ACS Combinatorial Science最新文献

Signaling cascades are crucial for transducing stimuli in biological systems, enabling multiple stimuli to regulate a downstream target with precisely controlled timing and amplifying signals through a series of intermediary reactions. Developing a robust signaling system with such capabilities would be pivotal for programming complex behaviors in synthetic DNA-based molecular devices. However, although “software” such as nucleic acid circuits could potentially be harnessed to relay signals to DNA-based nanostructure hardware, such explorations have been limited. Here, we develop a platform for transducing a variety of stimuli via messenger-mediated reactions to regulate the release and reloading of gold nanoparticles (AuNPs) in a 3D DNA framework. In the first step, an in vitro transcription circuit is engineered to sense and amplify chemical stimuli, including arbitrary DNA sequences and proteins, producing RNA. In the second step, the RNA releases the DNA-coated AuNPs from the DNA framework via a strand displacement reaction. AuNP reloading is controlled by a separate step driven by degradation of the RNA. Our platform holds promise for applications requiring dynamic multiagent control over DNA-based devices, offering a versatile tool for advanced molecular device engineering.

A novel structural motif for luminescent chiral crystalline molecular rotors with chiroptical properties correlated with the rotational motion in crystalline media is presented. This scaffold incorporates bulky chiral caps consisting of a homochiral binaphthyl moiety with a triisopropylsilyl (TIPS) group into triaryltriazine, as confirmed by single-crystal X-ray diffraction (XRD) analysis. Variable-temperature solid-state ²H NMR studies revealed a 4-fold rotation of the phenylenes occurred in the rotor crystal between 263 and 333 K, while a steric rotor analogue shows no rotational motion. Notably, a reduction in the dihedral angle of the binaphthyl moiety upon heating was observed in the chiral rotors, and a corresponding alteration of the circular dichroism (CD) signal was detected in the solid-state, while those of the steric rotors showed no alteration by the temperature change. We propose that the fast rotation of the phenyl rings affects the motion of neighboring isopropyl groups, leading to steric repulsion with the binaphthyl moieties and thereby inducing its conformational change. Furthermore, the chiral rotors exhibited circularly polarized phosphorescence in the solid-state at low temperature, originating from rotational displacement of the phenylene on triphenyltriazine during structural relaxation in the excited state. Meanwhile, the steric rotors showed significant circularly polarized fluorescence induced by the suppressed molecular motion via a sterically hindered lattice environment in the excited state. These results indicate that the bulky chiral cap introduced into the triaryltriazines, acting as a luminescent chiral crystalline molecular rotor, can be a useful scaffold for the modulation of solid-state chiroptical properties via molecular rotational motions.

Stereoselective reduction of dehydroamino acids is a common biosynthetic strategy to introduce d-amino acids into peptidic natural products. The reduction, often observed during the biosynthesis of lanthipeptides, is performed by dedicated dehydroamino acid reductases (dhAARs). Enzymes from the three known dhAAR families utilize nicotinamide, flavin, or F₄₂₀H₂ coenzymes as hydride donors, and little is known about the catalysis performed by the latter family proteins. Here, we perform a bioinformatics-guided identification and large-scale in vitro characterization of five F₄₂₀H₂-dependent dhAARs. We construct an mRNA display-based pipeline for ultrahigh throughput substrate specificity profiling of the enzymes. The pipeline relies on a 4-track selection strategy to deliver large quantities of clean data, which were leveraged to build accurate substrate fitness models. Our results identify a remarkably promiscuous enzyme, referred to as MaeJ_C, that is capable of installing d-Ala residues into arbitrary substrates with minimal recognition requirements. We integrate MaeJ_C into a thiopeptide biosynthetic pathway to produce d-amino acids-containing thiopeptides, demonstrating the utility of MaeJ_C for the programmable installation of d-amino acids in ribosomal peptides.

Meat discoloration is one of the challenges facing the food industry, which affects both quality and shelf life. In this report, we present our groundbreaking discovery of electrochemically probing specific redox peaks associated with meat discoloration and successfully monitor its delay when controlled biochemically with added antioxidants. We have validated the redox features by spectrophotometry measurements of the relative levels of oxymyoglobin, which gives meat its cherry red color, and metmyoglobin, which causes the meat to turn brown in relation to discoloration. The insights from this research open up new avenues for the development of innovative electroanalytical tools for studying meat color and quality. These new tools could potentially minimize nutritious beef waste, lessen the environmental burden associated with waste disposal, and reduce CO₂ emissions linked to discoloration issues.

The optimization of hit compounds into drug candidates is a pivotal phase in drug discovery but often hampered by cumbersome manual synthesis of derivatives. While automated organic molecule synthesis has enhanced efficiency, safety, and cost-effectiveness, achieving fully automated multistep synthesis remains a formidable challenge due to issues such as solvent and reagent incompatibilities and the accumulation of side-products. We herein demonstrate an automated solid-phase flow platform for synthesizing α-keto-amides and nitrile peptidomimetics, guided by docking simulations, to identify potent broad-spectrum antiviral leads. A compact parallel synthesizer was built in-house, capable of producing 5 distinct molecules per cycle; 525 reactions could be finished within three months to generate 42 derivatives for a structure–activity relationship (SAR) investigation. Among these, ten derivatives exhibited promising target inhibitory activity (IC₅₀ < 100 nM) including two with antiviral activity (EC₅₀ < 250 nM). The platform, coupled with digital chemical recipe files, offers rapid access to a wide range of peptidomimetics, serving as a valuable reservoir for broad-spectrum antiviral candidates. This automated solid-phase flow synthesis approach expedites the generation of previously difficult complex molecular scaffolds. By integration of SPS-flow synthesis with medicinal chemistry campaign, >10-fold target inhibitory activity was achieved from a small set of derivatives, which indicates the potential to shift the paradigm of drug discovery.

Molecules that contain bonds whose length significantly deviates from the average are of interest in the context of understanding the nature and limits of the chemical bonds. However, it is difficult to disentangle the individual contributions of the multiple factors that give rise to such bond-length deviations as reports on such molecules remain scarce. In the present study, we have succeeded in synthesizing hexafluorodihalocubanes of the type C₈F₆X₂ (2) (X = Cl (2_Cl), Br (2_Br), I (2_I)), which represent a new series of molecules with unusual C(sp³)–halogen bonds. The C(sp³)–halogen bonds of 2_Cl, 2_Br, and 2_I, determined via single-crystal X-ray diffraction analysis, are approximately 0.07–0.09 Å shorter than typical C(sp³)–halogen bonds. In particular, the carbon–iodine bonds of 2_I are the shortest C(sp³)–I bonds reported to date. The solution-state structures and electronic states of the C(sp³)–halogen bonds in these hexafluorodihalocubanes were analyzed by X-ray absorption spectroscopy, which revealed detailed information on the length of these C(sp³)–halogen bonds in solution and the solid state as well as on the electron-deficient nature of 2. Detailed theoretical calculations and a comparison with halotrinitromethanes (1), which represent another series of molecules with shortened C(sp³)–halogen bonds, revealed that the factors responsible for the shortening of the C(sp³)–halogen bond vary among the different C(sp³)–halogen bonds, i.e., for C(sp³)–Cl and C(sp³)–Br, the s-character and hyperconjugation effects predominate, whereas for C(sp³)–I, the interatomic Coulombic interaction effect prevails.

Aryl-substituted aliphatic amines are widely recognized as immensely valuable molecules. Consequently, the development of practical strategies for the construction of these molecules becomes increasingly urgent and critical. Here, we have successfully achieved multifunctionalization reactions of alkenyl alcohols in a sequential relay process, which enables transformation patterns of arylamination, deuterated arylamination, and methylenated arylamination to the easy access of multifarious arylalkylamines. Notably, a novel functionalization mode for carbonyl groups has been developed to facilitate the processes of deuterium incorporation and methylene introduction, thereby providing new means for the diverse transformations of carbonyl groups. This methodology displays a wide tolerance toward functional groups, while also exhibiting good applicability across various skeletal structures of alkenols and amines.

Prior studies of the solution conformation of the Lewis^x (Le^x) trisaccharide, αFuc-(1→3)[βGal-(1→4)]-βGlcNAc, suggest that nonclassical inter-residue C–H···O hydrogen bonding in aqueous solution contributes to the stabilization of its 3D structure and affects its biological properties. Experimental evidence for this hydrogen bond in aqueous solution has been reported in the form of a ^4hJ_CHOCH NMR spin-coupling constant between C5′Fuc and H1″Gal measured by 2D NMR methods in unlabeled samples. A methyl glycoside of Le^x (MeβLe^x) was prepared containing selective ¹³C-labeling at C5′Fuc, and the H1″Gal signal was examined in high-field ¹H NMR spectra for evidence of splitting or line-broadening caused by the ¹³C at C5′Fuc. High-resolution ¹H NMR spectra obtained at high field and at different temperatures using different FID processing parameters showed no resolved splitting of the H1″Gal signal or evidence of line-broadening. Spectral simulation showed that this splitting and/or line-broadening would be observable if the reported J-value (∼1.1 Hz) is correct. DFT calculations on MeβLe^x and a carbon analog (O5″Gal replaced by a CH₂ group) gave very small and nearly identical calculated ^4hJ_C5′,H1″ values, suggesting that the coupling is essentially zero. DFT calculations also showed that an alternate inter-residue ^3hJ_H5′,H1″ is small. Based on NMR analyses and DFT calculations, we found that ^4hJ_C5′,H1″ in MeβLe^x has an upper limit of ∼0.4 Hz and that the value could be lower, possibly zero, calling into question its value as experimental proof of persistent nonclassical hydrogen bonding in aqueous solutions of MeβLe^x and related structures.

During the electrochemical CO₂ reduction reaction (eCO₂RR) on copper catalysts, linear-bonded CO (*CO_L) is commonly regarded as the key intermediate for the CO-CO coupling step, which leads to the formation of multicarbon products. In this work, we unveil the significant role of bridge-bonded *CO (*CO_B) as an active species. By combining in situ Raman spectroscopy, gas and liquid chromatography, and density functional theory (DFT) simulations, we show that adsorbed *OH domains displace *CO_L to *CO_B. The electroreduction of a ¹²CO+¹³CO₂ cofeed demonstrates that *CO_B distinctly favors the production of acetate and 1-propanol, while *CO_L favors ethylene and ethanol formation. This work enhances our understanding of the mechanistic intricacies of eCO₍₂₎RR and suggests new directions for designing operational conditions by modifying the competitive adsorption of surface species, thereby steering the reaction toward specific multicarbon products.

The recent emergence of organometallic chemistry for modification of biomolecular nanostructures has begun to rewrite the long-standing assumption among practitioners that small-molecule organometallics are fundamentally incompatible with biological systems. This Perspective sets out to clarify some of the existing misconceptions by focusing on the growing organometallic toolbox for biomolecular modification. Specifically, we highlight key organometallic transformations in constructing complex biologically relevant systems on the nanomolecular scale, and the organometallic synthesis of hybrid nanomaterials composed of classical nanomaterial components combined with biologically relevant species. As research progresses, many of the challenges associated with applying organometallic chemistry in this context are rapidly being reassessed. Looking to the future, the growing utility of organometallic transformations will likely make them more ubiquitous in the construction and modification of biomolecular nanostructures.