AsqJ, an iron(II)‐ and 2‐oxoglutarate‐dependent enzyme found in viridicatin‐type alkaloid biosynthetic pathways, catalyzes sequential desaturation and epoxidation to produce cyclopenins. Crystal ...structures of AsqJ bound to cyclopeptin and its C3 epimer are reported. Meanwhile, a detailed mechanistic study was carried out to decipher the desaturation mechanism. These findings suggest that a pathway involving hydrogen atom ion at the C10 position of the substrate by a short‐lived FeIV‐oxo species and the subsequent formation of a carbocation or a hydroxylated intermediate is preferred during AsqJ‐catalyzed desaturation.
Make it a double: The mechanism of the desaturation catalyzed by AsqJ, a non‐heme iron enzyme, was elucidated using a complementary approach including probe design, X‐ray crystallography, molecular dynamics simulations, and spectroscopic characterizations. Subsequent to primary C−H bond activation, a carbocation or a hydroxylated intermediate is likely to be involved in the desaturation.
The novel coronavirus disease (COVID-19) pandemic remains a global public health crisis, presenting a broad range of challenges. To help address some of the main problems, the scientific community ...has designed vaccines, diagnostic tools and therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rapid pace of technology development, especially with regard to vaccines, represents a stunning and historic scientific achievement. Nevertheless, many challenges remain to be overcome, such as improving vaccine and drug treatment efficacies for emergent mutant strains of SARS-CoV-2. Outbreaks of more infectious variants continue to diminish the utility of available vaccines and drugs. Thus, the effectiveness of vaccines and drugs against the most current variants is a primary consideration in the continual analyses of clinical data that supports updated regulatory decisions. The first two vaccines granted Emergency Use Authorizations (EUAs), BNT162b2 and mRNA-1273, still show more than 60% protection efficacy against the most widespread current SARS-CoV-2 variant, Omicron. This variant carries more than 30 mutations in the spike protein, which has largely abrogated the neutralizing effects of therapeutic antibodies. Fortunately, some neutralizing antibodies and antiviral COVID-19 drugs treatments have shown continued clinical benefits. In this review, we provide a framework for understanding the ongoing development efforts for different types of vaccines and therapeutics, including small molecule and antibody drugs. The ripple effects of newly emergent variants, including updates to vaccines and drug repurposing efforts, are summarized. In addition, we summarize the clinical trials supporting the development and distribution of vaccines, small molecule drugs, and therapeutic antibodies with broad-spectrum activity against SARS-CoV-2 strains.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Dicyclopentaghi,pqrperylene (DCPP) is a substructural fragment on the surface of C70 yet not on C60. Unlike its intensely investigated buckybowl cousins, corannulene and sumanene, DCPP is largely ...ignored due to the lack of synthetic accessibility. This communication describes the first preparation of a DCPP derivative from bay substituted perylene bis(4-(trifluoromethyl)phenyl)methanol as the key cyclization precursor. Further incorporation of indeno substitutions at peri positions was accomplished through Suzuki–Heck benzannulation. DCPP derivatives 4 adopts a planar structure in crystal. On the contrary, indeno DCPP 5 and bis-indeno DCPP 6 adopt the bowl-shaped conformation in both the solid state and solution. Density functional theory (DFT) calculation reveals that the lowest-energy conformations of 4, 5, and 6 are all bowl-shaped. Nevertheless, small bowl-to-bowl inversion barrier for 4 (3.4 kcal/mol) is overcome by the crystal packing force, which leads to its observed planar structure. However, the bowl-shaped structures of 5 and 6 are affirmed by DFT calculation with intermediate and high bowl-to-bowl inversion barriers (10.4 and 18.5 kcal/mol, respectively).
Two non-heme iron enzymes, IsnB and AmbI3, catalyze a novel decarboxylation-assisted olefination to produce indole vinyl isonitrile, an important building block for many natural products. Compared to ...other reactions catalyzed by this enzyme family, decarboxylation-assisted olefination represents an attractive biosynthetic route and a mechanistically unexplored pathway in constructing a CC bond. Using mechanistic probes, transient state kinetics, reactive intermediate trapping, spectroscopic characterizations, and product analysis, we propose that both IsnB and AmbI3 initiate stereoselective olefination via a benzylic C–H bond activation by an Fe(IV)–oxo intermediate, and the reaction likely proceeds through a radical- or carbocation-induced decarboxylation to complete CC bond installation.
Mechanisms of enzymatic epoxidation via oxygen atom transfer (OAT) to an olefin moiety is mainly derived from the studies on thiolate-heme containing epoxidases, such as cytochrome P450 epoxidases. ...The molecular basis of epoxidation catalyzed by nonheme-iron enzymes is much less explored. Herein, we present a detailed study on epoxidation catalyzed by the nonheme iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase, AsqJ. The native substrate and analogues with different para substituents ranging from electron-donating groups (e.g., methoxy) to electron-withdrawing groups (e.g., trifluoromethyl) were used to probe the mechanism. The results derived from transient-state enzyme kinetics, Mössbauer spectroscopy, reaction product analysis, X-ray crystallography, density functional theory calculations, and molecular dynamic simulations collectively revealed the following mechanistic insights: (1) The rapid O2 addition to the AsqJ Fe(II) center occurs with the iron-bound 2OG adopting an online-binding mode in which the C1 carboxylate group of 2OG is trans to the proximal histidine (His134) of the 2-His-1-carboxylate facial triad, instead of assuming the offline-binding mode with the C1 carboxylate group trans to the distal histidine (His211); (2) The decay rate constant of the ferryl intermediate is not strongly affected by the nature of the para substituents of the substrate during the OAT step, a reactivity behavior that is drastically different from nonheme Fe(IV)-oxo synthetic model complexes; (3) The OAT step most likely proceeds through a stepwise process with the initial formation of a C(benzylic)–O bond to generate an Fe-alkoxide species, which is observed in the AsqJ crystal structure. The subsequent C3–O bond formation completes the epoxide installation.
In vitro reconstitution of a newly discovered isonitrile synthase (AmbI1 and AmbI2) and the detection of an elusive intermediate (S)-3-(1H-indol-3-yl)-2-isocyanopropanoic acid 1 in indolyl vinyl ...isocyanide biogenesis are reported. The characterization of iron/2-oxoglutarate (Fe/2OG) dependent desaturases IsnB and AmbI3 sheds light on the possible mechanism underlying stereoselective alkene installation to complete the biosynthesis of (E)- and (Z)-3-(2-isocyanovinyl)-1H-indole 2 and 5. Establishment of a tractable isonitrile synthase system (AmbI1 and AmbI2) paves the way to elucidate the enigmatic enzyme mechanism for isocyanide formation.
The molecular packing motifs within crystalline domains should be a key determinant of charge transport in thin‐film transistors (TFTs) based on small organic molecules. Despite this implied ...importance, detailed information about molecular organization in polycrystalline thin films is not available for the vast majority of molecular organic semiconductors. Considering the potential of fused thiophenes as environmentally stable, high‐performance semiconductors, it is therefore of interest to investigate their thin film microstructures in relation to the single crystal molecular packing and OTFT performance. Here, the molecular packing motifs of several new benzod,d′thieno3,2‐b;4,5‐b′dithiophene (BTDT) derivatives are studied both in bulk 3D crystals and as thin films by single crystal diffraction and grazing incidence wide angle X‐ray scattering (GIWAXS), respectively. The results show that the BTDT derivative thin films can have significantly different molecular packing from their bulk crystals. For phenylbenzod,d′thieno3,2‐b;4,5‐b′dithiophene (P‐BTDT), 2‐biphenylbenzod,d′thieno‐3,2‐b;4,5‐b′dithiophene (Bp‐BTDT), 2‐naphthalenylbenzod,d′thieno3,2‐b;4,5‐b′dithiophene (Np‐BTDT), and bisbenzod,d′thieno3,2‐b;4,5‐b′dithiophene (BBTDT), two lattices co‐exist, and are significantly strained versus their single crystal forms. For P‐BTDT, the dominance of the more strained lattice relative to the bulk‐like lattice likely explains the high carrier mobility. In contrast, poor crystallinity and surface coverage at the dielectric/substrate interface explains the marginal OTFT performance of seemingly similar PF‐BTDT films.
The thin film molecular packing motifs of several new benzod,dthieno3,2‐b;4,5‐bdithiophene (BTDT) derivatives have different molecular packings from their bulk crystals. Co‐existence of strained lattices with their single crystal forms is speculated to have a significant effect on organic thin‐film transistor (OTFT) performance.
For bedridden elderly people, pressure ulcer is the most common and serious complication and could be prevented by regular repositioning. However, due to a shortage of long-term care workers, ...repositioning might not be implemented as often as required. Posture monitoring by using modern health/medical caring technology can potentially solve this problem. We propose a RGB-D camera system to recognize the posture of the bedridden elderly patients based on the analysis of 3D human skeleton which consists of articulated joints. Since practically most bedridden patients were covered with a blanket, only four 3D joints were used in our system. After the recognition of the posture, a warning message will be sent to the caregiver for assistance if the patient stays in the same posture for more than a predetermined period (e.g., two hours). Experimental results indicate that our proposed method is capable of achieving a high accuracy in posture recognition (above 95%). To the best of our knowledge, this application of using human skeleton analysis for patient care is novel. The proposed scheme is promising for clinical applications and will undertake an intensive test in health care facilities in the near future after redesigning a proper RGB-D (Red-Green-Blue-Depth) camera system. In addition, a desktop computer can be used for multi-point monitoring to reduce cost, since real-time processing is not required in this application.
A series of dithieno2,3-b:3′,2′-dthiophene (
DTT;
1) derivatives were synthesized and characterized. Facile, one-pot 2
+
1 and 1
+
1
+
1 synthetic methods of
DTT were developed, which enabled the ...efficient realization of a new
DTT-based semiconductor series for organic thin-film transistors (OTFTs). These
DTTs are end-functionalized with perfluorophenyl (FP-), perfluorobenzoyl (FB-), benzoyl (B-), 2-naphthylcarbonyl (Np-), 2-benzothiazolyl (BS-), 2-thienylcarbonyl (T-), and 2-(5-hexyl)thienylcarbonyl (HT-) groups. The molecular structures of
DFP-DTT (
3),
DFB-DTT (
4),
FBB-DTT (
5),
DB-DTT (
6), and
DNp-TT (
7) were determined via single-crystal X-ray diffraction. Our studies reveal that the majority of these carbonyl-containing derivatives exhibit p-channel transport with hole mobilities of up to 0.01
cm
2/Vs for
DB-DTT and
DBS-DTT, while perfluorobenzoyl and perfluorophenyl-substituted compounds exhibit n-channel transport with mobilities up to 0.002
cm
2/Vs for
DFB-DTT, 0.03
cm
2/Vs for
FBB-DTT, and 0.07
cm
2/Vs for
DFP-DTT, rendering the latter the
DTT derivative currently having the highest electron mobility in OTFT devices. Within this family, the carrier mobility values are strongly dependent upon the semiconductor growth temperature and the dielectric surface treatment.
We have successfully transformed the terminal alkenes of dihydropyridones to the α,β-unsaturated esters by cross metathesis (CM). After detosylation the secondary amides can undergo the ...intramolecular aza-Michael reaction to give the bicyclic piperidine structures. The stereoselectivity of the aza-Michael reaction is determined by the size of the newly formed ring. With simple transformations we have also achieved the synthesis of indolizidine 167E.
![Dicyclopenta[ghi,pqr]peryle...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1523-7060/small "Dicyclopenta[ghi,pqr]perylene as a Structural Motif for Bowl-Shaped Hydrocarbons: Synthetic and Conformational Studies")
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