Metal-promoted synthetic chemistry within living cells

Bioorthogonal chemistry refers to the set of chemical reactions that can be used in vivo for covalent modification biomolecules and biopolymers.Most these rely on metal-free cycloadditions use tailored, strained reactants; therefore, their scope terms synthetic potential versatility is limited.A crescent number examples demonstrate organometallic catalysts also implemented biological environments, yet with modest efficiencies mainly uncaging/deprotection processes.Metal-promoted bioorthogonal transformations involving bond-forming, processes, are now starting see light.Considering enormous breadth catalysis chemistry, this emerging field promises have a profound impact biology biomedicine. The ability perform 'new-to-nature' within living cells organisms transforming way which scientists interrogate and/or manipulate processes. In recent years, toolbox cell-compatible has been enriched incorporation transition metal-mediated Whereas efficiency still low, generality significantly chemistry. Particularly attractive possibility using performing synthetically relevant reactions, as could allow assembly biorelevant products at specific sites. Cells complex factories thousands perfectly orchestrated provide food energy required life. These either break (catabolic) or build (anabolic) functional molecules most them promoted by enzymes (see Glossary), nature [1.Nelson D.L. Cox M.M. Lehninger Principles Biochemistry: International Edition.7th edn. W.H. Freeman, 2021Google Scholar]. Enzymes exhibit excellent rates turnovers present impressive selectivity orthogonality, even under environment organisms. However, evolved catalyze only those and, they usually limited generality. contrast, human-invented catalysts, especially based metals, tend much more general promote an impressively broad range well beyond [2.Chanda A. Fokin V.V. Organic synthesis “on water” Chem.Rev. 2009; 109: 725-748Google Scholar,3.Crabtree R.H. Organometallic Chemistry Transition Metals.6th Wiley, 2014Crossref Scopus (612) Google shortcomings when compared enzymes, such inferior kinetics, poorer usual requirement water- oxygen-free atmospheres prevent deactivation catalyst [4.Cornils B. Herrman W.A. Aqueous-Phase Catalysis.2nd 2004Crossref there increasing reports demonstrating operate conditions, (Figure 1A ) [5.Seoane Mascareñas J.L. Exporting homogeneous metal habitats.Eur. J. Org. Chem. 2022; 32e202200118Google Scholar, 6.Destito P. et al.Transition metal-promoted aqueous media settings.Chem. Eur. 2021; 27: 4789-4816Crossref PubMed (38) 7.Liang T. al.Bioorthogonal biomedical applications.Trends 4: 157-167Abstract Full Text PDF (11) Scholar], although so far studied consist processes [8.Wang al.Unleashing power bond cleavage systems.ACS Cent. Sci. 7: 929-943Crossref (61) Scholar,9.Van de L‘Isle, M.O.N. bioactive agents.Curr. Opin. Biol. 61: 32-42Crossref (44) Transformations namely, building large, from smaller exogenous reactants 1B), light [10.Nguyen D.P. al.Tools methods investigating metal-catalyzed cells.ACS Catal. 11: 5148-5165Crossref (15) types intrinsically fundamental conceptual perspective, but promise yield applications medicine, synthesize compounds designed situ. manuscript, we will review discuss progress translating 'synthetic' cellular presenting brief perspective nascent/emerging A classical enduring endeavor development enable chemoselective proteins other biomolecules. This requires appropriate engineering groups well-paired, orthogonal reactivity [11.Tian Y. Lin Q. Fitness factors probes.ACS 2019; 14: 2489-2496Crossref (29) conditions chemoselectivity orthogonality challenging considering live cells, because reaction vessels, crowded interfere desired reactivity. Moreover, highly compartmentalized, further hamper necessary collision between branch science devoted inventing studying biocompatible, non-natural proceed effectively complex, biomolecular soup called [12.Hang H.C. al.A metabolic labeling approach toward proteomic analysis mucin-type O-linked glycosylation.Proc. Natl. Acad. U. S. 2003; 100: 14846-14851Crossref (393) 13.Patterson D.M. al.Finding right (bioorthogonal) chemistry.ACS 2014; 9: 592-605Crossref (514) 14.Scinto S.L. chemistry.Nat. Rev. Methods Primers. 1: 30Crossref term was coined C. Bertozzi 2003 working tools study glycans organism relevance recognized 2022 Nobel prize awarded Bertozzi. From very beginning, explored consisted conjugations modify biopolymers exhibiting reactive sites [15.Mahal L.K. al.Engineering cell surfaces through oligosaccharide biosynthesis.Science. 1997; 276: 1125-1128Crossref (613) 16.Bertozzi C.R. Saxon E. Cell surface modified Staudinger reaction.Science. 2000; 287: 2007-2010Crossref (1875) 17.Sletten E.M. chemistry: fishing sea functionality.Angew. Int. Ed. 48: 6974-6998Crossref (2221) 18.Sletten mechanism mouse: tale two reactions.Acc. Res. 2011; 44: 666-676Crossref (765) were essentially restricted extracellular An obvious sort copper-catalyzed azide-alkyne cycloaddition (CuAAC). benchmarking Click deserved recognition M. Meldal Sharpless (https://www.nobelprize.org/prizes/chemistry/2022/press-release/). fitted almost owing its high rate selectivity, copper bound tris-triazole ligands 2A [19.Chan T.R. al.Polytriazoles copper(I)-stabilizing catalysis.Org. Lett. 2004; 6: 2853-2855Crossref (1376) Scholar,20.Medal Diness F. Recent fascinating aspects CuAAC click reaction.Trends 2020; 2: 569-584Abstract (92) redox lability toxicity somewhat discouraged settings [21.Kennedy D.C. al.Cellular consequences complexes reactions.J. Am. Soc. 133: 17993-18001Crossref (281) Scholar,22.Gaetke L.M. al.Copper toxicity, oxidative stress, antioxidant nutrients.Toxicology. 189: 147-163Crossref (1523) Scholar] alternatives (metal-free) pursued. efforts led strain-promoted (SPAAC) 2B), slower than [23.Agard N.J. [3+2] systems.J. 126: 15046-15047Crossref (1912) Scholar,24.Beatty K.E. al.Live-cell imaging cycloaddition.ChemBioChem. 2010; 2092-2095Crossref (117) faster alternative inverse electron-demand Diels-Alder (IEDDA), 1,2,4,5-tetrazine alkyne/alkene 2C). [4+2] shows kinetics thus it widely used, mice [25.Oliveira B.L. al.Inverse electron demand biology.Chem. 2017; 46: 4895-4950Crossref Despite success energetic may generate problems side options externally controlling limited. context, stable until react catalyst, offer higher transformative potential. preliminary example viability environments published 1985, Cséplö coworkers reported hydrogenation unsaturated fatty acids presence mesophyll protoplast plant water-soluble ruthenium process showed severe [26.Vigh L. al.Modulation membrane fluidity protoplasts Nicotiana plumbaginifolia catalytic hydrogenation.Eur. Biochem. 1985; 146: 241-244Crossref It not 2000s really took off discovery reaction. next groundbreaking advance group Meggers 2006 [27.Streu Ruthenium-induced allylcarbamate cells.Angew. 2006; 45: 5645-5648Crossref (195) They claimed Cp*RuCl(COD) allylcarbamates release parent amines, cytoplasm mammalian 2D). Later, same found out 2-carboxyquinoline-based Ru efficient similar [28.Völker al.Progress towards compounds.Angew. 53: 10536-10540Crossref (184) 2014, demonstrated transformation applied controlled DNA binders inside [29.Sánchez M.I. al.Metal-catalyzed uncaging DNA-binding agents cells.Chem. 5: 1901-1907Crossref results sparked new research area significant related deprotections [30.Latocheski Mechanistic insights into reactions.Chem. 49: 7710-7729Crossref 31.Tomás-Gamasa mitochondria cells.Nat. Commun. 2016; 12538Crossref (126) 32.Sing N. al.Iridium-triggered cells.Inorg. 60: 12644-12650Crossref (7) Although employ discrete salts complexes, some important contributions metal-supported nanoparticles (NPs) [33.Tonga G.Y. al.Supramolecular regulation nanoparticle-embedded catalysts.Nat. 2015; 597-603Crossref (315) 34.Pérez-López A.M. al.Gold-triggered systems.Angew. 56: 12548-12552Crossref (104) 35.Zhang X. al.Intracellular activation nanozymes endosomal proteolysis protein corona.ACS Nano. 4767-4773Crossref (47) metal–organic frameworks (MOFs) [36.Martínez R. al.Core-shell palladium/MOF platforms diffusion-controlled nanoreactors tissue models.Cell. Rep. Phys. 1100076PubMed Scholar,37.Carrillo-Carrión al.Plasmonic-assisted thermocyclizations framework nanoreactors.ACS 15: 16924-16933Crossref artificial metalloenzymes [38.Okamoto cell-penetrating metalloenzyme regulates gene switch designer cell.Nat. 2018; 1943Crossref (75) 39.Szponarski al.On-cell metalloenzyme.Commun. 84Crossref (30) 40.Learte-Aymamí bis(histidine) miniproteins stapled palladium(II) complexes.Angew. 59: 9149Crossref (41) published. As highlighted earlier, advances trying merge deal deprotection/cleavage Reactions substrates bond-forming aimed settings, less explored. Initial dealing focused modifications on/in bacteria [41.Link A.J. Tirrel Escherichia coli via copper(I)-catalyzed cycloaddition.J. 125: 11164-11165Crossref (550) Scholar,42.Yang al.Biocompatible enabled compartment-specific pH measurement coli.Nat. 4981Crossref (81) [43.Beatty al.Fluorescence visualization newly synthesized 7364-7367Crossref (229) Scholar,44.Bevilacqua V. al.Copper-chelating azides conjugation media.Angew. 5872-5876Crossref (103) intracellular triazoles reactants. sense, 2016 Zimmerman copper-containing NPs antimicrobial tristriazoles bacteria, fluorescent tristriazol-coumarin NCI-H460 MDA-MB-231 3A [45.Bai single-chain metal-organic nanoparticle alkyne-azide “click” water cells.J. 138: 11077-11080Crossref (150) Apparently, embedding polymeric scaffolds key catalysis. Nonetheless, shown coworkers. authors 2018 predefined tristriazole trispyrazole Cu(I) coupling added anthracenyl alkynes, without apparent [46.Miguel-Ávila al.Discrete annulations small 1947-1952Crossref Another interesting application Zhang possible make analog stilbenoid combretastatin A4, tubulin polymerization inhibitor, HeLa crosslinked lipoic acid doped 3B) [47.Huang al.Nanocopper-doped cross-linked morphology-dependent catalysis.ACS 8: 5941-5946Crossref (26) drug-analog strategy Qu compound mimicking apoptotic agent resveratrol, MCF-7 reagents trapped water-compatible MOFs 3C) [48.Wang biocompatible heterogeneous MOF-Cu drug targeted subcellular organelles.Angew. 58: 6987-6992Crossref (115) cellulo generation resveratrol mimetic considerable decrease viability, directly incubated drug. Qu’s triggered photoactivable Cu(0) mesoporous carbon nanospheres [49.You al.Neat-infrared dual-promoted nanocatalyst vivo.ACS 4178-4187Crossref (48) Under NIR irradiation, systems induce production oxygen species (ROS), copper(I) nematodes mice. expanded strategies different anticancer therapy [50.Zhao al.NIR-II leveraged dual orthotopic combination therapy.ACS 16: 20353-20363Crossref (4) 51.You al.DNA-based platform precisely systems.Nat. 13: 1459Crossref (20) 52.Wang Z. bimetallic encapsulated DNAzyme self-sufficient therapy.Angew. 12431-12437Crossref (46) All confirm 'in cellulo' long-term implications applications. Metal-catalyzed cross-couplings (Sonogashira, Suzuki-Miyaura, etc.) among organic Considering tolerate matter time before methodologies biologically conditions. modifying bacterial proteins, palladium [53.Li al.Copper-free Sonogashira cross-coupling functionalization alkyne-encoded medium 15316-15319Crossref (202) 54.Li al.Ligand-free palladium-mediated site-specific gram-negative pathogens.J. 2013; 135: 7330Crossref 55.Li genetically encoded alkyne directs surface.ACS 10: 379-384Crossref (36) 2011, Bradley Unciti-Broceta Pd(0)-NPs boronic esters fluorescein derivative featuring alkenyl triflate moiety, 4A [56.Yusop R.M. al.Palladium-mediated 3: 239-243Crossref (370) later described coworkers, Pd-NPs embedded microporous silica nanostructures functionalized photoresponsive azobenzene units [57.Wang al.Designed reversible light-controlled 1209Crossref (109) Discrete likely tendency deactivated media. Tian recently Pd(OAc)2/TPPTS localized push–pull fluorophore HepG2 [58.Li situ light-up fluorophores Suzuki-Miyaura cross-coupling.Chin. 33: 4223-4228Crossref Finally, example, Rappsilber employed salicylate Pd-based metallopeptide A549 linifanib [59.Pérez-López al.Dual-bioorthogonal peptide complex.J. Med. 2023; 66: 3301-3311Crossref (1) Importantly, performed better Pd able propargylated microtubule inhibitor linifanib, synergetic therapeutic effect. nice Weissleder aminocoumarins HT1080 intramolecular Heck [60.Miller M.A. Nano-palladium 15906Crossref (166) For successful outcome, had polymer, improves stability uptake. Overall, viable, scarce. Along cross-coupling, metathesis C–C Ruthenium carbene long known quite compatible water. regard, 2016, Ward streptavidin bearing second-generation Hoveyda-Grubbs attached biotinylated moiety ring-closing (RCM) coumarins 4B). needs carried periplasm avoid native thiols [61.Jeschek al.Directed evolution metathesis.Nature. 537: 661-665Crossref Ru-promoted Michel. BODIPY-based ethylene allyl alcohols cross-metathesis [62.Toussaint S.N.W. al.Olefin metathesis-based probes selective detection 140: 13151-13155Crossref (34) sensing rather 2019, Tanaka addressed passivation issues developing coumarin located hydrophobic pocket albumin protein. resulting hybrid initially coumarin-based umbelliprenin RCM, lines, disturbing endogenous [63.Eda al.(2019) Biocompatibility glycosylated metalloenzymes.Nat. 780-792Crossref (77) methodology adapted biosensing fruits plants [64.Vong K. al.An biosensor detect gas Arabidopsis leaves.Nat. 5746Crossref system A4 several cancer lines circulatory xenografted 4C) [65.Nasibullin I. al.Synthetic prodrug design enables biocatalytic elicit tumor growth suppression.Nat. 39Crossref (18) first new-to-nature photoautotrophic (microalgae) Mecking advantage amounts cyclic alkyl amino carbene-based [66.Schunck N.S. olefin microalgae upgrades lipids blocks polymers chemicals.Angew. 61e202211285Crossref (3) Altogether, indicate Ru-based olefin-metathesis carry formations, scaffolds. Further appear coming years. Gold well-known π potential, bind activate groups, manner. alkynes uncommon nature, gold seems media, problem. initial demonstration gold-promoted 2009, fluorogenic Au(III) [67.Yang gold(III) ion-selective probe bioimagings.Org. 5610-5613Crossref (125) Other [68.Do J.H. rationally fluorescence turn-on ion.Org. 12: 932-934Crossref (145) Scholar,69.Patil N.T. al.Exploiting alkynophilicity Au-species: ions.Chem. 2012; 11229-11231Crossref (58) oxazole [70.Jou M.J. al.Highly Au3 cyclization propargylamide.Chem. : 7218-7220PubMed Scholar,71.Egorova O.A. al.Reaction-based Au(I)/Au(III) species: mechanistic vinylgold intermediates.Org. 401-403Crossref (122) after gold-catalyzed