assembly of CDR building blocks from a smaller repertoire comprising a high frequency of aggregation-resistant antibody domains. Here we show that the frequency of aggregation-resistant domains in the combinatorial repertoire remained high. Furthermore, one of the antigen-binding domains selected from the combinatorial repertoire retained its binding properties through 25 cycles of thermal denaturation, suggesting that antibody domains can be created that rival the heat-resistance of thermophilic proteins such as Taq polymerase.     

Implication of microRNAs in Carcinogenesis with Emphasis on Hematological Malignancies and Clinical Translation

MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs, that are involved in the multistep process of carcinogenesis, contributing to all established hallmarks of cancer. In this review, implications of miRNAs in hematological malignancies and their clinical utilization fields are discussed. As components of the complex regulatory network of gene expression, influenced by the tissue microenvironment and epigenetic modifiers, miRNAs are “micromanagers” of all physiological processes including the regulation of hematopoiesis and metabolic pathways. Dysregulated miRNA expression levels contribute to both the initiation and progression of acute leukemias, the metabolic reprogramming of malignantly transformed hematopoietic precursors, and to the development of chemoresistance. Since they are highly stable and can be easily quantified in body fluids and tissue specimens, miRNAs are promising biomarkers for the early detection of hematological malignancies. Besides novel opportunities for differential diagnosis, miRNAs can contribute to advanced chemoresistance prediction and prognostic stratification of acute leukemias. Synthetic oligonucleotides and delivery vehicles aim the therapeutic modulation of miRNA expression levels. However, major challenges such as efficient delivery to specific locations, differences of miRNA expression patterns between pediatric and adult hematological malignancies, and potential side effects of miRNA-based therapies should be considered.     

合成化学新概念——组合化学

简明地介绍 2 0世纪 90年代刚刚问世的组合化学新概念以及组合合成基本方法 ,着重叙述了“一珠一肽”混合均分合成法的基本原理及其在新药合成及筛选研究中的应用 ,并对组合合成中编码技术作了初步介绍     

Hydrothermal synthesis of hierarchical hydroxyapatite: Preparation, growth mechanism and drug release property

Hydroxyapatite (HAP) hierarchical microspheres were synthesized by a facile hydrothermal method using calcium nitrate and ammonium dihydrogen phosphate through controlling complexing agents. The influences of two kinds of complexing agents (potassium sodium tartrate tetrahydrate and trisodium citrate) and reaction time on the morphology of HAP crystals have been investigated. These results indicate that complexing agents have a great influence on the morphology of HAP. When potassium sodium tartrate tetrahydrate was used as complexing agent, HAP flowers were composed of the network of nanosheet building blocks. Well-crystallized HAP dandelions with nanorods radiating from the center can be obtained by the introduction of trisodium citrate. Broader XRD diffraction peaks imply a nanometer scale size. Based on XRD and SEM results, the formation mechanism of HAP crystals has been discussed. The hierarchically structured HAP microspheres were explored as drug carriers. The results indicate that HAP flowers and dandelions showed a favorable sustained release property for ibuprofen; thus, they are very promising for application in drug delivery.     

Lactation behavior and delivery care in a group of women from a Mexican rural community]

This article presents a brief discussion on the role that "medical practice" plays, related to the type of infant lactation after delivery, and breast-feeding practice during the first months of life. Data on hospital routines and how these predispose artificial feeding practices are seen from a critical angle. The information presented in this paper corresponds to a project carried out in a rural community of the state of México, called Malinalco, where the lactation behavior of 65 women after birth of the child, was followed as of their last period of pregnancy. The main objectives of the study were to determine the relationship between the place of delivery (hospital or home delivery) and the type of lactation practiced by the mothers, as well as to determine the infants nutritional status during their first year of life. Results showed that the greater part of women from the sample were young others (less than 30 years old) with one or two children. As to the place where delivery took place, 72% of the sample were attended by midwives at their own homes, and at last 65% practiced breast feeding exclusively during the first three months. No significant correlation between these two indicators (place of delivery and type of lactation) was found, although a tendency to a more prolonged breast-feeding practice was observed in those women who delivered at home. Problems related to weaning practices were detected, since they start this only with bean broth after five months of life. Finally, information on nutritional status during the first 12 months of life, shows serious nutritional problem after the child's third month of life, since the normality percentage starts decreasing while there occurs a significant increase of 1st an 2nd degree malnutrition.     

Allylsilanes and vinylsilanes from silylcupration of carbon-carbon multiple bonds: scope and synthetic applications

Silylcupration of multiple bonds (allenes, acetylenes, dienes, and styrenes) has become one of the most efficient procedures for the synthesis of vinyl- and allylsilanes. These substrates are useful building blocks in organic synthesis since they undergo a great variety of silicon-assisted transformations. The methodology reported has been widely used in the synthesis of different natural products, as well as in the construction of carbo- and heterocycles. In this Account, we wish to illustrate our contribution to this field, as well as to highlight the contributions of others.     

Probing the Substrate Promiscuity of Isopentenyl Phosphate Kinase as a Platform for Hemiterpene Analogue Production

Isoprenoids are a large class of natural products with wide-ranging applications. Synthetic biology approaches to the manufacture of isoprenoids and their new-to-nature derivatives are limited due to the provision in nature of just two hemiterpene building blocks for isoprenoid biosynthesis. To address this limitation, artificial chemo-enzymatic pathways such as the alcohol-dependent hemiterpene (ADH) pathway serve to leverage consecutive kinases to convert exogenous alcohols into pyrophosphates that could be coupled to downstream isoprenoid biosynthesis. To be successful, each kinase in this pathway should be permissive of a broad range of substrates. For the first time, we have probed the promiscuity of the second enzyme in the ADH pathway—isopentenyl phosphate kinase from Thermoplasma acidophilum—towards a broad range of acceptor monophosphates. Subsequently, we evaluate the suitability of this enzyme to provide unnatural pyrophosphates and provide a critical first step in characterizing the rate-limiting steps in the artificial ADH pathway.     

Biological Characterization,Mechanistic Investigation and Structure-Activity Relationships of Chemically Stable TLR2 Antagonists

Toll-like receptors (TLRs) build the first barrier in the innate immune response and therefore represent promising targets for the modulation of inflammatory processes. Recently, the pyrogallol-containing TLR2 antagonists CU-CPT22 and MMG-11 were reported; however, their 1,2,3-triphenol motif renders them highly susceptible to oxidation and excludes them from use in extended experiments under aerobic conditions. Therefore, we have developed a set of novel TLR2 antagonists ( 1 – 9 ) based on the systematic variation of substructures, linker elements, and the hydrogen-bonding pattern of the pyrogallol precursors by using chemically robust building blocks. The novel series of chemically stable and synthetically accessible TLR2 antagonists ( 1 – 9 ) was pharmacologically characterized, and the potential binding modes of the active compounds were evaluated structurally. Our results provide new insights into structure-activity relationships and allow rationalization of structural binding characteristics. Moreover, they support the hypothesis that this class of TLR ligands bind solely to TLR2 and do not directly interact with TLR1 or TLR6 of the functional heterodimer. The most active compound from this series ( 6 ), is chemically stable, nontoxic, TLR2-selective, and shows a similar activity with regard to the pyrogallol starting points, thus indicating the variability of the hydrogen bonding pattern.