An effective and practical strategy has been established for the direct and site‐selective arylation of indoles at the C4 and C5 positions with the aid of a readily accessible, cheap, and removable ...pivaloyl directing group at the C3 position. This transformation shows good functional‐group tolerance and could serve as a powerful synthetic tool for the synthesis of medicinally relevant compounds. This method and those developed in previous research together enable the regiocontrolled direct arylation of indole at each C−H bond without prefunctionalization of the reactive sites.
Grand Slam: An effective and practical strategy has been established for the direct site‐selective arylation of indoles at the C4 or C5 position (see scheme) by the use of a readily available and removable pivaloyl directing group (DG) at the indole C3 position. Now the direct site‐selective arylation of indoles at any given C−H bond is possible by the appropriate choice of this or a previously developed complementary method.
Cu-Catalyzed Direct C6-Arylation of Indoles Yang, Youqing; Li, Ruirui; Zhao, Yue ...
Journal of the American Chemical Society,
07/2016, Letnik:
138, Številka:
28
Journal Article
Recenzirano
The first example of direct and site-selective arylation of indoles at the C6 position has been reported. The key to this high regioselectivity is the appropriate choice of the N–P(O) t Bu2 ...directing group and the use of diaryliodonium triflate salts as the coupling partners in the presence of catalytic CuO. The protocol is distinguished by mild reaction system that avoids ligand and additives, exhibiting wide scope of indole and arene coupling components without compromising its efficiency and scalability, thus representing a significant advancement in the implementation of regioselective direct arylation of indoles.
Prized for their ability to generate chemical complexity rapidly, catalytic carbon-hydrogen (C-H) activation and functionalization reactions have enabled a paradigm shift in the standard logic of ...synthetic chemistry. Directing group strategies have been used extensively in C-H activation reactions to control regio- and enantioselectivity with transition metal catalysts. However, current methods rely heavily on coordination with nitrogen and/or oxygen atoms in molecules and have therefore been found to exhibit limited generality in asymmetric syntheses. Here, we report enantioselective C-H activation with unsaturated hydrocarbons directed by phosphorus centres to rapidly construct libraries of axially chiral phosphines through dynamic kinetic resolution. High reactivity and enantioselectivity are derived from modular assembly of an iridium catalyst with an endogenous phosphorus atom and an exogenous chiral phosphorus ligand, as confirmed by detailed experimental and computational studies. This reaction mode significantly expands the pool of enantiomerically enriched functional phosphines, some of which have shown excellent efficiency for asymmetric catalysis.
Different site selectivities have been reported for indoles with different directing groups in copper-catalyzed site-selective C–H arylations. Computational and mass spectrometric studies have been ...conducted in an effort to understand the origin of site selectivity and the effects of the directing groups. A Heck-like mechanism involving a four-membered ring is found in all three of the cases studied. For N-acetyl indole with a weak directing group, a neutral Heck-like mechanism is controlled by an electronic effect resulting in C2 site selectivity. In contrast, indole with a N-P(O) t Bu2 group and N-benzyl-3-pivaloyl indole prefer a cationic Heck-like reaction in which a favorable six-membered chelation between the directing group and the CuIII center determines the C6 and C5 site selectivities.
Venous hypertension(VH) plays an important role in the pathogenesis of cerebral arteriovenous malformations (AVMs) and is closely associated with the HIF-1α/VEGF signaling pathway. Nuclear factor ...erythroid 2-related factor 2(Nrf2) significantly influences angiogenesis; however, the interplay between Nrf2 and VEGF under VH in brain AVMs remains unclear. Therefore, our study aimed to investigate the interplay between Nrf2 and VEGF due to VH in brain AVMs. Immunohistochemistry indicated that Nrf2 and VEGF were highly expressed in human brain AVM tissues. In vivo, we established a VH model in both wild-type (WT) and siRNA-mediated Nrf2 knockdown rats. VH significantly increased the expression of Nrf2 and VEGF. Loss of Nrf2 markedly inhibited the upregulation of VEGF, as determined by Western blot analysis and qRT-PCR. In vitro, primary brain microvascular endothelial cells (BMECs) were isolated from WT and Nrf2
mice, and a VEGF-Nrf2 positive feed-back loop was observed in BMECs. By trans well assay and angiogenesis assay, Nrf2 knockout significantly inhibited the migration and vascular tube formation of BMECs. These findings suggest that the interplay between Nrf2 and VEGF can contribute to VH-induced angiogenesis in brain AVMs pathogenesis.
The present study was aimed to evaluate the neuroprotective effects of NBP in the mice models of TBI, as well as the possible role of Nrf2-ARE pathways in the assumptive neuroprotection. In mice,a ...modified Marmarou’s weight-drop model was employed to induce TBI. ICR mice were randomly assigned to four experimental groups: sham, TBI, TBI+vehicle(V) and TBI+NBP. NBP (100 mg/kg) was administered via an intraperitoneal (i.p.) injection at 1 h following TBI. The administration of NBP significantly ameliorated the effects of the brain injury, including neurological deficits, brain water content, and cortical neuronal apoptosis. Furthermore, the level of malondialdehyde and the activity of superoxide dismutase (SOD) paired with glutathione peroxidase (GPx) were restored in the NBP treatment group. NBP promoted the translocation of Nrf2 protein from the cytoplasm to the nucleus markedly, increased the expressions of Nrf2-ARE pathway-related downstream factors, including hemeoxygenase-1(HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1), and prevented the decline of antioxidant enzyme activities, including SOD and GPx. NBP enhanced the translocation of Nrf2 to the nucleus from the cytoplasm,verified by a western blot, immunofluorescence. Additionally, it upregulated the expression of the Nrf2 downstream factors such as HO-1 and NQO1 were also confirmed via a western blot and real-time quantitative polymerase chain reaction. In conclusion, NBP administration may increase the activities of antioxidant enzymes and attenuate brain injury in a TBI model, potentially via the mediation of the Nrf2-ARE pathway.
Subarachnoid hemorrhage (SAH) is a neurological emergency characterized by dysfunctional inflammatory response. However, no effective therapeutic options have been reported so far. Microglia ...polarization has been proposed to exert an essential role in modulating inflammatory response after SAH. Sestrin2 is a stress response protein. Growing evidence has reported that sestrin2 could inhibit M1 microglia and promote M2 microglia polarization. The current study investigated the effects of sestrin2 on microglia phenotype switching and the subsequent brain injury and sought to elucidate the underlying mechanism. We conducted an endovascular perforation SAH model in mice. It was found that sestrin2 was significantly increased after SAH and was mainly distributed in neurons and microglia. Exogenous recombinant human sestrin2 (rh-sestrin2) evidently alleviated inflammatory insults and oxidative stress, and improved neurofunction after SAH. Moreover, rh-sestrin2 increased M2-like microglia polarization and suppressed the number of M1-like microglia after SAH. The protection by rh-sestrin2 was correlated with the activation of Nrf2 signaling. Nrf2 inhibition by ML385 abated the cerebroprotective effects of rh-sestrin2 against SAH and further manifested M1 microglia polarization. In conclusion, promoting microglia polarization from the M1 to M2 phenotype and inducing Nrf2 signaling might be the major mechanism by which sestrin2 protects against SAH insults. Sestrin2 might be a new molecular target for treating SAH.
Over the past several decades, the endoscopic endonasal transsphenoidal approach (EETA) has gradually become a preferred option of pituitary adenomas surgery because of its minimal invasiveness and ...high efficiency. However, some EETA operations were performed through one nostril (mononostril), while other EETA operations were performed through both nostrils (binostril). Therefore, we conducted this study to compare the pros and cons of these two methods in an attempted to confirm which method is more effective.
We executed a systematic literature search of PubMed, the Cochrane Library, and the Web of Science and Medline (1992-2015). The language is limited to English and all studies should meet the inclusion criteria. Comparisons were made for postoperative outcomes, complications, and other relevant parameters between the mononostril and the binostril group. Statistical analyses of categorical variables were undertaken by the use of Stata 12.0 and SPASS 19.0.
Thirty studies, involving 4805 patients, were included. The two groups had similar results in GTR rate (included GTR rate of macroadenomas), hormonal remission rate, improvement in visual function, postoperative CSF leak, permanent diabetes insipidus, meningitis, and sinusitis. The binostril group had less temporary diabetes insipidus (2.9% vs. 5.3%, p = 0.022), less anterior pituitary insufficiency (2.3% vs. 6.4%, p = 0.000) and few hospitalization days (3.2 days vs. 4.4 days, p<0.05) than the mononostril group. However, the mononostril group had less rate of epistaxis (0.4% vs. 1.5%, p = 0.008) than the binostril group. For invasive macroadenomas, the binostril group seem to demonstrate a tendency towards better outcomes though there was no subgroup analysis between the two groups.
The binostril approach had less temporary diabetes insipidus, anterior pituitary insufficiency, and a shorter length of hospital stay, although they demonstrated a higher rate of epistaxis than the mononstril group. Additionally, the binostril group seemed to suggest a tendency towards better outcomes for invasive macroadenomas.
Objective
The surgical management of lesions involving the lateral area of the suprasellar region, including the lateral aspect of the planum sphenoidale and the tight junction region of the optic ...canal (OC), anterior clinoid process (ACP), and internal carotid artery (ICA) and its dural rings, is extremely challenging. Here, these regions, namely, the “parasuprasellar” area, are described from the endonasal perspective. Moreover, the authors introduce two novels endoscopic endonasal supraoptic (EESO) and endoscopic endonasal infraoptic (EEIO) approaches to access the parasuprasellar area.
Methods
Surgical simulation of the EESO and EEIO approaches to the parasuprasellar area was conducted in 5 silicon-injected specimens. The same techniques were applied in 12 patients with lesions involving the parasuprasellar area.
Results
The EESO approach provided excellent surgical access to the lateral region of the planum sphenoidale, which corresponds to the orbital gyrus of the frontal lobe. With stepwise bone (OC, optic strut and ACP) removal, dissociation of the ophthalmic artery (OA) and optic nerve (ON), the EEIO approach enables access to the lateral region of the supraclinoidal ICA. These approaches can be used independently or in combination, but are more often employed as a complement to the endoscopic endonasal midline and transcavernous approaches. In clinical application, the EESO and EEIO approaches were successfully performed in 12 patients harboring tumors as well as multiple aneurysms involving the parasuprasellar area. Gross total and subtotal tumor resection were achieved in 9 patients and 1 patient, respectively. For two patients with multiple aneurysms, the lesions were clipped selectively according to location and size. Visual acuity improved in 7 patients, remained stable in 4, and deteriorated in only 1. No postoperative intracranial infection or ICA injury occurred in this series.
Conclusions
The EESO and EEIO approaches offer original treatment options for well-selected lesions involving the parasuprasellar area. They can be combined with the endoscopic endonasal midline and transcavernous approaches to remove extensive pathologies involving the intrasellar, suprasellar, sphenoid, and cavernous sinuses and even the bifurcation of the ICA. This work for the first time pushes the boundary of the endoscopic endonasal approach lateral to the supraclinoidal ICA and ON.
Objective
Suprasellar pituitary adenomas (PAs) can be located in either extradural or intradural spaces, which impacts surgical strategies and outcomes. This study determined how to distinguish these ...two different types of PAs and analyzed their corresponding surgical strategies and outcomes.
Methods
We retrospectively analyzed 389 patients who underwent surgery for PAs with suprasellar extension between 2016 to 2020 at our center. PAs were classified into two main grades according to tumor topography and their relationships to the diaphragm sellae (DS) and DS-attached residual pituitary gland (PG). Grade 1 tumors were located extradurally and further divided into grades 1a and 1b, while grade 2 tumors were located intradurally.
Results
Of 389 PAs, 292 (75.1%) were surrounded by a bilayer structure formed by the DS and the residual PG and classified as grade 1a, 63 (16.2%) had lobulated or daughter tumors resulting from the thinning or absence of the residual PG and subsequently rendering the bilayer weaker were classified as Grade 1b, and the remaining 34 (8.7%) PAs that broke through the DS or traversed the diaphragmic opening and encased suprasellar neurovascular structures were classified as Grade 2. We found that the gross total removal of the suprasellar part of grade 1a, 1b, and 2 PAs decreased with grading (88.4%, 71.4%, and 61.8%, respectively). The rate of major operative complications, including cerebrospinal fluid leakage, hemorrhage, and death, increased with grading.
Conclusions
It is essential to identify whether PAs with suprasellar extension are located extradurally or intradurally, which depends on whether the bilayer structure is intact. PAs with an intact bilayer structure were classified as grade 1. These were extradural and usually had good surgical outcomes and lower complications. PAs with no bilayer structure surrounding them were classified as grade 2. These were intradural, connected to the cranial cavity, and had increased surgical complications and a lower rate of gross total removal. Different surgical strategies should be adopted for extradural and intradural PAs.
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