Reactive Building Blocks Research Articles

A deep learning approach for rational ligand generation with toxicity control via reactive building blocks.

Deep generative models are gaining attention in the field of de novo drug design. However, the rational design of ligand molecules for novel targets remains challenging, particularly in controlling the properties of the generated molecules. Here, inspired by the DNA-encoded compound library technique, we introduce DeepBlock, a deep learning approach for block-based ligand generation tailored to target protein sequences while enabling precise property control. DeepBlock neatly divides the generation process into two steps: building blocks generation and molecule reconstruction, accomplished by a neural network and a rule-based reconstruction algorithm we proposed, respectively. Furthermore, DeepBlock synergizes the optimization algorithm and deep learning to regulate the properties of the generated molecules. Experiments show that DeepBlock outperforms existing methods in generating ligands with affinity, synthetic accessibility and drug likeness. Moreover, when integrated with simulated annealing or Bayesian optimization using toxicity as the optimization objective, DeepBlock successfully generates ligands with low toxicity while preserving affinity with the target.

A New Architecture for DNA‐Templated Synthesis in Which Abasic Sites Protect Reactants from Degradation

AbstractThe synthesis of artificial sequence‐defined polymers that match and extend the functionality of proteins is an important goal in materials science. One way of achieving this is to program a sequence of chemical reactions between precursor building blocks by means of attached oligonucleotide adapters. However, hydrolysis of the reactive building blocks has so far limited the length and yield of product that can be obtained using DNA‐templated reactions. Here, we report an architecture for DNA‐templated synthesis in which reactants are tethered at internal abasic sites on opposite strands of a DNA duplex. We show that an abasic site within a DNA duplex can protect a nearby thioester from degradation, significantly increasing the yield of a DNA‐templated reaction. This protective effect has the potential to overcome the challenges associated with programmable, sequence‐controlled synthesis of long non‐natural polymers by extending the lifetime of the reactive building blocks.

A New Architecture for DNA-Templated Synthesis in Which Abasic Sites Protect Reactants from Degradation.

The synthesis of artificial sequence-defined polymers that match and extend the functionality of proteins is an important goal in materials science. One way of achieving this is to program a sequence of chemical reactions between precursor building blocks by means of attached oligonucleotide adapters. However, hydrolysis of the reactive building blocks has so far limited the length and yield of product that can be obtained using DNA-templated reactions. Here, we report an architecture for DNA-templated synthesis in which reactants are tethered at internal abasic sites on opposite strands of a DNA duplex. We show that an abasic site within a DNA duplex can protect a nearby thioester from degradation, significantly increasing the yield of a DNA-templated reaction. This protective effect has the potential to overcome the challenges associated with programmable, sequence-controlled synthesis of long non-natural polymers by extending the lifetime of the reactive building blocks.

A New Avenue in Hybrid Polyoxometalate Chemistry: Synthesis and Characterization of Mn (II) Functionalized POM Based Ionic Liquids

The synthesis of novel hybrid materials, combining the properties of organic and inorganic components in one compound, results in materials with unique physical and chemical properties. The organic-functionalization of POMs with covalently or non-covalently linked organic species opens a large spectrum of possibilities and research challenges. The development of such novel systems for metal−organic architectures is an attractive research field. Lacunary polyoxometalates (POMs) offer structurally well-defined coordination sites with various coordination directions; thus, lacunary POMs are ideal building blocks for inorganic−organic architectures. Here, we report the successful self-assembly of transition metal substituted anionic POM along with a new generation POM based ionic liquid. We know that the counter-cations in polyoxometalate chemistry play immense role beyond charge balance. That is why the resultant structure is furthermore utilized as a stable and reactive building block to synthesize POM based ionic liquid (POM-IL), an inorganic−organic architecture comprising 3d-metal substituted mono-lacunary POM and tetrabutyl ammonium (TBA) ligands.

Functionalization of octaspherosilicate (HSiMe2O)8Si8O12 with buta-1,3-diynes by hydrosilylation

Hydrosilylation with octaspherosilicate (HSiMe2O)8Si8O12 (1) has provided hundreds of molecular and macromolecular systems so far, making this method the most popular in the synthesis of siloxane-based, nanometric, cubic, and reactive building blocks. However, there are no reports on its selective reaction with 1,3-diynes, which allows for the formation of new products with unique properties. Therefore, herein we present an efficient protocol for monohydrosilylation of symmetrically and non-symmetrically 1,4-disubstituted buta-1,3-diynes with 1. The compounds obtained bear double and triple bonds and other functionalities (e.g., Br, F, OH, SiR3), making them highly desirable, giant building blocks in organic synthesis and material chemistry. These compounds were fully characterized by 1H, 13C, 29Si, 1D NOE, 1H–13C HSQC NMR, FT–IR, and MALDI TOF MS, EA, UV–Vis, and TGA analysis. The TGA proved their high thermal stability up to 427 ℃ (Td10%) for compound 3j.

Ecological Niche-Inspired Genome Mining Leads to the Discovery of Crop-Protecting Nonribosomal Lipopeptides Featuring a Transient Amino Acid Building Block.

Investigating the ecological context of microbial predator-prey interactions enables the identification of microorganisms, which produce multiple secondary metabolites to evade predation or to kill the predator. In addition, genome mining combined with molecular biology methods can be used to identify further biosynthetic gene clusters that yield new antimicrobials to fight the antimicrobial crisis. In contrast, classical screening-based approaches have limitations since they do not aim to unlock the entire biosynthetic potential of a given organism. Here, we describe the genomics-based identification of keanumycins A-C. These nonribosomal peptides enable bacteria of the genus Pseudomonas to evade amoebal predation. While being amoebicidal at a nanomolar level, these compounds also exhibit a strong antimycotic activity in particular against the devastating plant pathogen Botrytis cinerea and they drastically inhibit the infection of Hydrangea macrophylla leaves using only supernatants of Pseudomonas cultures. The structures of the keanumycins were fully elucidated through a combination of nuclear magnetic resonance, tandem mass spectrometry, and degradation experiments revealing an unprecedented terminal imine motif in keanumycin C extending the family of nonribosomal amino acids by a highly reactive building block. In addition, chemical synthesis unveiled the absolute configuration of the unusual dihydroxylated fatty acid of keanumycin A, which has not yet been reported for this lipodepsipeptide class. Finally, a detailed genome-wide microarray analysis of Candida albicans exposed to keanumycin A shed light on the mode-of-action of this potential natural product lead, which will aid the development of new pharmaceutical and agrochemical antifungals.

Regio- and Stereoselective Addition to gem-Difluorinated Ene-Ynamides: Access to Stereodefined Fluorinated Dienes.

The first synthesis of gem-difluorinated ene-ynamides is presented via deprotonation of trifluoromethylated N-allenamides and δ extrusion of fluorine. These highly reactive building blocks, owing to their dual functional groups, offer a unique entry to difluorinated dienes and to stereodefined, monofluoro-substituted dienes. Stereoselective addition to the ynamide moiety led to difluorinated dienes. A stereocontrolled domino δ elimination reaction followed by an addition/elimination sequence from trifluoromethylated N-allenamides provided exclusively stereodefined monofluorinated ene-ynamides.

Regiochemistry in Cycloaddition Reaction to Synthesize of Some Novel Lawsone-Spiro Compounds

Efficient synthesis of dispiro[indoline-3,4'-pyrrolidine-3',2''-naphthalene]-1'',2,3'',4''-tetraone (3) and spiro[imidazole-4,2'-naphthalene]-1',3',4'-trione derivatives 4 that derived from lawsone moiety as high reactive building block are confirmed via 1,3-dipolar cycloaddition of azomethine ylides generate in situ from benzyl amine and isatin occurred at the double bond of arylidene of lawsone upon heating and or via addition α,β-unsaturated ketone 2 with oxidizing agent hydrogen peroxide (H2O2) (30%) and guanidine.HCl in one portion.

Highly Fluorinated Trianglimine Macrocycles: A Supramolecular Organic Framework

AbstractA novel highly fluorinated dialdehyde was prepared by a two-stage synthesis. This reactive building block for dynamic imine chemistry was used in a condensation reaction to generate the first extensively fluorinated trianglimine. An analysis of the material properties and, especially, the crystal structure of the [3+3] macrocycle revealed a supramolecular organic framework with tubular porous channels. The use of fluorinated ligands to generate hydrophobic electron-deficient channel-like pores is an important addition to the ever-expanding field of supramolecular networks and to trianglimine chemistry in general.

A Track-Based Molecular Synthesizer that Builds a Single-Sequence Oligomer through Iterative Carbon-Carbon Bond Formation

Summary We report an artificial molecular machine that moves along a track, iteratively joining building blocks to form an oligomer of single sequence with a continuous backbone of carbon-carbon bonds. The rotaxane features a macrocycle bearing an aldehyde-terminated chain and an axle containing different phosphonium ylides separated by rigid spacers. Each ylide is large enough to block the passage of the macrocycle, trapping the ring between the stopper at the terminus of original threading and the next ylide along the track. Once a building block is reachable, it is removed from the track through a Wittig reaction that adds it to the terminus of the growing chain. Operation on a four-barrier tetra(phosphonium salt) track produces a tetra(diphenylpropane) of single sequence linked through alkene bonds. The prototype extends the principle for molecular machines that build polymers by moving along tracks to the synthesis of sequence-encoded chains with continuous carbon backbones.

Impact of Reactive Amphiphilic Copolymers on Mechanical Properties and Cell Responses of Fibrin‐Based Hydrogels

AbstractMechanical properties of hydrogels can be modified by the variation of structure and concentration of reactive building blocks. One promising biological source for the synthesis of biocompatible hydrogels is fibrinogen. Fibrinogen is a glycoprotein in blood, which can be transformed enzymatically to fibrin playing an important role in wound healing and clot formation. In the present work, it is demonstrated that hybrid hydrogels with their improved mechanical properties, tunable internal structure, and enhanced resistance to degradation can be synthesized by a combination of fibrinogen and reactive amphiphilic copolymers. Water‐soluble amphiphilic copolymers with tunable molecular weight and controlled amounts of reactive epoxy side groups are used as reactive crosslinkers to reinforce fibrin hydrogels. In the present work, copolymers that can influence the mechanical properties of fibrin‐based hydrogels are used. The reactive copolymers increase the storage modulus of the hydrogels from 600 Pa to 30 kPa. The thickness of fibrin fibers is regulated by the copolymer concentration. It could be demonstrated that the fibrin‐based hydrogels are biocompatible and support cell proliferation. Their degradation rate is considerably slower than that of native fibrin gels. In conclusion, fibrin‐based hydrogels with tunable elasticity and fiber thickness useful to direct cell responses like proliferation and differentiation are produced.

Self-Assembly of Anionic Polyoxometalate-Organic Architectures Based on Lacunary Phosphomolybdates and Pyridyl Ligands.

The development of novel systems for metal-organic architectures is an attractive research field because they are fascinating materials with unexplored functions. Lacunary polyoxometalates (POMs) offer structurally well-defined coordination sites with various coordination directions and numbers in addition to the designable properties; thus, lacunary POMs are ideal building blocks for inorganic-organic architectures. However, their utilization is currently limited by their low stability and difficulty in controlling the reactivity. Here, we report the successful self-assembly of anionic POM-organic architectures comprising multivacant lacunary POMs and pyridyl ligands. By introducing pyridine moieties to its vacant sites, the trivacant lacunary phosphomolybdate [A-α-PMo9O34]9- is significantly stabilized in organic solvents. Furthermore, the resultant structure can be utilized as a stable and reactive building block to synthesize a dimer pillared by 4,4'-bipyridyl and a tetramer bridged by two cofacial porphyrin ligands, which can intercalate aromatic molecules.

Cell-Based Kinetic Target-Guided Synthesis of an Enzyme Inhibitor.

Finding a new drug candidate for a selected target is an expensive and time-consuming process. Target guided-synthesis, or in situ click chemistry, is a concept where the drug target is used to template the formation of its own inhibitors from reactive building blocks. This could simplify the identification of drug candidates. However, with the exception of one example of an RNA-target, target-guided synthesis has always employed purified targets. This limits the number of targets that can be screened by the method. By applying methods from the field of metabolomics, we demonstrate that target-guided synthesis with protein targets also can be performed directly in cell-based systems. These methods offer new possibilities to conduct screening for drug candidates of difficult protein targets in cellular environments.

Biomimetic studies towards the total synthesis of highly complex araiosamines

Araiosamines are among the most complex indole alkaloids isolated from marine environments to date [1]. Indeed, the fascinating structures of several araiosamines were disclosed in 2011 (see the structure of araiosamine C) from a marine sponge (Clathria araiosa) [2]. Their structures reveal an original assembly of tryptophane-derived reactive building blocks and guanidine. Based on biosynthetic considerations, several cascades of reactions are studied involving simple indole-acetaldehydes and guanidine itself in order to better understand how such molecular architectures can arise in Nature [3]. Metabolomic tools appear appropriate for such approaches. Assemblies of the starting units give rise to interesting guanidine heterocycles.

Exploiting recognition-mediated assembly and reactivity in [2]rotaxane formation.

A small molecular reaction network exploits recognition-mediated reactive processes in order to drive the assembly and formation of both a self-replicating linear template (thread) and a [2]rotaxane, in which the linear template is encircled by a diamide macrocycle. Complementary recognition sites, placed at strategic positions on the reactive building blocks, drive these assembly and replication processes. Template-instructed experiments show that the thread is capable of efficient self-replication and that no cross-catalytic relationships exist between the thread and the [2]rotaxane. The rate of [2]rotaxane formation is insensitive to the addition of a preformed template, however, [2]rotaxane formation does show enhanced diastereoselectivity, most likely originating from its recognition-mediated formation through a ternary reactive complex.

Modulation of reactivity in the cavity of liposomes promotes the formation of peptide bonds.

In living cells, reactions take place in membrane-bound compartments, often in response to changes in the environment. Learning how the reactions are influenced by this compartmentalization will help us gain an optimal understanding of living organisms at the molecular level and, at the same time, will offer vital clues on the behavior of simple compartmentalized systems, such as prebiotic precursors of cells and cell-inspired artificial systems. In this work we show that a reactive building block (an activated amino acid derivative) trapped in the cavity of a liposome is protected against hydrolysis and reacts nearly quantitatively with another building block, which is membrane-permeable and free in solution, to form the dipeptide. By contrast, when the activated amino acid is found outside the liposome, hydrolysis is the prevalent reaction, showing that the cavity of the liposomes promotes the formation of peptide bonds. We attribute this result to the large lipid concentration in small compartments from the point of view of a membrane-impermeable molecule. Based on this result, we show how the outcome of the reaction can be predicted as a function of the size of the compartment. The implications of these results on the behavior of biomolecules in cell compartments, abiogenesis, and the design of artificial cell-inspired systems are considered.

Preparation of self-healing organic–inorganic nanocomposites with the reactions between methacrylated polyhedral oligomeric silsesquioxanes and furfurylamine

Abstract Multifunctional methacrylated polyhedral oligomeric silsesquioxanes (MMA-POSS) and furfurylamine (FA) are utilized as the monomers to demonstrate an example of utilization of nanosized inorganic molecule as a reactive building block in preparation of nanohybrids materials. Both of the MA-amine Michael addition and MA-furan Diels–Alder (DA) reaction occur between the two monomers and contribute to build up the hybrid structures of the resulting materials. Based on the strong interaction between the POSS units, the nanohybrids materials exhibit self-assembled lamellar structures with a spacing width of about 455 nm. Moreover, the residual methacrylate groups of the POSS-based hybrid materials make them are thermally crosslinkable. The corresponding crosslinked nanocomposite exhibits thermally-induced self-healing ability based on the thermally-reversible MA-furan DA adducts built in the nanocomposites structure.

Hierarchical Striped Walls Constructed by the Photopolymerization of Discotic Reactive Building Blocks in the Anisotropic Liquid Crystal Solvents

A triphenylene-based reactive mesogenic molecule (abbreviated as HABET) was newly designed and synthesized as a programmed building block to construct the striped walls by the photopolymerization in the anisotropic liquid crystal (LC) solvents. On the basis of thermal, scattering and microscopic analyses, it was found that HABET formed three ordered structures: a columnar hexagonal LC phase (ΦH), a tilted columnar hexagonal LC phase (ΦT) and a highly ordered columnar oblique crystal phase (ΦOK). The microscopic molecular orientations in the hierarchical superstructures were controlled in the anisotropic LC solvents with the help of surface anchoring forces, while the dimensions of the striped wall morphologies were determined by the patterned photomasks. The long axis of self-assembled columns in the striped walls was perpendicular to the surface alignment direction regardless of the photomask direction. Additionally, it was realized that the shapes of water drops as well as the surface water contact angles can be tuned by the hierarchical superstructures and morphologies of the polymerized HABET networks. The anisotropic hierarchical superstructures and morphologies concurrently fabricated during the polymerization in the anisotropic LC medium can offer a potential pathway for liquid transportation in the microfluidic devices.

Symmetrical tetra-β″-sulfoleno-meso-aryl-porphyrins — synthesis, spectroscopy and structural characterization

We report here the preparation (in "one-pot") of a tetra-β″-sulfoleno-meso-aryl-porphyrin in about 80% yield by using an optimized modification of Lindsey's variant of the Adler–Longo approach. The Zn ( II )-, Cu ( II )- and Ni ( II )-complexes of the symmetrical porphyrin were prepared and characterized spectroscopically. Crystal structures of the fluorescent Zn ( II )- and of the non-fluorescent Ni ( II )-tetra-β″-sulfoleno-meso-aryl-porphyrinates showed the highly substituted porphyrin ligands to be nearly perfectly planar. The Zn ( II )-complex of this porphyrin has been used as a thermal precursor of a reactive diene, and — formally — of lateral and diagonal bis-dienes, of a tris-diene and of a tetra-diene, which all underwent [4 + 2]-cycloaddition reactions in situ with a range of dienophiles. Thus, the tetra-β″-sulfoleno-meso-aryl-porphyrin and its metal complexes represent reactive building blocks, "programmed" for the syntheses of symmetrical and highly functionalized porphyrins.

Macromolecular platinum-drugs based on statistical and block copolymer structures and their DNA binding ability

Macromolecular platinum drugs were prepared from statistical copolymers or block copolymers. Reversible addition–fragmentation chain-transfer (RAFT) polymerisation was applied to obtain copolymers based on 3-(trimethylsilyl) prop-2-ynyl methacrylate (TMSPMA) as the reactive building block for the conjugation of platinum drugs and oligo(ethylene glycol methyl ether) methacrylate (OEGMEMA) as the water-soluble part. Two statistical copolymers and one block copolymer were obtained, which were deprotected to allow the subsequent ‘click’ reaction. Inspired by the platinum anti-cancer drug cisplatin (cis-diamminedichloroplatinum(II)), the platinum drug was conjugated to the polymer via a stable, permanent amino ligand. Therefore, a BOC protected 2-azidopropane-1,3-diamine (N3-DAP-BOC) ligand was prepared, which was attached to the polymers by copper catalysed azide–alkyne Huisgen cycloaddition ‘click’ (CuACC) reaction. Purification of the polymer to remove the copper complex was found to be difficult and several approaches were investigated. Subsequent platinum drug conjugation led to three different macromolecular platinum drugs P(OEGMEMA64-co-[(PMA-DAP)8-Pt7]), P(OEGMEMA62-co-[(PMA-DAP)16-Pt14]), and P(OEGMEMA84-b-[(PMA-DAP)48-Pt20]) with conjugation efficiencies of more than 80% for the statistical copolymers and 40% for the block copolymer. Binding efficiency to DNA of all three polymers was studied using fluorescence spectroscopy revealing the highest binding with the statistical copolymer with the highest drug density. Interestingly, the toxicity of all three polymers towards the ovarian cancer cell line OVCAR-3 highlights the importance of further work that investigates cellular uptake and stability of the aggregates in vitro.