Activatable fluorescent probes for real-time imaging-guided tumor therapy.

Surgery and drug therapy are the two principal options for cancer treatment. However, their clinical benefits are hindered by the difficulty of accurate location of the tumors and timely monitoring of the treatment efficacy of drugs, respectively. Rapid development of imaging techniques provides promising tools to address these challenges. Compared with conventional imaging techniques such as magnetic resonance imaging and computed tomography etc., fluorescence imaging exhibits high spatial resolution, real-time imaging capability, and relatively low costs devices. The advancements in fluorescent probes further accelerate the implementation of fluorescence imaging in tumor diagnosis and treatment monitoring. In particular, the emergence of site-specifically activatable fluorescent probes fits the demands of tumor delineation and real-time feedback of the treatment efficacy. A variety of small molecule probes or nanoparticle-based probes have been developed and explored for the above-mentioned applications. This review will discuss recent advances in fluorescent probes with a special focus on activatable nanoprobes and highlight the potential implementation of activatable nanoprobes in fluorescence imaging-guided surgery as well as imaging-guided drug therapy.

Screening and identification of 3-aryl-quinolin-2-one derivatives as antiviral agents against influenza A.

Quinolin-2-one represents an important and valuable chemical motif that possesses a wide variety of biological activities; however, the anti-influenza activities of quinolin-2-one-containing compounds were rarely reported. Herein, we describe the screening and identification of 3-aryl-quinolin-2-one derivatives as a novel class of antiviral agents. The 3-aryl-quinolinone derivatives were synthesized via an efficient copper-catalyzed reaction cascade that we previously developed. Using this synthetic method, preliminary structure-activity relationships of this scaffold against the influenza A virus infection were systematically explored. The most potent compound 34 displayed IC50 values of 2.14 and 4.88 µM against the replication of H3N2 (A/HK/8/68) and H1N1 (A/WSN/33) strains, respectively, without apparent cytotoxicity on MDCK cells. We further demonstrated that 27 and 34 potently inhibited the plaque formation of the IAV, rendering this scaffold attractive for pursuing novel anti-influenza agents.

Modulating Polymerization Thermodynamics of Thiolactones Through Substituent and Heteroatom Incorporation.

A central challenge in the development of next-generation sustainable materials is to design polymers that can easily revert back to their monomeric starting material through chemical recycling to monomer (CRM). An emerging monomer class that displays efficient CRM are thiolactones, which exhibit rapid rates of polymerization and depolymerization. This report details the polymerization thermodynamics for a series of thiolactone monomers through systematic changes to substitution patterns and sulfur heteroatom incorporation. Additionally, computational studies highlight the importance of conformation in modulating the enthalpy of polymerization, leading to monomers that display high conversions to polymer at near-ambient temperatures, while maintaining low ceiling temperatures (Tc). Specifically, the combination of a highly negative enthalpy (-19.3 kJ/mol) and entropy (-58.4 J/(mol·K)) of polymerization allows for a monomer whose equilibrium polymerization conversion is very sensitive to temperature.

Alternating Cascade Metathesis Polymerization of Enynes and Cyclic Enol Ethers with Active Ruthenium Fischer Carbenes.

Ruthenium alkoxymethylidene complexes have rarely been demonstrated as active species in metathesis reactions and are frequently regarded as inert. Herein, we highlight the ability of these Fischer-type carbenes to participate in cascade alternating ring-opening metathesis polymerization through their efficient alkyne addition reactions. When enyne monomers are combined with low-strain cyclic vinyl ethers, a controlled chain-growth copolymerization occurs that exhibits high degrees of alternation (>90% alternating diads) and produces degradable poly(vinyl ether) materials with low dispersities and targetable molecular weights. This new method is amenable to the synthesis of alternating diblock polymers that can be degraded to small-molecule fragments under aqueous acidic conditions. This work furthers the potential of Fischer-type ruthenium alkylidenes in polymerization strategies and presents new avenues for the generation of functional metathesis materials.

Efficient Synthesis of Asymmetric Miktoarm Star Polymers.

Asymmetric miktoarm star polymers comprising an unequal number of chemically-distinct blocks connected at a common junction produce unique material properties, yet existing synthetic strategies are beleaguered by complicated reaction schemes that are restricted in both monomer scope and yield. Here, we introduce a new synthetic approach coined "µSTAR" - Miktoarm Synthesis by Termination After Ring-opening metathesis polymerization - that circumvents these traditional synthetic limitations by constructing the block-block junction in a scalable, one-pot process involving (1) grafting-through polymerization of a macromonomer followed by (2) in-situ enyne-mediated termination to install a single mikto-arm with exceptional efficiency. This modular µSTAR platform cleanly generates AB n and A(BA') n miktoarm star polymers with unprecedented versatility in the selection of A and B chemistries as demonstrated using many common polymer building blocks: poly(siloxane), poly(acrylate), poly(methacrylate), poly(ether), poly(ester), and poly(styrene). The average number of B or BA' arms (n) is easily controlled by the molar equivalents of macromonomer relative to Grubbs catalyst in the initial ring-opening metathesis polymerization step. While these materials are characterized by dispersity in n that arises from polymerization statistics, they self-assemble into mesophases that are identical to those predicted for precise miktoarm stars as evidenced by small-angle X-ray scattering experiments and self-consistent field theory simulations. In summary, the µSTAR technique provides a significant boost in design flexibility and synthetic simplicity while retaining the salient phase behavior of precise miktoarm star materials.

Modular Approach to Degradable Acetal Polymers Using Cascade Enyne Metathesis Polymerization.

A modular synthetic approach to degradable metathesis polymers is presented using acetal-containing enyne monomers. The monomers are prepared in a short and divergent synthetic sequence that features two points of modification to tune polymerization behavior and introduce molecular cargo. Steric and stereochemical elements are critical in the monomer design in order to provide rapid and living polymerizations capable of generating block polymers. The developed polyacetal materials readily undergo pH-dependent degradation in aqueous mixtures, and the rate of hydrolysis can be tuned through post-polymerization modification with triazolinedione click chemistry. This presents a new scaffold for responsive metathesis polymers that may find use in applications that requires controllable breakdown and release of small molecules.

Halide-Rebound Polymerization of Twisted Amides.

The first living polymerization of twisted amides is reported, achieved using simple primary alkyl iodides as initiators. Polymerization occurs through a halide-rebound mechanism in which the nucleophilic twisted amide is quaternized and subsequently ring-opened by the iodide counterion. The covalent electrophilic polymerization generates polymers with living chain ends that are both isolable and stable to ambient conditions, enabling the synthesis of block polymers. This presents a new class of polymers for study that possess high glass transition temperatures and robust thermal stability.

Relay Conjugation of Living Metathesis Polymers.

The covalent coupling of complex macromolecules is a modern challenge in both chemistry and biology. The development of efficient and chemoselective methods for polymer coupling and functionalization are increasingly important for designing new advanced materials and interfacing with biochemical systems. Herein, we present a new strategy to directly conjugate living polymers prepared using ring-opening metathesis polymerization (ROMP) to both small molecules and synthetic macromolecules. Central to this methodology is a terminal alkyne that serves as a directing group to promote a rapid, intramolecular reaction with an otherwise unreactive olefin. This highly chemoselective relay conjugation is compatible with a range of monomer families and uses a bench-stable enyne motif that can be easily introduced to functional targets. The rapid rate of the conjugation reaction paves the way for greatly streamlined construction of complex macromolecular systems derived from metathesis polymerization techniques without the need for specialized equipment.

Formation of Tertiary Alcohols from the Rhodium-Catalyzed Reactions of Donor/Acceptor Carbenes with Esters.

Rhodium(II)-catalyzed reactions between isopropyl acetate and trichloroethyl aryldiazoacetates result in the formation of oxirane intermediates that ring open under the reaction conditions to form tertiary alcohols. When the reaction is catalyzed by the dirhodium tetrakis(triarylcyclopropanecarboxylate) complex, Rh2( S-2-Cl,4-BrTPCP)4, the tertiary alcohols are formed with good asymmetric induction (80-88% ee).

Scope of the Reactions of Indolyl- and Pyrrolyl-Tethered N-Sulfonyl-1,2,3-triazoles: Rhodium(II)-Catalyzed Synthesis of Indole- and Pyrrole-Fused Polycyclic Compounds.

An efficient synthesis of tetrahydrocarboline-type products and polycyclic spiroindolines has been achieved. The transformation proceeds via rhodium(II)-catalyzed intramolecular annulations of indolyl- and pyrrolyl-tethered N-sulfonyl-1,2,3-triazoles. The reaction could be tuned toward either the formal [3 + 2] cycloaddition or the C-H functionalization reaction depending on the electronic and structural features of the substrates, leading to the production of a variety of structurally related heterocyclic compounds.

Synthesis of 2,2,2,-Trichloroethyl Aryl- and Vinyldiazoacetates by Palladium-Catalyzed Cross-Coupling.

An efficient and convenient synthesis of 2,2,2-trichloroethyl (TCE) aryl- and vinyldiazoacetates was achieved by palladium-catalyzed cross-coupling reactions between TCE diazoacetates and aryl or vinyl iodides. The broad substrate scope allows for rapid and facile formation of TCE aryl- and vinyldiazoacetates, which recently have emerged as versatile reagents for rhodium-carbene chemistry.

Rhodium(II)-Catalyzed C-H Functionalization of Electron-Deficient Methyl Groups.

Enantioselective C-H functionalization of relatively electron-deficient methyl sites was achieved with the combination of 2,2,2-trichloroethyl aryldiazoacetates and tetrakis(triarylcyclopropanecarboxylate) dirhodium catalysts. The substrate scope of the transformation was relatively broad, and C-H functionalization products were furnished with excellent levels of enantioselectivity. As a strategic reaction, crotonate derivatives give 1,6-dicarbonyl compounds, which are useful for further diversification.

One-Step Semisynthesis of a Segetane Diterpenoid from a Jatrophane Precursor via a Diels-Alder Reaction.

A novel segetane diterpenoid (1) and four jatrophane diterpenoids (2-5) were isolated from an acetone extract of Euphorbia peplus. Due to quantity limitations, we prepared 1 via a Diels-Alder reaction, an approach motivated by this compound's biosynthetic pathway and successfully performed X-ray analysis of 1. Furthermore, in an in vitro activity test, 1 exhibited moderate anti-inflammatory activity, whereas both its precursor (2) and the relevant intermediate (2a, IC50 = 1.56 µM) exhibited significant anti-inflammatory activity.

Role of ortho-substituents on rhodium-catalyzed asymmetric synthesis of ß-lactones by intramolecular C-H insertions of aryldiazoacetates.

A rhodium-catalyzed asymmetric synthesis of ß-lactones via intramolecular C-H insertion into the ester group of aryldiazoacetates has been developed. The ß-lactones were synthesized in high yields and with high levels of diastereo- and enantioselectivity. Halo and trifluoromethyl substituents at the ortho position of the aryldiazoacetates enhance intramolecular C-H insertions over intermolecular reactions, allowing C-H insertion of even methyl C-H bonds.

Copper-catalyzed tandem reactions of 1-(2-iodoary)-2-yn-1-ones with isocyanides for the synthesis of 4-oxo-indeno[1,2-b]pyrroles.

A novel copper-catalyzed tandem reaction of 1-(2-iodoaryl)-2-yn-1-ones with isocyanides is described. The reaction is through a formal [3 + 2] cycloaddition/coupling tandem process and leads to efficient formation of 4-oxo-indeno[1,2-b]pyrroles.