In Vivo Photopharmacology

Chemical Reviews, Journal Year: 2018, Volume and Issue: 118(21), P. 10710 - 10747

Published: July 9, 2018

Synthetic photoswitches have been known for many years, but their usefulness in biology, pharmacology, and medicine has only recently systematically explored. Over the past decade photopharmacology grown into a vibrant field. As photophysical, pharmacodynamic, pharmacokinetic properties of photoswitches, such as azobenzenes, become established, they applied to wide range biological targets. These include transmembrane proteins (ion channels, transporters, G protein-coupled receptors, receptor-linked enzymes), soluble (kinases, proteases, factors involved epigenetic regulation), lipid membranes, nucleic acids. In this review, we provide an overview using synthetic switches that vivo, i.e., living cells organisms. We discuss scope limitations approach study function challenges it faces translational medicine. The relationships between natural chromophores used optogenetics, caged ligands are addressed.

Language: Английский

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The Art of Building Small: From Molecular Switches to Motors (Nobel Lecture)

Angewandte Chemie International Edition, Journal Year: 2017, Volume and Issue: 56(37), P. 11060 - 11078

Published: July 27, 2017

A journey into the nano-world: The ability to design, use and control motor-like functions at molecular level sets stage for numerous dynamic systems. In his Nobel Lecture, B. L. Feringa describes evolution of field motors explains how program molecules by incorporating responsive adaptive properties. At start my uncharted territory synthetic I consider it apt emphasize joy discovery that have experienced through chemistry. beauty, structural diversity ingenious machinery life,1, 2 which evolved from a remarkably limited repertoire building blocks, offers tremendous source inspiration chemist entering However, far beyond Nature's designs, creative power chemistry provides unlimited opportunities realize our own world as we experience every day with products ranging drugs displays sustain modern society. their practice art small, chemists shown amazing successes in total synthesis natural products,3 design enantioselective catalysts4 assembly functional materials,5 mention but few developments seen over past decades. Beyond chemistry's contemporary frontiers, moving systems, explorer faces fundamental challenge motion nano-scale.6 considering first successful, albeit primitive, steps this endeavor, thoughts often turn Wright brothers demonstration flying airplane Kitty Hawk on 17th December 1903.7 Why does mankind need fly? do or machines? Nobody would predicted future one build passenger planes each carrying several hundred people close speed sound between continents. While admiring elegance bird, materials principle entirely artificial is quintessentially distinct designs. Despite fabulous advances science engineering century, manifested most clearly aircraft, are nevertheless humbled realization still cannot synthesize single cell bird even its complex biological machines. It fascinating omnipresent living systems key almost essential process transport division, muscle generation ATP fuels life processes.8 macroscopic hard imagine daily without engines machines, although drawing analogies these mechanical machines largely inappropriate. particular effect length scales should be emphasized when comparing instance robot car manufacturing plant ATPase. case size, momentum, inertia force important parameters, non-covalent interactions, conformational flexibility, viscosity, chemical reactivity dominate function.9 addition, operating low Reynolds numbers, go question "How achieve motion?" face motion"? where Brownian rules noting commonly operate ratchets,10 precisely defined translational rotary main challenge.11 Making leap while lessons itself, an ultimately out-of-equilibrium phenomena. Molecular switches perfectly suited introduce behavior, reach metastable states drive away thermal equilibrium. We focused three aspects: triggering switching, self-assembly organization, motion, perspective directed towards materials, smart among others. initial attempts intrinsic motors, took vision.12 This based elementary step, photochemical cis–trans isomerization around carbon–carbon double bond retinal chromophore (Figure 1 a). envisioned exploration simple switching information storage units elements materials. Although bi-stability can induced various input signals including light, redox reactions, pH changes, metal ion binding, temperature, stimuli, has advantages non-invasive high spatial-temporal precision.13 Building seminal work Hirshberg azobenzenes,14 Heller fulgides,15 Irie diarylethylenes16 others,17 photochromic been explored recent years group function, optical electronic properties materials,18 supramolecular processes19, 25 function.20 Optical bistable molecules. a) Retinal photoisomerization vision. b) Chiroptical switch overcrowded alkenes system. excellent photoreversibility fatigue resistance, chiral b).21 Non-destructive read-out state central aspect any potential system, was addressed taking advantage right (P)- left (M)-handed helicities enabling chiroptical techniques outside regime. interconversion two isomers chirality, is, switch, defines zero/one digital system level. high-density approach prospectful, addressing individual nanoscale closely packed all-optical device, remains solved despite spectacular single-molecule detection last decades.22 point appropriate aspects studies. Firstly formed basis genesis Ph.D. studies under guidance Hans Wijnberg biaryl atropisomers. idea twisted olefins might show atropisomerism explored, using then recently invented McMurry coupling reaction, cis- trans-isomers inherently dissymmetric (see Figure time line).23 novel structures had stilbene type immune notorious photo-cyclization stilbenes, provided stepping stone more than decade later decades light-driven motors. Secondly, alkenes, reported 1991,24 demonstrated controlled clockwise counterclockwise either direction half molecule respect other achieved simply changing wavelength irradiation. Control directionality development photoresponsive were used dopants mesoscopic cholesteric liquid crystal phases,25 well rotors26 photoswitching handedness circular polarized luminescence.27 Journey alkene 1977 led motor 1999 presentation electric (designed University Groningen 1835 Professor Sibrandus Stratingh) nanocar (developed 2011) museum Stockholm. wavelengths stereoselectivity tuned via donor–acceptor substituents. series together Harada Tohoku University, established properties, absolute configuration racemization pathways biphenanthrylidenes.28 An milestone amplification chirality light (CPL).25 Here CPL irradiation shifted equilibrium P M helices tiny imbalance amplified formation nematic crystalline phase. strengthened unidirectional possible although, Kuhn anisotropy factor such efficiency parameter will very low.29 offer behavior part functions, 30 years, wide variety both alkenes. examples discussed here illustrate areas soft biomedical applications. Modulation integrating optics electronics molecular-based devices components properly incorporated semiconductor-based For instance, diarylethene photo-switches mechanically breakjunctions enabled opto-electronic bistability initially compromised.19 designs large array fabricated inorganic semiconductor conducting polymer hybrid combination monolayers photo-switches.30 bottom-up electronics31 approaches explored.32 pioneering Heath Stoddart team rotaxane devices33 alternative azobenzenes spiropyrans spring immediately mind.34 now apparent photo- redox-switchable fertile test ground storage, sensing, electronics, imaging introduction designed undergo allows construction adapt reconfigure response external signal. redox-active bisthioxanthylidene unit core amphiphiles specifically form highly stable nanotubes 3 Following approach, self-assembled multicomponent nano-objects, vesicle-capped vesicles embedded nanotubes, obtained disassembly light.35 Slight modification photo-responsive resulted bidirectional surface tension Langmuir layers.36 Taking step further nanotube vesicle transitions illustrating responding heat fully reversible b).37 Small-molecule gelators another class studied context self-assembly. bisamide-based photoswitchable allowed modulation gel states.19, 38 intriguing light-responsive gels observation aggregates manner (in light) setting Embedding macromolecules likely provide surfaces applications drug delivery, growth coatings. Light-responsive nanoobjects. Bisthioxanthylidene-based self-assemble nanotubes. Overcrowded alkene-based transitions. nano-valve able membranes deliver demand capsules appealing target switches. Towards goal mechanosensitive channel MscL protein conductance membrane E. coli 4).39 pentamer peptide sensitive osmotic pressure opening 3–4 nm pore allowing material flow out preventing damage. Using genetic five cysteine moieties introduced specific sites constriction zone thiol attachment photoswitches. After failures proper biohybrid spiropyran reasoning light-induced rigid zwitterionic flexible merocyanine simultaneously enhancing hydrophilicity. Electrostatic repulsion enhanced propensity recruit water near anticipated result sufficient change open complex. successful incorporation functioning modified readily required extensive electrophysiology patch-clamp establish photochemically closing (using nanopore. critical came giant vesicle. Calcein efflux measurements showed upon demonstrated. Follow-up pH-sensitive channels40 photoswitches Sec-Y channels light.41 capsules, here, nanopores ample controlling delivery self-healing Giant nanopore engineered Light superb regulatory element With available activity dynamically within bypass issues associated selectivity.20, 42, 43 delivered spatial temporal precision, feature tuning action bioactive shows degree orthogonality usually toxicity attractive order regulate processes. By adjusting intensity, processes quantitative manner. term photopharmacology coined approach,42 small-molecule compounds functions; indeed activated/eactivated 5). Of course clear necessitates application biomedicine. Photodynamic therapy sophisticated fluorescence routine clinic optogenetics, neural photocleavable groups activate prodrugs precision exciting opportunities. Photopharmacology, on-off drug. ciprofloxacin-based antibiotic. c) Patterning bacterial analogue Bortezomib proteasome inhibitor. Antibiotic resistance increasingly urgent global societal problem many strategies being pursued overcome avoid it. conceptual antibiotic (cis-isomer) off (trans-isomer) azobenzene motifs quinolone-based broad spectrum antibiotics.44 photo-activation patterning plates photomask techniques. wealth organic photochromism community built up century efforts, rational stability cis-isomer modifications allow taken back precisely. proof light-activated antibiotics prospect efficacy high-precision treatment infection avoiding harmful effects beneficial bacteria organism. Arguably possibility automatically switched given after providing unconventional way fight build-up antibiotics. Having applying techniques, excited interference communication.45 Bacteria rely communication quorum sensing (QS) synchronize gene expression for, e.g., biofilm formation. N-acyl homoserine lactones, small QS auto-inducers play role Gram-negative bacteria. Two switchable identified opposite UV-irradiation bioluminescence assays coli; gaining losing trans–cis unit. These also virulence genes Pseudomonas aeruginosa light. findings new long history oncology, primarily singlet-oxygen strategies. Photoresponsive antitumor agents combined activity, imagined could function. As study Bortezomib, chemotherapeutic agent clinical use, motif.46 strong weak inhibition UV visible respectively. Instead much desired function on-switching activity. realized azobenzene-modified version SAHA, histone deacetylase (HDAC) inhibitor anti-cancer chemotherapy.47 accessible less nearly active vitro) clinically applied reverts inactive form; process, rate design. solutions mitigate severe side chemotheurapeutic agents. scenario directly acquired guide light-activation of, inaccessible tumors. course, that, prior strategies, hurdles overcome. challenges analogs, and, importantly, applied, visible/near-infrared needed enable deep tissue penetration. Recently therapeutic window interest applications.48 principles potent mast inhibitors49 nociception, human carbonic anhydrase inhibition, division others demonstrating scope photopharmacology.42, 43, 50 next arriving effective medical therapies multiple orthogonally stimuli. Recently, selective orthogonal multifunctional groups.51 there combine functions. up- down-regulation competitive (bio-)molecular networks biology systems.50 Our alkenes23 switches24 paved motor52 line 2). Chirality pertinent lines devoted magnificent phenomenon stereochemistry, fascinated me entire scientific career. Standing shoulders laureate Jacobus van't Hoff who, LeBel, founding father scholars Cram, Mislow, Prelog, Eliel, driven explore handle structure asymmetric catalysis again mother nature stage, homochirality playing Albert Eschenmoser, "Chirality Signature Life". To questions facing induce right- (clockwise) left- (counterclockwise) handed rotation nanoscale. unique stereochemistry us continue direction. 1999, 6, stereochemical elements: helical (P helicity switches) stereocenters (R S) upper lower halves52 methyl substituents, originally purpose determination, adopt pseudo-axial pseudo-equatorial orientation. Photochemical experiments revealed surprising result: helix inversion detected CD spectroscopy indicated same starting product. NMR, kinetic studies, supported calculations, "the missing isomer" sequential trans unstable cis followed cis. generated sterically crowded orientation restoring orientation, strain relieved. serendipitous 180° energetically uphill downhill inversion, quickly full cycle repeating process. four steps, ultrafast steps6, 53 rate-determining add 360° repeated times. all characteristics power-stroke motor;6, 52 achieved, fueled energy, directionality, repetitive First-generation cycle. interesting note mechanism Anabaena sensory rhodopsin related lead Olivucci.54 Again olefin photoisomerizations interconversions conformations involved emphasizing seemingly limitless number elegant achieving first-generation synthesized group55 enhance speed, shift absorption region attach groups.6, 56 Through systematic steric especially widening "fjord region" facilitate size substituents stereogenic centers, per hour seconds. noted overall speeds strongly dependent parameters energy input, quantum yield, medium confinement. issue view what extent affect behavior. pendant rods different lengths flexibility prepared thermodynamic determined.57 solvent viscosity dominant showing retardation longer arms. Analysis fraction terms free volume model displacement rather exceptionally alpha Extending excited-state dynamics cooperation teams Meech Browne, confirmed relaxation polarity-independent governed viscosity.53 developed motor-driven helicates states. double-stranded copper pioneered Lehn, rod-like (oligo-)bipyridine ligands motors.58 Upon copper(I) binding monomer oligomer aggregation assemblies. typically barriers, second uniform modification.59 stereocenter present axle generates isomer substituent higher conformation. Strain released subsequent adopting favorable rewarding program, center bearing govern

Language: Английский

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Photochromism into nanosystems: towards lighting up the future nanoworld

Chemical Society Reviews, Journal Year: 2017, Volume and Issue: 47(3), P. 1044 - 1097

Published: Dec. 18, 2017

This review provides a state-of-the-art account of photochromism into diverse functional nanosystems such as nanomachines, nanoparticles, nanoelectronics, nanoassemblies and biological nanosystems.

Language: Английский

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Fluorogenic probes for disease-relevant enzymes

Chemical Society Reviews, Journal Year: 2018, Volume and Issue: 48(2), P. 683 - 722

Published: Dec. 6, 2018

Traditional biochemical methods for enzyme detection are mainly based on antibody-based immunoassays, which lack the ability to monitor spatiotemporal distribution and, in particular, situ activity of enzymes live cells and vivo. In this review, we comprehensively summarize recent progress that has been made development small-molecule as well material-based fluorogenic probes sensitive activities related a number human diseases. The principles utilized design these their applications reviewed. Specific attention is given have developed analysis including oxidases reductases, those act biomacromolecules DNAs, proteins/peptides/amino acids, carbohydrates lipids, responsible translational modifications. We envision review will serve an ideal reference practitioners beginners relevant research fields.

Language: Английский

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Advances and opportunities in the exciting world of azobenzenes

Nature Reviews Chemistry, Journal Year: 2021, Volume and Issue: 6(1), P. 51 - 69

Published: Nov. 18, 2021

Language: Английский

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Recent Implementations of Molecular Photoswitches into Smart Materials and Biological Systems

Chemistry - A European Journal, Journal Year: 2019, Volume and Issue: 25(20), P. 5128 - 5144

Published: Jan. 8, 2019

Light is a nearly ideal stimulus for molecular systems. It delivers information encoded in the form of wavelengths and their intensities with high precision space time. mild trigger that does not permanently contaminate targeted samples. Its energy can be reversibly transformed into motion, polarity, or flexibility changes. This leads to sophisticated functions at supramolecular macroscopic levels, from light-triggered nanomaterials photocontrol over biological New methods adapters light are reported almost daily. Recently applications photoresponsive systems, particularly azobenzenes, spiropyrans, diarylethenes, indigoids, smart materials setups described herein aim demonstrate 21st century has become Age Enlightenment-"Le siècle des Lumières"-in sciences.

Language: Английский

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Photocontrol of Antibacterial Activity: Shifting from UV to Red Light Activation

Journal of the American Chemical Society, Journal Year: 2017, Volume and Issue: 139(49), P. 17979 - 17986

Published: Nov. 14, 2017

The field of photopharmacology aims to introduce smart drugs that, through the incorporation molecular photoswitches, allow for remote spatial and temporal control bioactivity by light. This concept could be particularly beneficial in treatment bacterial infections, reducing systemic environmental side effects antibiotics. A major concern realization such light-responsive is wavelength light that applied. Studies on photocontrol biologically active agents mostly rely UV light, which cytotoxic poorly suited tissue penetration. In our efforts develop photoswitchable antibiotics, we here antibacterial whose activity can controlled visible while getting into therapeutic window. For purpose, a UV-light-responsive core structure based diaminopyrimidines with suitable properties was identified. Subsequent modification an azobenzene photoswitch moiety led structures allowed us their against Escherichia coli both directions region. first time, full situ presence bacteria attained green violet Most remarkably, one revealed at least 8-fold difference before after irradiation red 652 nm, showcasing effective "activation" biological agent otherwise inactive within investigated concentration range, doing so

Language: Английский

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Molecular photoswitches in aqueous environments

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 50(22), P. 12377 - 12449

Published: Jan. 1, 2021

Molecular photoswitches are inherently lipophilic and do not spontaneously dissolve in water. We describe the effect of water on photochemical properties strategies to solubilize organic apply them aqueous media.

Language: Английский

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Photoswitchable molecules as key ingredients to drive systems away from the global thermodynamic minimum

Chemical Society Reviews, Journal Year: 2017, Volume and Issue: 46(18), P. 5536 - 5550

Published: Jan. 1, 2017

We highlight the unique features of photodynamic equilibria that drive chemical reactions and transport, structure formation molecular motion.

Language: Английский

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The (photo)chemistry of Stenhouse photoswitches: guiding principles and system design

Chemical Society Reviews, Journal Year: 2018, Volume and Issue: 47(6), P. 1910 - 1937

Published: Jan. 1, 2018

Stenhouse switches are a novel class of photoswitches with great potential for visible-light-controlled applications.

Language: Английский

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