Design,Synthesis, and Phenotypic Profiling of Pyrano‐Furo‐Pyridone Pseudo Natural Products

Natural products (NPs) inspire the design and synthesis of novel biologically relevant chemical matter, for instance through biology‐oriented synthesis (BIOS). However, BIOS is limited by the partial coverage of NP‐like chemical space by the guiding NPs. The design and synthesis of “pseudo NPs” overcomes these limitations by combining NP‐inspired strategies with fragment‐based compound design through de novo combination of NP‐derived fragments to unprecedented compound classes not accessible through biosynthesis. We describe the development and biological evaluation of pyrano‐furo‐pyridone (PFP) pseudo NPs, which combine pyridone‐ and dihydropyran NP fragments in three isomeric arrangements. Cheminformatic analysis indicates that the PFPs reside in an area of NP‐like chemical space not covered by existing NPs but rather by drugs and related compounds. Phenotypic profiling in a target‐agnostic “cell painting” assay revealed that PFPs induce formation of reactive oxygen species and are structurally novel inhibitors of mitochondrial complex I.     

Synthesis of Indomorphan Pseudo‐Natural Product Inhibitors of Glucose Transporters GLUT‐1 and ‐3

Bioactive compound design based on natural product (NP) structure may be limited because of partial coverage of NP‐like chemical space and biological target space. These limitations can be overcome by combining NP‐centered strategies with fragment‐based compound design through combination of NP‐derived fragments to afford structurally unprecedented “pseudo‐natural products” (pseudo‐NPs). The design, synthesis, and biological evaluation of a collection of indomorphan pseudo‐NPs that combine biosynthetically unrelated indole‐ and morphan‐alkaloid fragments are described. Indomorphane derivative Glupin was identified as a potent inhibitor of glucose uptake by selectively targeting and upregulating glucose transporters GLUT‐1 and GLUT‐3. Glupin suppresses glycolysis, reduces the levels of glucose‐derived metabolites, and attenuates the growth of various cancer cell lines. Our findings underscore the importance of dual GLUT‐1 and GLUT‐3 inhibition to efficiently suppress tumor cell growth and the cellular rescue mechanism, which counteracts glucose scarcity.     

Phenotyping Reveals Targets of a Pseudo‐Natural‐Product Autophagy Inhibitor

Pseudo‐natural‐product (NP) design combines natural product fragments to provide unprecedented NP‐inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo‐NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell‐based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd‐catalyzed annulation. Exploration of indocinchona alkaloid bioactivities in phenotypic assays revealed a novel class of azaindole‐containing autophagy inhibitors, the azaquindoles. Subsequent characterization of the most potent compound, azaquindole‐1, in the morphological cell painting assay, guided target identification efforts. In contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation‐ and rapamycin‐induced autophagy by targeting the lipid kinase VPS34.     

Unprecedented Combination of Polyketide Natural Product Fragments Identifies the New Hedgehog Signaling Pathway Inhibitor Grismonone

Pseudo-natural products (pseudo-NPs) are de novo combinations of natural product (NP) fragments that define novel bioactive chemotypes. For their discovery, new design principles are being sought. Previously, pseudo-NPs were synthesized by the combination of fragments originating from biosynthetically unrelated NPs to guarantee structural novelty and novel bioactivity. We report the combination of fragments from biosynthetically related NPs in novel arrangements to yield a novel chemotype with activity not shared by the guiding fragments. We describe the synthesis of the polyketide pseudo-NP grismonone and identify it as a structurally novel and potent inhibitor of Hedgehog signaling. The insight that the de novo combination of fragments derived from biosynthetically related NPs may also yield new biologically relevant compound classes with unexpected bioactivity may be considered a chemical extension or diversion of existing biosynthetic pathways and greatly expands the opportunities for exploration of biologically relevant chemical space by means of the pseudo-NP principle.     

A Light‐Triggerable Nanoparticle Library for the Controlled Release of Non‐Coding RNAs

RNA‐based therapies offer a wide range of therapeutic interventions including the treatment of skin diseases; however, the strategies to efficiently deliver these biomolecules are still limited due to obstacles related to the cellular uptake and cytoplasmic delivery. Herein, we report the synthesis of a triggerable polymeric nanoparticle (NP) library composed of 160 formulations, presenting physico‐chemical diversity and differential responsiveness to light. Six formulations were more efficient (up to 500 %) than commercially available lipofectamine in gene‐knockdown activity. These formulations showed differential internalization by skin cells and the endosomal escape was rapid (minutes range). The NPs were effective in the release of siRNA and miRNA. Acute skin wounds treated with the top hit NP complexed with miRNA‐150‐5p healed faster than wounds treated with scrambled miRNA. Light‐activatable NPs offer a new strategy to topically deliver non‐coding RNAs.     

Inhibition of Pathogen Adhesion by Bacterial Outer Membrane‐Coated Nanoparticles

Anti‐adhesion therapies interfere with the bacterial adhesion to the host and thus avoid direct disruption of bacterial cycles for killing, which may alleviate resistance development. Herein, an anti‐adhesion nanomedicine platform is made by wrapping synthetic polymeric cores with bacterial outer membranes. The resulting bacterium‐mimicking nanoparticles (denoted “OM‐NPs”) compete with source bacteria for binding to the host. The “top‐down” fabrication of OM‐NPs avoids the identification of the adhesins and bypasses the design of agonists targeting these adhesins. In this study, OM‐NPs are made with the membrane of Helicobacter pylori and shown to bind with gastric epithelial cells (AGS cells). Treatment of AGS cells with OM‐NPs reduces H. pylori adhesion and such anti‐adhesion efficacy is dependent on OM‐NP concentration and its dosing sequence.     

Divergent Solid‐Phase Synthesis of Natural Product‐Inspired Bipartite Cyclodepsipeptides: Total Synthesis of Seragamide A

Macrocyclic natural products (NPs) and analogues thereof often show high affinity, selectivity, and metabolic stability, and methods for the synthesis of NP‐like macrocycle collections are of major current interest. We report an efficient solid‐phase/cyclorelease method for the synthesis of a collection of macrocyclic depsipeptides with bipartite peptide/polyketide structure inspired by the very potent F‐actin stabilizing depsipeptides of the jasplakinolide/geodiamolide class. The method includes the assembly of an acyclic precursor chain on a polymeric carrier, terminated by olefins that constitute complementary fragments of the polyketide section and cyclization by means of a relay‐ring‐closing metathesis (RRCM). The method was validated in the first total synthesis of the actin‐stabilizing cyclodepsipeptide seragamide A and the synthesis of a collection of structurally diverse bipartite depsipeptides.     

A Biomimetic Nanoparticle to “Lure and Kill” Phospholipase A2

Inhibition of phospholipase A2 (PLA2) has long been considered for treating various diseases associated with an elevated PLA2 activity. However, safe and effective PLA2 inhibitors remain unavailable. Herein, we report a biomimetic nanoparticle design that enables a “lure and kill” mechanism designed for PLA2 inhibition (denoted “L&K‐NP”). The L&K‐NPs are made of polymeric cores wrapped with modified red blood cell membrane with two inserted key components: melittin and oleyloxyethyl phosphorylcholine (OOPC). Melittin acts as a PLA2 attractant that works together with the membrane lipids to “lure” in‐coming PLA2 for attack. Meanwhile, OOPC acts as inhibitor that “kills” PLA2 upon enzymatic attack. Both compounds are integrated into the L&K‐NP structure, which voids toxicity associated with free molecules. In the study, L&K‐NPs effectively inhibit PLA2‐induced hemolysis. In mice administered with a lethal dose of venomous PLA2, L&K‐NPs also inhibit hemolysis and confer a significant survival benefit. Furthermore, L&K‐NPs show no obvious toxicity in mice. and the design provides a platform technology for a safe and effective anti‐PLA2 approach.     

Identification of Inhibitors for Mycobacterial Protein Tyrosine Phosphatase B (MptpB) by Biology‐Oriented Synthesis (BIOS)

Protein phosphatases have recently emerged as important targets for research in chemical biology and medicinal chemistry, and new classes of phosphatase inhibitors are in high demand. BIOS (biology‐oriented synthesis) employs the criteria of relevance to nature and biological prevalidation for the design and synthesis of compound collections. In an application of the BIOS principle, an efficient solid‐phase synthesis of highly substituted indolo[2,3‐a]quinolizidines by using a vinylogous Mannich–Michael reaction in combination with phosgene‐ or acid‐mediated ring closure was developed. Screening of this library for phosphatase inhibitors yielded a new inhibitor class for the Mycobacterium tuberculosis phosphatase MptpB.     

Mussel‐Inspired Protein Nanoparticles Containing Iron(III)–DOPA Complexes for pH‐Responsive Drug Delivery

A novel bioinspired strategy for protein nanoparticle (NP) synthesis to achieve pH‐responsive drug release exploits the pH‐dependent changes in the coordination stoichiometry of iron(III)–3,4‐dihydroxyphenylalanine (DOPA) complexes, which play a major cross‐linking role in mussel byssal threads. Doxorubicin‐loaded polymeric NPs that are based on Fe^III–DOPA complexation were thus synthesized with a DOPA‐modified recombinant mussel adhesive protein through a co‐electrospraying process. The release of doxorubicin was found to be predominantly governed by a change in the structure of the Fe^III–DOPA complexes induced by an acidic pH value. It was also demonstrated that the fabricated NPs exhibited effective cytotoxicity towards cancer cells through efficient cellular uptake and cytosolic release. Therefore, it is anticipated that Fe^III–DOPA complexation can be successfully utilized as a new design principle for pH‐responsive NPs for diverse controlled drug‐delivery applications.     

New 3‐(Heteroaryl)‐2‐iminocoumarin‐based Borate Complexes: Synthesis,Photophysical Properties,and Rational Functionalization for Biosensing/Biolabeling Applications

Members of a series of boron difluoride complexes with 3‐(heteroaryl)‐2‐iminocoumarin ligands bearing both a phenolic hydroxyl group (acting as a fluorogenic center) and an N‐aryl substituent (acting as a stabilizing moiety) have been synthesized in good yields by applying a straightforward two‐step method. These novel fluorogenic dyes belong to the family of “Boricos” (D. Frath et al., Chem. Commun.­ 2013 , 49, 4908–4910) and are the first examples of phenol‐based fluorophores of which the photophysical properties in the green‐yellow spectral range are dramatically improved by N,N‐chelation of a boron atom. Modulation of their fluorescence properties through reversible chemical modification of their phenol moieties has been demonstrated by the preparation of the corresponding 2,4‐dinitrophenyl (DNP) ethers, which led to a dramatic “OFF‐ON” fluorescence response upon reaction with thiols. Additionally, to expand the scope of these “7‐hydroxy‐Borico” derivatives, particularly in biolabeling, amine or carboxylic acid functionalities amenable to (bio)conjugation have been introduced within their scaffold. Their utility has been demonstrated in the preparation of fluorescent bovine serum albumin (BSA) conjugates and “Borico”‐DOTA‐like scaffolds in an effort to design novel monomolecular multimodal fluorescence‐ radioisotope imaging agents.     

Covalently Binding of Bovine Serum Albumin to Unsaturated Poly(Globalide‐Co‐ε‐Caprolactone) Nanoparticles by Thiol‐Ene Reactions

When nanoparticles (NPs) are introduced to a biological fluid, different proteins (and other biomolecules) rapidly get adsorbed onto their surface, forming a protein corona capable of giving to the NPs a new “identity” and determine their biological fate. Protein–nanoparticle conjugation can be used in order to promote specific interactions between living systems and nanocarriers. Non‐covalent conjugates are less stable and more susceptible to desorption in biological media, which makes the development of engineered nanoparticle surfaces by covalent attachment an interesting topic. In this work, the surface of poly(globalide‐co‐ε‐caprolactone) (PGlCL) nanoparticles containing double bonds in the main polymer chain is covalently functionalized with bovine serum albumin (BSA) by thiol‐ene chemistry, producing conjugates which are resistant to dissociation. The successful formation of the covalent conjugates is confirmed by flow cytometry (FC) and fluorescence correlation spectroscopy (FCS). Transmission electron microscopy (TEM) allows the visualization of the conjugate formation, and the presence of a protein layer surrounding the NPs can be observed. After conjugation with BSA, NPs present reduced cell uptake by HeLa and macrophage RAW264.7 cells, in comparison to uncoated NP. These results demonstrate that it is possible to produce stable conjugates by covalently binding BSA to PGlCL NP through thiol‐ene reaction.     

Nanocatalosomes as Plasmonic Bilayer Shells with Interlayer Catalytic Nanospaces for Solar‐Light‐Induced Reactions

Interest and challenges remain in designing and synthesizing catalysts with nature‐like complexity at few‐nm scale to harness unprecedented functionalities by using sustainable solar light. We introduce “nanocatalosomes”—a bio‐inspired bilayer‐vesicular design of nanoreactor with metallic bilayer shell‐in‐shell structure, having numerous controllable confined cavities within few‐nm interlayer space, customizable with different noble metals. The intershell‐confined plasmonically coupled hot‐nanospaces within the few‐nm cavities play a pivotal role in harnessing catalytic effects for various organic transformations, as demonstrated by “acceptorless dehydrogenation”, “Suzuki–Miyaura cross‐coupling” and “alkynyl annulation” affording clean conversions and turnover frequencies (TOFs) at least one order of magnitude higher than state‐of‐the‐art Au‐nanorod‐based plasmonic catalysts. This work paves the way towards next‐generation nanoreactors for chemical transformations with solar energy.     

Programmed Synthesis by Stimuli‐Responsive DNAzyme‐Modified Mesoporous SiO2 Nanoparticles

DNAzyme‐capped mesoporous SiO₂ nanoparticles (MP SiO₂ NPs) are applied as stimuli‐responsive containers for programmed synthesis. Three types of MP SiO₂ NPs are prepared by loading the NPs with Cy3‐DBCO (DBCO=dibenzocyclooctyl), Cy5‐N₃, and Cy7‐N₃, and capping the NP containers with the Mg²⁺, Zn²⁺, and histidine‐dependent DNAzyme sequences, respectively. In the presence of Mg²⁺ and Zn²⁺ ions as triggers, the respective DNAzyme‐capped NPs are unlocked, leading to the “click” reaction product Cy3‐Cy5. In turn, in the presence of Mg²⁺ ions and histidine as triggers the second set of DNAzyme‐capped NPs is unlocked leading to the Cy3‐Cy7 conjugated product. The unloading of the respective NPs and the time‐dependent formation of the products are followed by fluorescence spectroscopy (FRET). A detailed kinetic model for the formation of the different products is formulated and it correlates nicely with the experimental results.     

Synthesis and reactions of 3‐cyano‐4,6‐dimethyl‐2‐pyridone

Rapid synthesis of 3‐cyano‐4,6‐dimethyl‐2‐pyridone 3 , using piprazine as a catalyst was reported. X‐ray data of the 4,6‐dimethyl‐2‐oxo‐1,2‐dihydropyridine‐3‐carbonitrile exhibited its oxo form. Synthesis of isoquinolinecarbonitrile and pyridylpyridazine using compound 3 was investigated. Reactivity of the synthesized pyridone toward different organic reagents was also studied. J. Heterocyclic Chem., (2011).     

Developing A “Polysulfide‐Phobic” Strategy to Restrain Shuttle Effect in Lithium–Sulfur Batteries

Inspired by hydrophobic interface, a novel design of “polysulfide‐phobic” interface was proposed and developed to restrain shuttle effect in lithium–sulfur batteries. Two‐dimensional VOPO₄ sheets with adequate active sites were employed to immobilize the polysulfides through the formation of a V?S bond. Moreover, owing to the intrinsic Coulomb repulsion between polysulfide anions, the surface anchored with polysulfides can be further evolved into a “polysulfide‐phobic” interface, which was demonstrated by the advanced time/space‐resolved operando Raman evidences. In particular, by introducing the “polysulfide‐phobic” surface design into separator fabrication, the lithium–sulfur battery performed a superior long‐term cycling stability. This work expands a novel strategy to build a “polysulfide‐phobic” surface by “self‐defense” mechanism for suppressing polysulfides shuttle, which provides new insights and opportunities to develop advanced lithium–sulfur batteries.     

Dual‐Mode Controlled Self‐Assembly of TiO2 Nanoparticles Through a Cucurbit[8]uril‐Enhanced Radical Cation Dimerization Interaction

The realization of controllable multicomponent self‐assembly through reversible supramolecular interactions is a challenging goal, and is an important strategy for the fabrication of switchable nanomaterials. Herein we show that the self‐assembly of TiO₂ nanoparticles (NP) functionalized with methyl viologen can be controlled both by light irradiation and chemical reduction through cucurbit[8]uril‐enhanced radical cation dimerization interactions. Moreover, the controlled assembly and disassembly of this system are accompanied by switchable photocatalytic activity of the TiO₂ NPs, which shows potential application as a novel smart and recyclable photocatalyst.     

In Situ Synthesis of Self‐Assembled Gold Nanoparticles on Glass or Silicon Substrates through Reactive Inkjet Printing

A facile and low cost method for the synthesis of self‐assembled nanoparticles (NPs) with minimal size variation and chemical waste by using reactive inkjet printing was developed. Gold NPs with diameters as small as (8±2) nm can be made at low temperature (120 °C). The size of the resulting NPs can be readily controlled through the concentration of the gold precursor and oleylamine ink. The pure gold composition of the synthesized NPs was confirmed by energy‐dispersive X‐ray spectroscopy (EDXS) analysis. High‐resolution SEM (HRSEM) and TEM (HRTEM), and X‐ray diffraction revealed their size and face‐centered cubic (fcc) crystal structure, respectively. Owing to the high density of the NP film, UV/Vis spectroscopy showed a red shift in the intrinsic plasmonic resonance peak. We envision the extension of this approach to the synthesis of other nanomaterials and the production of tailored functional nanomaterials and devices.     

Non‐linear,cata‐Condensed,Polycyclic Aromatic Hydrocarbon Materials: A Generic Approach and Physical Properties

A generic approach to the regiospecific synthesis of halogenated polycyclic aromatics is made possible by the one‐ or two‐directional benzannulation reactions of readily available (ortho‐allylaryl)trichloroacetates (the “BHQ” reaction). Palladium‐catalysed cross‐coupling reactions of the so‐formed haloaromatics enable the synthesis of functionalised polycyclic aromatic hydrocarbons (PAHs) with surgical precision. Overall, this new methodology enables the facile mining of chemical space in search of new electronic functional materials.     

Synthesis of a Novel Oligoaniline: “Dumbbell‐Shaped” Oligoaniline

Summary: A new kind of aniline oligomer with a “dumbbell” shape was synthesized through a simple oxidative coupling reaction with a new rigid aromatic amine as starting material. The oligomer was characterized with mass spectrometry, IR and NMR spectroscopies. Its redox property was checked by cyclic voltammetry and chemical oxidation/reduction process was monitored by UV spectroscopy. We found it has a reversible electrochemical property like common oligoanilines. Combined with its well‐defined structure, it is expected to act as a model compound for a molecular electronic switch.

The “dumbbell‐shaped” oligoaniline compound synthesized here.