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1.
Quang Luu Quoc Youngwoo Choi Tra Cao Thi Bich Eun-Mi Yang Yoo Seob Shin Hae-Sim Park 《Experimental & molecular medicine》2021,53(7):1170
The biomarkers and therapeutic targets of neutrophilic asthma (NA) are poorly understood. Although S100 calcium-binding protein A9 (S100A9) has been shown to correlate with neutrophil activation, its role in asthma pathogenesis has not been clarified. This study investigated the mechanism by which S100A9 is involved in neutrophil activation, neutrophil extracellular trap (NET)-induced airway inflammation, and macrophage polarization in NA. The S100A9 levels (by ELISA) in sera/culture supernatant of peripheral blood neutrophils (PBNs) and M0 macrophages from asthmatic patients were measured and compared to those of healthy controls (HCs). The function of S100A9 was evaluated using airway epithelial cells (AECs) and PBNs/M0 macrophages from asthmatic patients, as well as a mouse asthma model. The serum levels of S100A9 were higher in NA patients than in non-NA patients, and there was a positive correlation between serum S100A9 levels and sputum neutrophil counts (r = 0.340, P = 0.005). Asthmatic patients with higher S100A9 levels had lower PC20 methacholine values and a higher prevalence of severe asthma (SA) (P < .050). PBNs/M0 macrophages from SA released more S100A9 than those from non-SA patients. PBNs from asthmatic patients induced S100A9 production by AECs, which further activated AECs via the extracellular signal-regulated kinase (ERK) pathway, stimulated NET formation, and induced M1 macrophage polarization. Higher S100A9 levels in sera, bronchoalveolar lavage fluid, and lung tissues were observed in the mouse model of NA but not in the other mouse models. These results suggest that S100A9 is a potential serum biomarker and therapeutic target for NA.Subject terms: Prognostic markers, Adaptive immunity, Immunological disorders, Diagnostic markers 相似文献
2.
Dr. Carolina Fontana Prof. Dr. Andrej Weintraub Prof. Dr. Göran Widmalm 《ChemistryOpen》2015,4(1):47-55
Shiga-toxin-producing Escherichia coli (STEC) is an important pathogen associated to food-borne infection in humans; strains of E. coli O181, isolated from human cases of diarrhea, have been classified as belonging to this pathotype. Herein, the structure of the O-antigen polysaccharide (PS) from E. coli O181 has been investigated. The sugar analysis showed quinovosamine (QuiN), glucosamine (GlcN), galactosamine (GalN), and glucose (Glc) as major components. Analysis of the high-resolution mass spectrum of the oligosaccharide (OS), obtained by dephosphorylation of the O-deacetylated PS with aqueous 48 % hydrofluoric acid, revealed a pentasaccharide composed of two QuiNAc, one GlcNAc, one GalNAc, and one Glc residue. The 1H and 13C NMR chemical shift assignments of the OS were carried out using 1 D and 2 D NMR experiments, and the OS was sequenced using a combination of tandem mass spectrometry (MS/MS) data and NMR 13C NMR glycosylation shifts. The structure of the native PS was determined using NMR spectroscopy, and it consists of branched pentasaccharide repeating units joined by phosphodiester linkages: →4)[α-l-QuipNAc-(1→3)]-α-d-GalpNAc6Ac-(1→6)-α-d-Glcp-(1→P-4)-α-l-QuipNAc-(1→3)-β-d-GlcpNAc-(1→; the O-acetyl groups represent 0.4 equivalents per repeating unit. Both the OS and PSs exhibit rare conformational behavior since two of the five anomeric proton resonances could only be observed at an elevated temperature. 相似文献
3.
Iris Solymosi Swathi Krishna Edurne Nuin Harald Maid Barbara Scholz Dirk M. Guldi M. Eugenia Prez-Ojeda Andreas Hirsch 《Chemical science》2021,12(47):15491
Cyclophanes of different ring sizes featuring perylene-3,4:9,10-tetracarboxylic acid bisimide (PBI) linked by flexible malonates were designed, synthesized, and investigated with respect to their structural, chemical and photo-physical properties. It is predominantly the number of PBIs and their geometric arrangement, which influence dramatically their properties. For example, two-PBI containing cyclophanes reveal physico-chemical characteristics that are governed by strong co-facial π–π interactions. This is in stark contrast to cyclophanes with either three or four PBIs. Key to co-facial π–π stackings are the flexible malonate linkers, which, in turn, set up the ways and means for diastereoselectivity of the homochiral PBIs at low temperatures, on one hand. In terms of selectivity, diastereomeric (M,M)/(P,P) : (M,P)/(P,M) pairs with a ratio of approximately 10 : 1 are discernible in the 1H NMR spectra in C2D2Cl4 and a complete diastereomeric excess is found in CD2Cl2. On the other hand, symmetry-breaking charge transfer as well as charge separation at room temperature are corroborated in steady-state and time-resolved photo-physical investigations. Less favourable are co-facial π–π stackings in the three-PBI containing cyclophanes. For statistical reasons, the diastereoisomers (M,M,M)/(P,P,P) and (M,M,P)/(P,P,M) occur here in a ratio of 1 : 3. In this case, symmetry-breaking charge transfer as well as charge separation are both slowed down. The work was rounded-off by integrating next to the PBIs, for the first time, hydrophobic or hydrophilic fullerenes into the resulting cyclophanes. Our novel fullerene–PBI cyclophanes reveal unprecedented diastereoselective formation of homochiral (M,M)/(P,P) pairs exceeding the traditional host–guest approach. Hybridization with fullerenes allows us to modulate the resulting solubility, stacking, cavity and chirality, which is of tremendous interest in the field.Perylene bisimide (PBI) cyclophanes linked by flexible malonates were functionalized with fullerenes. Modulation of the chemical environment enhances the chiral self-sorting, leading exclusively to the homochiral diastereomeric pair (M,M)/(P,P). 相似文献
4.
Won Sohn Jonghwa Kim So Hee Kang Se Ra Yang Ju-Yeon Cho Hyun Chin Cho Sang Goon Shim Yong-Han Paik 《Experimental & molecular medicine》2015,47(9):e184
Recent studies have shown that circulating microRNAs are a potential biomarker in various types of malignancies. The aim of this study was to investigate the feasibility of using serum exosomal microRNAs as novel serological biomarkers for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We measured the serum exosomal microRNAs and serum circulating microRNAs in patients with CHB (n=20), liver cirrhosis (LC) (n=20) and HCC (n=20). Serum exosomal microRNA was extracted from 500 μl of serum using an Exosome RNA Isolation kit. The expression levels of microRNAs were quantified by real-time PCR. The expression levels of selected microRNAs were normalized to Caenorhabditis elegans microRNA (Cel-miR-39). The serum levels of exosomal miR-18a, miR-221, miR-222 and miR-224 were significantly higher in patients with HCC than those with CHB or LC (P<0.05). Further, the serum levels of exosomal miR-101, miR-106b, miR-122 and miR-195 were lower in patients with HCC than in patients with CHB (P=0.014, P<0.001, P<0.001 and P<0.001, respectively). There was no significant difference in the levels of miR-21 and miR-93 among the three groups. Additionally, the serum levels of circulating microRNAs showed a smaller difference between HCC and either CHB or LC. This study suggests that serum exosomal microRNAs may be used as novel serological biomarkers for HCC. 相似文献
5.
A general strategy to enable the formal anti-hydrozirconation of arylacetylenes is reported that merges cis-hydrometallation using the Schwartz Reagent (Cp2ZrHCl) with a subsequent light-mediated geometric isomerization at λ = 400 nm. Mechanistic delineation of the contra-thermodynamic isomerization step indicates that a minor reaction product functions as an efficient in situ generated photocatalyst. Coupling of the E-vinyl zirconium species with an alkyne unit generates a conjugated diene: this has been leveraged as a selective energy transfer catalyst to enable E → Z isomerization of an organometallic species. Through an Umpolung metal–halogen exchange process (Cl, Br, I), synthetically useful vinyl halides can be generated (up to Z : E = 90 : 10). This enabling platform provides a strategy to access nucleophilic and electrophilic alkene fragments in both geometric forms from simple arylacetylenes.A general strategy to enable the formal anti-hydrozirconation of arylacetylenes is reported that merges cis-hydrometallation using the Schwartz Reagent (Cp2ZrHCl) with a subsequent light-mediated geometric isomerization at λ = 400 nm.The venerable Schwartz reagent (Cp2ZrHCl) is totemic in the field of hydrometallation,1 where reactivity is dominated by syn-selective M–H addition across the π-bond.2,3 This mechanistic foundation can be leveraged to generate well-defined organometallic coupling partners that are amenable to stereospecific functionalization. Utilizing terminal alkynes as readily available precursors,4 hydrozirconation constitutes a powerful strategy to generate E-configured vinyl nucleophiles that, through metal–halogen exchange, can be converted to vinyl electrophiles in a formal Umpolung process.5 Whilst this provides a versatile platform to access the electronic antipodes of the E-isomer, the mechanistic course of addition renders access to the corresponding Z-isomer conspicuously challenging. To reconcile the synthetic importance of this transformation with the intrinsic challenges associated with anti-hydrometallation and metallometallation,6 it was envisaged that a platform to facilitate geometric isomerization7 would be of value. Moreover, coupling this to a metal–halogen exchange would provide a simple Umpolung matrix to access both stereo-isomers from a common alkyne precursor (Fig. 1).Open in a separate windowFig. 1The stereochemical course of alkyne hydrometallation using the Schwartz reagent and an Umpolung platform to generate both stereo-isomers from a common alkyne precursor.Confidence in this conceptual blueprint stemmed from a report by Erker and co-workers, in which irradiating the vinyl zirconium species derived from phenyl acetylene (0.5 M in benzene) with a mercury lamp (Philips HPK 125 and Pyrex filter) induced geometric isomerization.8 Whilst Hg lamps present challenges in terms of safety, temperature regulation, cost and wavelength specificity, advances in LED technology mitigate all of these points. Therefore, a process of reaction development was initiated to generalize the anti-hydrozirconation of arylacetylenes. Crucial to the success of this venture was identifying the light-based activation mode that facilitates alkene isomerization. Specifically, it was necessary to determine whether this process was enabled by direct irradiation of the vinyl zirconium species, or if the E → Z directionality results from a subsequent selective energy transfer process involving a facilitator. Several accounts of the incipient vinyl zirconium species reacting with a second alkyne unit to generate a conjugated diene have been disclosed.9,10 It was therefore posited that the minor by-product diene may be a crucial determinant in driving this isomerization (Fig. 2).Open in a separate windowFig. 2A working hypothesis for the light-mediated anti-hydrozirconation via selective energy transfer catalysis.To advance this working hypothesis and generalize the formal anti-hydrozirconation process, the reaction of Cp2ZrHCl with 1-bromo-4-ethynylbenzene (A-1) in CH2Cl2 was investigated (‡ for full details). This generates a versatile electrophile for downstream synthetic applications. Gratifyingly, after only 15 minutes, a Z : E-composition of 50 : 50 was reached (entry 1) and, following treatment with NBS, the desired vinyl bromide (Z)-1 was obtained in 76% yield (isomeric mixture) over the two steps. Further increasing the irradiation by 15 minute increments (entries 2–4) revealed that the optimum reaction time for the isomerization is 45 minutes (74%, Z : E = 73 : 27, entry 3). Extending the reaction time to 60 minutes (entry 4, 54%) did not lead to an improvement in selectivity and this was further confirmed by irradiating the reaction mixture for 90 minutes (entry 5). In both cases, a notable drop in yield was observed and therefore the remainder of the study was performed using the conditions described in entry 3. Next, the influence of the irradiation wavelength on the isomerization process was examined (entries 6–11). From a starting wavelength of λ = 369 nm, which gave a Z : E-ratio of 27 : 73 (entry 6), a steady improvement was observed by increasing the wavelength to λ = 374 nm (Z : E = 44 : 56, entry 7) and λ = 383 nm (Z : E = 53 : 47, entry 8). The selectivity reached a plateau at λ = 400 nm, with higher wavelengths proving to be detrimental (Z : E = 60 : 40 at λ = 414 nm, entry 9; Z : E = 26 : 74 at λ = 435 nm, entry 10). It is interesting to note that at λ = 520 nm, Z-1 was not detected by 1H NMR (entry 11).Reaction optimizationa
Open in a separate windowa(i) Cp2ZrHCl (62 mg, 0.24 mmol, 1.2 eq.), CH2Cl2 (1.5 mL), alkyne A-1 (36 mg, 0.2 mmol, 1.0 eq.) in CH2Cl2 (0.5 mL); (ii) irradiation; (iii) NBS (39 mg, 0.22 mmol, 1.1 eq.).baverage yield and Z : E ratio of two reactions determined by 1H-NMR with DMF as internal standard; isolated yield of the Z : E-mixture and Z : E-ratio in parentheses.Having identified standard conditions to enable a hydrozircononation/isomerization/bromination sequence, the scope and limitations of the method was explored using a range of electronically and structurally diverse phenylacetylenes (Fig. 3). This constitutes a net anti-Markovnikov hydrobromination of alkynes.11Open in a separate windowFig. 3Aromatic scope for the formal anti-hydrozirconation of terminal alkynes; reaction conditions: (i) Cp2ZrHCl (62 mg, 0.24 mmol, 1.2 eq.), CH2Cl2 (1.5 mL), alkyne A-1-17 (0.2 mmol, 1.0 eq.) in CH2Cl2 (0.5 mL), 15 min; (ii) irradiation (λ = 400 nm), 45 min; (iii) NBS (39 mg, 0.22 mmol, 1.1 eq.), 15 min; aisolated yield of Z : E-mixture as average of two reactions; b(i) Cp2ZrHCl (62 mg, 0.24 mmol, 1.2 eq.), CH2Cl2 (1.5 mL), alkyne A-15 (26 mg, 0.2 mmol, 1.0 eq.) in CH2Cl2 (0.5 mL); (ii) irradiation (λ = 400 nm), 45 min; (iii) PdPPh3 (7 mg, 0.006 mmol, 0.03 eq.) in THF (0.4 mL), BnBr (24 μL, 0.2 mmol, 1.0 eq.), rt, 18 h.12The introduction of halogen substituents in the 4-position proved to be compatible with the reaction conditions, enabling the formation of (Z)-1-4 in up to 81% yield (up to Z : E = 74 : 26). Interestingly, the introduction of the o-F (Z)-5 substituent led to a drop in the yield and selectivity: this is in stark contrast to cinnamoyl derivatives that have previously been examined in this laboratory.12 The m-Br proved to be less challenging enabling (Z)-6 to be generated smoothly (74%, Z : E = 67 : 33). The parent phenylacetylene (A-7) could be converted with a similar Z : E-ratio to (Z)-7 albeit less efficiently (36%, Z : E = 72 : 28). Electron donating groups in the para position such as (Z)-8-10 led to a general improvement in selectivity (up to 80%, Z : E = 81 : 19). Whereas methylation at the ortho-position compromised efficiency [(Z)-11, 37%, Z : E = 68 : 32], translocation to the meta-position led to a recovery in terms of yield and Z : E-ratio [(Z)-12, 71%, Z : E = 75 : 25]. Extending the π-system from phenyl to naphthyl enabled the generation of (Z)-13 90% and with a Z : E-ratio of 77 : 23. To enable a direct comparison of strongly and weakly donating groups on the reaction outcome the p-CF3 and p-OMe derivatives were examined. In the trifluoromethyl derivative (Z)-14 a decrease in yield (31%) and selectivity (Z : E = 48 : 52) was noted. In contrast, the para methoxy group in (Z)-15 led to an enhanced Z : E ratio of 86 : 14 (68% yield). This behavior was also observed with the trimethoxy derivative (Z)-16 (Z : E-ratio of 81 : 19). The piperonyl derivative performing similarly to the para methoxy derivative thereby enabling the formation of (Z)-17 with a Z : E-ratio of 85 : 15 (67% yield). Finally, to demonstrate the utility of the method, a direct transmetallation protocol was performed to intercept the Z-vinyl zirconium species with benzyl bromide.13 This enabled the synthesis of (Z)-18 in 67% yield.To demonstrate the compatibility of this platform with other common electrophiles, the deuterated, chlorinated and iodinated systems (Z)-19, -20 and -21 were prepared (Fig. 4). Yields and selectivities that are fully comparable with Fig. 3 were observed (up to 80% yield and Z : E = 80 : 20). Finally, to augment the photostationary composition further, a process of structural editing was conducted. It was envisaged that integrating a stabilizing non-covalent interaction in the Z-vinyl zirconium species may bias isomerization selectivity. Recent studies from this laboratory have established that a stabilizing interaction between the boron p-orbital and an adjacent non-bonding electron pair can be leveraged to induce a highly selective geometric isomerization of β-borylacrylates (Fig. 5, top).14Open in a separate windowFig. 4Scope of electrophiles for the formal anti-hydrozirconation; reaction conditions: (i) Cp2ZrHCl (62 mg, 0.24 mmol, 1.2 eq.), CH2Cl2 (1.5 mL), A-9 (36 mg, 0.2 mmol, 1.0 eq.) in CH2Cl2 (0.5 mL); (ii) irradiation (λ = 400 nm), 45 min; (iii) E+ (DCl, NCS or NIS) (0.22 mmol, 1.1 eq.), 15 min; isolated yields of the Z : E-mixture are reported.Open in a separate windowFig. 5Enhancing the selectivity of anti-hydrozirconation by leveraging a postulated nS → Zr interaction. Reaction conditions: (i) Cp2ZrHCl (62 mg, 0.24 mmol, 1.2 eq.), CH2Cl2 (1.5 mL), alkyne A-22-24 (0.2 mmol, 1.0 eq.) in CH2Cl2 (0.5 mL), rt, 15 min; (ii) irradiation (λ = 400 nm), 45 min; (iii) NBS (39 mg, 0.22 mmol, 1.1 eq.), rt, 15 min.Gratifyingly, the 5-bromo thiophenyl derivative (Z)-22 was generated with a Z : E ratio of 87 : 13 in 73% yield, and the unsubstituted derivative (Z)-23 was obtained in 41% yield higher selectivity (Z : E = 90 : 10). As a control experiment, the regioisomeric product (Z)-24 was prepared in which the sulfur atom is distal from the zirconium center. This minor alteration resulted in a conspicuous drop of selectivity (Z : E = 78 : 22), which is in line with the phenyl derivatives. Given the prominence of Frustrated-Lewis-Pairs (FLPs) in small molecule activation,15 materials such as (Z)-22 and (Z)-23 may provide a convenient starting point for the development of future candidates.To provide structural support for the formation of a Z-vinyl zirconium species upon irradiation at λ = 400 nm, the standard experiment was repeated in deuterated dichloromethane and investigated by 1H NMR spectroscopy. The spectra shown in Fig. 6 confirm the formation of transient E- and Z-vinyl zirconium species (E)-Zr1 and (Z)-Zr1 and are in good agreement with literature values.8 Diagnostic resonances of (E)-Zr1 include H1 at 7.76 ppm, whereas the analogous signal in (Z)-Zr1 is high field shifted to 6.33 ppm (Δδ(H1Z−E) = −1.43 ppm). In contrast, the H2 signal for (Z)-Zr1 appears at 7.56 ppm, which is at lower field compared to the H2 signal for (E)-Zr1 at 6.64 ppm (Δδ(H2Z−E) = 0.92 ppm). In the 13C-NMR spectra (see the ESI‡) the carbon signal of C1 and C2 are both low field shifted for (Z)-Zr1 compared to (E)-Zr1 (Δδ(C1Z−E) = 10.5 ppm and Δδ(C1Z-E) = 5.6 ppm).Open in a separate windowFig. 61H-NMR of the transient vinylzirconium species (E)-Zr1 (top) and (Z)-Zr1 (bottom).A computational analysis of the vinyl zirconium isomers (E)-Zr1 and (Z)-Zr1 revealed two low energy conformers for each geometry (Fig. 7. For full details see the ESI‡). These optimized structures served as a basis for more detailed excited state calculations using a time-dependent density functional theory (TDDFT) approach. These data indicate that isomerization of the styrenyl zirconium species by direct irradiation is highly improbable using λ = 400 nm LEDs. However, upon measuring the absorption spectrum of the reaction mixture (Fig. 8, bottom), the shoulder of a band reaching to the visible part of the spectrum is evident (for more details see the ESI‡). Furthermore, the fluorescence spectrum (Fig. 8, top) clearly shows light emission from the reaction mixture. Collectively, these data reinforce the working hypothesis that a minor reaction product functions as a productive sensitizer, thereby enabling the isomerization to occur via selective energy transfer.Open in a separate windowFig. 7A comparative analysis of (E)-Zr1 and (Z)-Zr1.Open in a separate windowFig. 8(Top) Fluorescence spectra of the reaction mixture before and after irradiation, and the diene 25 (c = 0.1 mm, irradiation at λ = 350 nm). (Bottom) Absorption spectra of the reaction mixture before and after irradiation (c = 0.1 mm), the alkyne A-1 and the diene 25 (c = 0.05 mm).As previously highlighted, phenylacetylenes are known to dimerize in the presence of Cp2Zr* based complexes.9,16 Therefore, to provide support for the involvement of such species, diene 25 was independently prepared and its absorption and emission spectra were compared with those of the reaction mixture (Fig. 8). The emission spectra of the reaction mixture and of diene 25 are closely similar. It is also pertinent to note that diene 25 was also detected in the crude reaction mixture by HRMS (see the ESI‡).Whilst the spectral measurements in Fig. 8 are in line with diene 25 functioning as an in situ photocatalyst, more direct support was desirable. Frustratingly, efforts to subject (E)-Zr-1 and (Z)-Zr-1 to standard Stern–Volmer quenching studies were complicated by difficulties in removing diene 25 from the samples. It was therefore envisaged that doping reactions with increasing quantities of diene 25 might be insightful. To that end, the hydrozirconation/isomerization sequence was performed with 0.5, 1.0 and 2.5 mol% of diene 25 and the reactions were shielded from light after 5 minutes. Analysis of the mixture by 1H NMR spectroscopy revealed a positive impact of 25 on the Z : E selectivity, (Z : E = 23 : 77, 24 : 76 and 30 : 70, respectively. Fig. 9, top). To further demonstrate the ability of diene 25 to act as an energy transfer catalyst for geometric isomerization, two model alkenes containing the styrenyl chromophore were exposed to the standard reaction conditions and the photostationary composition was measured after 45 min. Exposing trans-stilbene (E)-26 to the isomerization conditions furnished a Z : E photostationary composition of 44 : 56. Similarly, trans-β-methyl styrene (E)-27 could be isomerized to the cis-β-methyl styrene (Z)-27 with a Z : E ratio of 47 : 53. No isomerization was observed at λ = 400 nm in the absence of the catalyst. Whilst direct comparison with the isomerization of vinyl zirconium species must be made with caution, these experiments demonstrate that dienes such as 25 have the capacity to act as photosensitizers with styrenyl chromophores.Open in a separate windowFig. 9(Top) Exploring the impact of adding diene 25 as an external photocatalyst. (Bottom) Validating photosensitization of the styrenyl chromophore using diene 25.Collectively, these data support the hypothesis that isomerization does not result from direct irradiation alone,17 but that conjugated dienes, which are produced in small amounts, function as in situ energy transfer catalysts (Fig. 10). This antenna undergoes rapid inter-system crossing (ISC)18 to generate the triplet state and, upon energy transfer to the alkene fragment, returns to the ground state.19 This mechanistic study has guided the development of an operationally simple anti-hydrozirconation of alkynes that relies on inexpensive LED irradiation. Merging this protocol with a sequential metal–halogen exchange enables the formal anti-Markovnikov hydrobromination of alkynes11 and provides a sterodivergent platform to access defined alkene vectors from simple alkynes. This complements existing strategies to isomerize vinyl bromides,20 and circumvents the risks of vinyl cation formation and subsequent degradation.21 Finally, the selectivity of this geometric isomerization can be further augmented through the judicious introduction of stabilizing non-covalent interactions (up to Z : E = 90 : 10). It is envisaged that this selective, controlled geometric isomerization of an organometallic species will find application in contemporary synthesis. Furthermore, it contributes to a growing body of literature that describes the in situ formation of photoactive species upon irradiation.22Open in a separate windowFig. 10Postulated energy transfer catalysis cycle predicated on in situ formation of a conjugated diene photocatalyst. 相似文献
Entry | λ [nm] | Time [min] | Yieldb | Z : E ratiob |
---|---|---|---|---|
1 | 400 | 15 | 76% | 50 : 50 |
2 | 400 | 30 | 72% | 68 : 32 |
3 | 400 | 45 | 74% (74%) | 74 : 26 (73 : 27) |
4 | 400 | 60 | 54% | 73 : 27 |
5 | 400 | 90 | 49% | 73 : 27 |
6 | 369 | 45 | 66% | 27 : 73 |
7 | 374 | 45 | 61% | 44 : 56 |
8 | 383 | 45 | 64% | 53 : 47 |
9 | 414 | 45 | 67% | 60 : 40 |
10 | 435 | 45 | 72% | 26 : 74 |
11 | 520 | 45 | 67% | <5 : 95 |
6.
Young-Woo Kim Bang Wool Eom Myeong-Cherl Kook Han-Seong Kim Mi-Kyung Kim Hai-Li Hwang Vishal Chandra Shiv Poojan Yura Song Jae-Soo Koh Chang-Dae Bae Jungsil Ro Kyeong-Man Hong 《Experimental & molecular medicine》2015,47(11):e193
Proliferation activity has already been established as a prognostic marker or as a marker for anticancer drug sensitivity. In gastric cancer, however, the prognostic significance of proliferation activity is still being debated. Several studies evaluating proliferation activity using Ki-67 have shown controversial results in terms of the relationship between proliferation activity and overall survival (OS) or drug sensitivity in gastric cancer patients. Because cytoskeleton-associated protein 2 (CKAP2) staining has recently been introduced as a marker of proliferation activity, we analyzed 437 gastric cancer tissues through CKAP2 immunohistochemistry, and we evaluated the chromatin CKAP2-positive cell count (CPCC) for proliferation activity. Although the CPCC did not show any significant correlation with OS in the male, female or total number of cases, it did show a significant correlation in the T1 or T2 male patient subgroup, according to log-rank tests (P=0.001) and univariate analysis (P=0.045). Additionally, multivariate analysis with the Cox proportional hazard regression model showed a significant correlation between the CPCC and OS (P=0.039) for the co-variables of age, gender, T stage, N stage, histology, tumor location, tumor size and adjuvant chemotherapy. In male gastric cancer cell lines, faster-growing cancer cells showed higher sensitivity to cisplatin than slow-growing cells. Thus our study indicates that CPCC-measured proliferation activity demonstrates a significantly worse prognosis in T1 or T2 male gastric cancer patients. The CPCC will help to more precisely classify gastric cancer patients and to select excellent candidates for adjuvant chemotherapy, which in turn will facilitate further clinical chemotherapeutic trials. 相似文献
7.
A peptide has been designed so that its chelating affinity for one type of metal ion regulates its affinity for a second, different type of metal ion. The prochelator peptide (PCP), which is a fusion of motifs evocative of calcium loops and zinc fingers, forms a 1 : 2 Zn : peptide complex at pH 7.4 that increases its affinity for Zn2+ ∼3-fold in the presence of Tb3+ (log β2 from 13.8 to 14.3), while the 1 : 1 luminescent complex with Tb3+ is brighter, longer lived, and 20-fold tighter in the presence of Zn2+ (log K from 6.2 to 7.5). This unique example of cooperative, heterometallic allostery in a biologically compatible construct suggests the possibility of designing conditionally active metal-binding agents that could respond to dynamic changes in cellular metal status. 相似文献
8.
We report the regioselective synthesis of dihydroisoquinolones from aliphatic alkenes and O-pivaloyl benzhydroxamic acids mediated by a Rh(iii) precatalyst bearing sterically bulky substituents. While the prototypical Cp* ligand provides product with low selectivity, sterically bulky Cpt affords product with excellent regioselectivity for a range of benzhydroxamic acids and alkenes. Crystallographic evidence offers insight as to the source of the increased regioselectivity.C–H activation mediated processes have provided a unique retrosynthetic approach to access a variety of substituted heterocycles.1 One tactic that has received increased attention is the coupling of π-components with heteroatom containing molecules.2 A variety of transition metals are capable of catalyzing this type of transformation, providing access to dozens of heterocyclic motifs.1–3 A challenge for these methods is controlling the regioselectivity of migratory insertion across alkenes and alkynes after the metallacycle forming C–H activation (eqn 1).Steric and electronic effects are understood to control migratory insertion of unsymmetrical alkynes in Rh(iii) catalyzed isoquinolone syntheses (eqn 1). When the substituents are electronically similar, the larger group resides β- to Rh in the metallacycle to avoid unfavorable steric interactions (selectivity is generally >10 : 1).4 When the substituents are electronically different, the more electron-donating group prefers being α- to rhodium in the metallacycle, presumably to stabilize the electron poor metal.5,6 The type of C–H bond being activated also plays an important role in the regioselectivity of migratory insertion; aromatic substrates typically provide synthetically useful regioselectivities when electronically different alkynes are used (>10 : 1) but alkenyl C–H activation leads to products with lower regioselectivities, presumably due to minimal steric interactions during migratory insertion.7,8 We found that sterically bulky di-tert-butylcyclopentadienyl ligand (Cpt) enhances the regioselectivity of the alkyne migratory insertion event in these cases, delivering regioselectivities (>10 : 1) modestly above those achievable by Cp* ligated Rh complexes (<6 : 1). However, when the alkyne migratory insertion was poorly selective with RhCp* (<3 : 1), RhCpt complex was ineffective at providing synthetically useful levels of selectivity. Furthermore, the Cpt ligand was only effective with aryl substituted alkynes, presumably because of strong steric interactions between the ligand and alkyne in the insertion event.
Migratory insertion of alkenes to access heterocycles using C–H activation chemistry is still relatively rare, with seminal studies by Glorius and Fagnou reporting the synthesis of dihydroisoquinolones.9–11 Similar to alkynes, alkenyl electron-donating groups favor the position adjacent to the metal in the metallacycle delivering high regioselectivity. In contrast to alkynes, aliphatic alkenes afford product with poor regioselectivity (2 : 1) (eqn 2).5h,12 We hypothesized competing steric and electronic effects cause the low regioselectivity, with steric effects favoring the formation of a 4-substituted product and electronics favoring the formation of a 3-substituted product.13 As a temporary solution to this problem, our group and others have employed tethering strategies to increase the regioselectivity of the migratory insertion event (eqn 3).14,15 Of course, regioselectivity controlled by the ligand on Rh would be the optimal solution to the selectivity problem (eqn 4).16 Consequently, we focused our attention toward developing an intermolecular variant of this reaction that would provide product with improved regioselectivity.As a model system, we explored the impact ligands have on the coupling of O-pivaloyl-benzhydroxamic acid 1a with 1-decene 2a to provide dihydroisoquinolones 3a and 3a′. When Cp* is used as a ligand, the desired products are isolated in excellent yield but poor selectivity (2.4 : 1 3a : 3a′) (
a
Open in a separate window
aReaction conditions: 1a (.2 mmol), 1-decene (.2 mmol), precatalyst (1 mol%), CsOAc (200 mol%), MeOH (0.1 M).
bCpCF3 = 1-trifluoromethyl-2-3,4,5-tetramethylcyclopentadienyl.
cCp‡ = 1,2-di-phenyl-3,4,5-trimethylcyclopentadienyl.
dCpt = 1,3-di-t-butylcyclopentadienyl.To determine the effect that ligand electronics have on product regioselectivity, we employed an electron deficient 1-trifluoromethyl-2,3,4,5-tetramethylcyclopentadienyl ligand originally developed by Gassman (CpCF3)17 and found that this catalyst provides 3a and 3a′ products in good yield but without an increase in selectivity (2.4 : 1) (18,19 Since ligand electronics did not appear to affect product regioselectivity, we tested an electron rich, sterically bulky di-phenyl-tri-methyl Cp ligand (Cp‡) and were pleased to find a remarkable increase in selectivity from 2.4 : 1 to 12 : 1 (3a : 3a′). Pleased by this improvement, we tested the sterically bulky di-tert-butyl Cp ligand Cpt and were surprised to find that RhCpt provides the desired product in 91% yield with exquisite regioselectivity (15 : 1) (
a
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aReaction conditions: amide (.2 mmol), 1-decene (.2 mmol), precatalyst (1 mol%), CsOAc (200 mol%), MeOH (0.1 M).
bIsolated yield of reaction using [RhCptCl2]2 as a precatalyst.
meta-Substituents also provide exquisite levels of regioselectivity for alkene migratory insertion when Cpt is used (>15 : 1) (
a
Open in a separate window
aReaction conditions: amide (.2 mmol), 1-decene (.2 mmol), precatalyst (1 mol%), CsOAc (200 mol%), MeOH (0.1 M). isolated yield of reaction using [RhCptCl2]2 as a precatalyst.
b67% yield.
c80% yield.
d85% yield.
e79% yield.We next explored the alkene tolerance of the method. Allyl benzene 2b furnishes a 1.6 : 1 ratio of dihydroisoquinolone with RhCp* (
a
Open in a separate window
aReaction conditions: 1a (.2 mmol), alkene (.2 mmol), precatalyst (1 mol%), CsOAc (200 mol%), MeOH (0.1 M).
bIsolated yield of reaction using [RhCptCl2]2 as a precatalyst.
cReaction conducted at 0 °C.
dProducts isolated as a 1 : 1 ratio of diastereomers.
eProduct isolated as a 2 : 1 ratio of diastereomers.While it is desirable to achieve high regioselectivity for a single regioisomer, it is even more attractive to use a ligand to access alternate regioisomers. Currently, the only example of Rh(iii)-catalyzed synthesis of 4-substituted dihydroisoquinolones is with potassium vinyltrifluoroborates where electronics are believed to control regioselectivity.20 We found that when vinylcyclohexane was submitted to a reaction with [RhCp*Cl2]2 as the precatalyst, the 3-substituted dihydroisoquinolone 4a was isolated in 90% yield with 11 : 1 regioselectivity (Fig. 1). However, when the same reaction was catalyzed by [RhCptCl2]2 the opposite isomer 4b was isolated in 75% yield and 10 : 1 (4b : 4a) regioselectivity. Given this unexpected discovery, we were interested in gleaning insight into how Cpt influences regioselectivity of alkene migratory insertion. A competition experiment between vinyl cyclohexane 2m and 1-decene 2a run to 10% conversion favored the formation of dihydroisoquinolone 3a in >19 : 1 ratio as determined by 1H NMR. This experiment suggests that enhanced steric interactions between the substrate and ligand slow the rate of migratory insertion.Open in a separate windowFig. 1Impact of ligand on reaction of vinyl cyclohexane.To investigate the steric differences between the RhCp* and RhCpt systems X-ray analysis was conducted on a 5-membered RhCpt metallacycle. While we were unable to obtain a 5-membered rhodacycle from our system, Jones and coworkers previously characterized 5-membered rhodacycle 5a from N-benzylidenemethanamine and [RhCp*Cl2]2.21 We found that a similar metallacycle 5b derived from [RhCptCl2]2 could be obtained in crystalline form under identical conditions and was evaluated by single crystal X-ray diffraction.A comparison of the bond lengths and angles reveals several notable differences between our Cpt rhodacycle and the Cp* rhodacycle reported by Jones (Fig. 2). The Rh–Cp centroid distance in 5b is 0.011 Å longer than 5a which is either the result of increased steric interactions, or an artifact of Cpt being a less electron-donating ligand. While there are subtle differences in many bond lengths and angles, the most striking difference is the angle C3–Rh–Cl, which is 98.03° in 5b while only 90.09° in 5a. The angle increase is likely the result of steric interactions caused by the tert-butyl moiety being situated directly over the Rh–Cl bond. As alkene exchange presumably occurs with Cl, we suggest that steric interactions between the t-butyl of the ligand and the alkene substituent affect both the alkene coordination and 1,2-insertion events.Open in a separate windowFig. 2X-Ray analysis.Based on the X-ray crystal structure and regioselectivity data, we propose the following model for regioselectivity of the 1,2-migratory insertion of alkenes, where steric contributions from the t-butyl groups influence both alkene coordination and insertion events to give high selectivity. With small alkyl alkenes, we propose that steric interactions from one t-butyl of Cpt disfavor alkene coordination (I) and subsequent insertion to give the β-substituted product 3a′ (Fig. 3). Coordination of the alkene with the steric bulk oriented away from the t-butyl group finds minimized steric interactions during coordination (II). Subsequent migratory insertion from II places the alkyl substituent α to Rh in the transition state, which we propose is able to stabilize a buildup of partial positive charge, making the α-substituted product 3a both sterically and electronically favored with Cpt. In the case of the Cp* ligand with small alkyl alkenes, neither steric nor electronic interactions dominate so low selectivity is observed.Open in a separate windowFig. 3Rationale for selectivity.However if the size of the alkene substituent is significantly increased, as in the case of vinyl cyclohexane, then Cpt favors the opposite regioisomer. While certainly a puzzling result, we propose that the selectivity can be explained by Cpt rotation such that the t-butyl groups both occupy the space above the metallacycle. Cpt rotation gears the O-piv toward the alkene coordination site disfavoring alkene coordination to this side (IV) favoring the α-substituted product 3a. At the same time, alkene coordination (III) with the cyclohexyl opposite the O-piv minimizes steric interactions enabling insertion of the large alkene and preferential formation of β-substituted product 3a′. While not conclusive, the observation that cyclohexyl alkene reacts significantly slower than n-octyl alkene suggests that migratory insertion of the cyclohexyl alkene proceeds through a higher energy and potentially highly ordered transition state, such as Cpt rotation. 相似文献
| |||
Entry | Catalyst | Yield (%) | Regioselectivity |
1 | [RhCp*Cl2]2 | 90 | 2.4 : 1 |
2 b | [RhCpCF3Cl2]2 | 85 | 2.4 : 1 |
3 c | [RhCp‡Cl2]2 | 82 | 12 : 1 |
4 d | [RhCptCl2]2 | 92 | 15 : 1 |
| ||||
Entry | Starting material | Yield b (%) | Cp* | Cpt |
1 | X = CF3 (1b) | 50 | 1.5 : 1 | 19 : 1 |
2 | X = Cl (1c) | 76 | 2.2 : 1 | 19 : 1 |
3 | X = OMe (1d) | 70 | 1.9 : 1 | 16 : 1 |
4 | X = Ph (1e) | 75 | 1.7 : 1 | 14 : 1 |
5 | 95 | 1.9 : 1 | 15 : 1 | |
6 | 84 | 2.5 : 1 | 19 : 1 | |
7 | 88 | 1.8 : 1 | 19 : 1 |
| ||||
Entry | Alkene | Yield b (%) | Cp* | Cpt |
1 c | 85 | 1.6 : 1 | 5.1 : 1 | |
2 | 68 | 1.6 : 1 | 9.4 : 1 | |
3 | 70 | 1.3 : 1 | 5.5 : 1 | |
4 | 95 | 2.3 : 1 | 14 : 1 | |
5 | 85 | 1.6 : 1 | 8 : 1 | |
6 d | 92 | 1.2 : 1 | 7.2 : 1 | |
7 | 80 | 1.4 : 1 | 12 : 1 | |
8 e | 93 | 1 : 1 | 11 : 1 | |
9 | 89 | 2 : 1 | 14 : 1 | |
10 | 94 | 3 : 1 | 14 : 1 |
9.
Jeong Eun Kim Jaeyong Choi Chang-Ohk Sung Yong Sang Hong Sun Young Kim Hyunjung Lee Tae Won Kim Jong-Il Kim 《Experimental & molecular medicine》2021,53(3):446
The global incidence of early-onset colorectal cancer (EO-CRC) is rapidly rising. However, the reason for this rise in incidence as well as the genomic characteristics of EO-CRC remain largely unknown. We performed whole-exome sequencing in 47 cases of EO-CRC and targeted deep sequencing in 833 cases of CRC. Mutational profiles of EO-CRC were compared with previously published large-scale studies. EO-CRC and The Cancer Genome Atlas (TCGA) data were further investigated according to copy number profiles and mutation timing. We classified colorectal cancer into three subgroups: the hypermutated group consisted of mutations in POLE and mismatch repair genes; the whole-genome doubling group had early functional loss of TP53 that led to whole-genome doubling and focal oncogene amplification; the genome-stable group had mutations in APC and KRAS, similar to conventional colon cancer. Among non-hypermutated samples, whole-genome doubling was more prevalent in early-onset than in late-onset disease (54% vs 38%, Fisher’s exact P = 0.04). More than half of non-hypermutated EO-CRC cases involved early TP53 mutation and whole-genome doubling, which led to notable differences in mutation frequencies between age groups. Alternative carcinogenesis involving genomic instability via loss of TP53 may be related to the rise in EO-CRC.Subject terms: Medical genomics, Colon cancer 相似文献
10.
1 : 1 mixtures of aminomethylenehelicene (P)-tetramer and (M)-pentamer with terminal C16 alkyl groups in fluorobenzene showed structural changes between hetero-double-helices B and C and random-coils 2A. Figure-eight thermal hysteresis appeared when the solution was cooled and heated at a constant rate and involved the crossing of cooling and heating curves in Δε/temperature profiles. This unusual thermal hysteresis emerged in the intermediate state between counterclockwise and clockwise thermal hystereses. This phenomenon arose from the competition between self-catalytic reactions to form B and C from 2A. Significant effects of terminal C16 alkyl groups on the thermodynamic and kinetic phenomena are also described.1 : 1 mixtures of aminomethylenehelicene (P)-tetramer and (M)-pentamer with terminal C16 alkyl groups in fluorobenzene showed structural changes between hetero-double-helices B and C and random-coils 2A. 相似文献
11.
Jing-Nan Liu Dong-Hyeon Suh Eun-Mi Yang Seung-Ihm Lee Hae-Sim Park Yoo Seob Shin 《Experimental & molecular medicine》2014,46(9):e113
Although some studies have explained the immunomodulatory effects of statins, the exact mechanisms and the therapeutic significance of these molecules remain to be elucidated. This study not only evaluated the therapeutic potential and inhibitory mechanism of simvastatin in an ovalbumin (OVA)-specific asthma model in mice but also sought to clarify the future directions indicated by previous studies through a thorough review of the literature. BALB/c mice were sensitized to OVA and then administered three OVA challenges. On each challenge day, 40 mg kg−1 simvastatin was injected before the challenge. The airway responsiveness, inflammatory cell composition, and cytokine levels in bronchoalveolar lavage (BAL) fluid were assessed after the final challenge, and the T cell composition and adhesion molecule expression in lung homogenates were determined. The administration of simvastatin decreased the airway responsiveness, the number of airway inflammatory cells, and the interleukin (IL)-4, IL-5 and IL-13 concentrations in BAL fluid compared with vehicle-treated mice (P<0.05). Histologically, the number of inflammatory cells and mucus-containing goblet cells in lung tissues also decreased in the simvastatin-treated mice. Flow cytometry showed that simvastatin treatment significantly reduced the percentage of pulmonary CD4+ cells and the CD4+/CD8+ T-cell ratio (P<0.05). Simvastatin treatment also decreased the expression of the vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 proteins, as measured in homogenized lung tissues (P<0.05) and human epithelial cells. The reduction in the T cell influx as a result of the decreased expression of cell adhesion molecules is one of the mechanisms by which simvastatin attenuates airway responsiveness and allergic inflammation. Rigorous review of the literature together with our findings suggested that simvastatin should be further developed as a potential therapeutic strategy for allergic asthma. 相似文献
12.
Described herein is a dirhodium(ii)-catalyzed asymmetric cycloisomerization reaction of azaenyne through a cap-tether synergistic modulation strategy, which represents the first catalytic asymmetric cycloisomerization of azaenyne. This reaction is highly challenging because of its inherent strong background reaction leading to racemate formation and the high capability of coordination of the nitrogen atom resulting in catalyst deactivation. Varieties of centrally chiral isoindazole derivatives could be prepared in up to 99 : 1 d.r., 99 : 1 er and 99% yield and diverse enantiomerically enriched atropisomers bearing two five-membered heteroaryls have been accessed by using an oxidative central-to-axial chirality transfer strategy. The tethered nitrogen atom incorporated into the starting materials enabled easy late-modifications of the centrally and axially chiral products via C–H functionalizations, which further demonstrated the appealing synthetic utilities of this powerful asymmetric cyclization.Rh(ii)-catalyzed asymmetric cycloisomerization of azaenyne through a cap-tether synergistic modulation strategy was described. Diverse centrally and axially chiral isoindazoles were prepared and directed C–H late-stage modifications were developed.Known as one of the most significant and reliable access methods to chiral heterocycles, asymmetric cycloisomerization of conjugated enyne has caught extensive attention and interest for its wide applications in synthetic route design and mechanistic investigation.1 Specifically, asymmetric cyclization of conjugated enynone (X = C, Z = O) has been successfully developed and applied to the rapid construction of various chiral furan-containing skeletons with high efficiency in an extremely operationally simple manner (Scheme 1a).2 However, compared to the fruitful research with enynone, it is surprising that the analogous asymmetric version of azaenyne (Z = N–R) still remains underdeveloped.3 In fact, no successful example of catalytic asymmetric cyclization of azaenyne has been reported in the literature despite the apparent significance of nitrogen-containing five-membered heterocycles in the synthetic and pharmaceutical community.4 In 2004, Haley and Herges reported a detailed experimental and theoretical study of the cyclization reaction of (2-ethynylphenyl)-phenyldiazene, which is a unique azaenyne.5 According to the DFT calculations, very close and low activation barriers for 5-exo-dig and 6-endo-dig cyclization pathways under catalyst-free conditions were found, which shed light on the inherent challenges of the asymmetric reaction of azaenyne (Scheme 1b). For instance, there was usually a regioselectivity issue (5-exo and 6-endo) in the cyclization reaction of azaenyne because of their close reaction barriers where the competitive 6-endo-dig cyclization3a,6 may lead to troublesome side-product formation. In addition, the low activation barrier deriving from the strong N-nucleophilicity of azaenyne may easily lead to self-cyclization which will cause severe background reactions to interfere with the asymmetric process. More troublingly, this transformation might suffer from catalyst deactivation arising from the high coordinating capability of the nitrogen atom in both starting materials and products, which might give more opportunities to the propagation of detrimental background reactions. In some cases, even a super-stoichiometric amount of transition metal has to be used to ensure effective conversion.3a,7 Therefore, although many nonchiral approaches have been reported,3,5 catalytic asymmetric cyclization of azaenyne still remains elusive due to the inherent obstacles aforementioned. With our continuous interest in alkyne chemistry,2a,8 herein we designed a cap-tether synergistic modulation strategy to tackle these challenges, envisioning that modulation of the tethered atom and protecting cap of nitrogen in the azaenyne would intrinsically perturb and alter the reactivity of the starting material, and therefore the azaenyne motif could be effectively harnessed as a promising synthon for asymmetric transformations (Scheme 1c). It should be noted that the obtained centrally chiral product produced from intramolecular C–H insertion of donor-type metal carbene9 might be potentially converted into the axially chiral molecule via a central-to-axial chirality conversion strategy.Open in a separate windowScheme 1Development of the asymmetric cyclization reaction of conjugated azaenyne.With this design in mind, different types of azaenynes bearing typical tethering atoms and capping groups were chosen to test our hypothesis and representative results are shown in Scheme 2. First, tBu-capping imine (X = C, R = tBu) was selected as a substrate to test our hypothesis.6a It was found that the imine exhibited low reactivity and the reaction temperature has to be elevated to 100 °C to initiate the transformation with or without catalyst. Unfortunately, the desired 5-exo-dig cyclization product was not detected, but isoquinoline from 6-endo-dig cyclization was obtained instead (Scheme 2a). To further regulate and control the regioselectivity and reactivity, triazene (X = N, R = N-piperidyl) was then investigated. Similarly, this substrate also showed low reactivity and it is still required to be heated at 100 °C for conversion. In the absence of a metal catalyst, an unexpected alkyne, deriving from the fragmentation of the triazene moiety, was produced in 41% yield. When 2 mol% Rh2(OPiv)4 was added as a catalyst, the side reaction could be efficiently suppressed and the reaction selectivity was apparently reversed. In this case, the target C–H insertion dihydrofuran was furnished as the major product in 30% yield but still accompanied by concomitant formation of 12% yield of undesired alkyne (Scheme 2b). The above investigations showed neither the imine nor triazene was an ideal substrate for the asymmetric reaction. Thus, we moved our attention to the diazene substrate (X = N, R = aryl). As demonstrated by Haley''s and Herges'' pioneering work, ortho-alkynyl diazene, compared with imine and triazene, was more unstable and tended to self-cyclization even at room temperature.5a As shown in Scheme 2c, the ortho-alkynyl diazene degrades and 5-exo-dig cyclization products could be observed even in DCE solvent without any catalyst at room temperature. When the phenyl capping group was installed in the substrate, the reaction furnished 10% yield of isoindazole derivative. The uncatalyzed self-cyclization reaction was obviously accelerated when an electron-rich capping group (4-MeO–C6H4–) was introduced, affording the corresponding product in 20% yield. Inspired by these findings, we assumed that installation of an electron deficient group on the capping phenyl would reduce the nucleophilicity of the nitrogen atom and thus the troublesome self-cyclization reaction might be effectively inhibited. To our delight, when a bromo-substituent was introduced onto the phenyl cap, the undesired self-cyclization was almost suppressed. When Rh2(OPiv)4 was added as a catalyst, the desired carbene-involved C–H insertion product was furnished in 90% yield at room temperature. Worthy of note was the total absence of any cinnoline formation from 6-endo-dig cyclization.3a,6b In short, the synthetic challenges associated with regioselectivity (5-exo-dig and 6-endo-dig), strong background reaction and catalyst deactivation could be successfully regulated and controlled via a tether-cap synergistic modulation strategy.Open in a separate windowScheme 2Typical substrate investigation.Encouraged by the above findings, ortho-alkynyl bromodiazene 1a was chosen as a model substrate and different types of chiral dirhodium catalysts10 were screened in DCE at room temperature for 48 h. As shown in Entry Rh(ii)* Solvent Yieldb [%] erc 1 Rh2(R-DOSP)4 DCE 56 29 : 71 2 Rh2(5S-MEPY)4 DCE 17 50 : 50 3 Rh2(S-BTPCP)4 DCE 61 8 : 92 4 Rh2(S-PTPA)4 DCE 91 91 : 9 5 Rh2(S-PTTL)4 DCE 86 97 : 3 6 Rh2(S-PTAD)4 DCE 93 94 : 6 7 Rh2(S-NTTL)4 DCE 92 96 : 4 8 Rh2(S-TCPTTL)4 DCE 95 98 : 2 9 Rh 2 (S-TFPTTL) 4 DCE 98 d 98 : 2 10 Rh2(S-TFPTTL)4 DCM 88 98 : 2 11 Rh2(S-TFPTTL)4 Toluene 92 98 : 2 12 Rh2(S-TFPTTL)4 MeCN 16 92 : 8 13 Rh2(S-TFPTTL)4 n-Hexane 96 98 : 2 14e Rh2(S-TFPTTL)4 DCE 65f 96 : 4