Panaxydol extracted from Panax ginseng inhibits NLRP3 inflammasome activation to ameliorate NASH-induced liver injury.

Activation of NOD-like receptor protein 3 (NLRP3) inflammasome exacerbates liver inflammation and fibrosis in nonalcoholic steatohepatitis (NASH), suggesting that development of inflammasome inhibitor can become leading candidate to ameliorate NASH. Panax ginseng (P. ginseng) contains numerous bioactive natural components to reduce inflammation. This study aims to identify inhibitory components of P. ginseng for NLRP3 inflammasome activation. We separated polar and non-polar fractions of P. ginseng and tested modulation of NLRP3 inflammasome, and then identified pure component for inflammasome inhibitor which ameliorates diet-induced NASH. Non-polar P. ginseng fractions obtained from ethyl acetate solvent attenuated IL-1ß secretion and expression of active caspase-1. We revealed that panaxydol (PND) is pure component to inhibit NLRP3 inflammasome activation. PND blocked inflammasome cytokines release, pyroptotic cell death, caspase-1 activation and specking of inflammasome complex. Inhibitory effect of PND was specific to NLRP3-dependent pathway via potential interaction with ATP binding motif of NLRP3. Moreover, in vivo studies showed that PND plays beneficial roles to reduce tissue inflammations through disruption of NLRP3 inflammasome and to ameliorate the development of NASH. These results provide new insight of natural products, panaxydol, for NLRP3 inflammasome inhibitor and could offer potential therapeutic candidate for reliving NASH.

Recent asymmetric synthesis of natural products bearing an α-tertiary amine moiety via temporary chirality induction strategies.

Covering: 2013 to 2023The α-tertiary amine moiety is a common structural motif in natural alkaloids and is frequently associated with intriguing biological activities and inherent synthetic challenges. A major hurdle in the total synthesis of these alkaloids is the asymmetric construction of the α-tertiary amine moiety. Temporary chirality inductions have been effective strategies employed to address this issue, particularly in natural product synthesis. The temporary chirality induction strategies in α-tertiary amine synthesis can be broadly classified into three categories based on the types of temporary chirality involved: Seebach's self-regeneration of stereocenters (SRS), C-to-N-to-C chirality transfer, and memory of chirality (MOC). This review highlights the recent advancements in temporary chirality induction strategies for the total synthesis of α-tertiary amine-containing natural products between 2013 and 2023.

Synthesis and evaluation of tirbanibulin derivatives: a detailed exploration of the structure-activity relationship for anticancer activity.

Tirbanibulin, an FDA-approved microtubule-targeting agent (MTA) introduced in 2020, represents a pioneering treatment for precancerous actinic keratosis. Despite its failure to gain approval as an anticancer agent due to insufficient efficacy, there remains potential value in extending its application into malignancy treatment through tirbanibulin-based derivatives. Tirbanibulin possesses a distinctive dual mechanism of action involving microtubule and Src inhibition, distinguishing it from other MTAs. In spite of its unique profile, exploration of tirbanibulin's structure-activity relationship (SAR) and the development of its derivatives are significantly limited in the current literature. This study addresses this gap by synthesizing various tirbanibulin derivatives and exploring their SAR through modifications in the core amide motif and the eastern benzylamine part. Our results underscore the critical role of the pyridinyl acetamide core structure for optimal cellular potency, with favorable tolerance observed for modifications at the para position of the benzylamine moiety. Particularly noteworthy is the analogue modified with p-fluorine benzylamine, which exhibited favorable in vivo PK profiles. These findings provide crucial insights into the potential advancement of tirbanibulin-based compounds as promising anticancer agents.

First-Pass Recanalization with EmboTrap II in Acute Ischemic Stroke (FREE-AIS): A Multicenter Prospective Study.

OBJECTIVE: We aimed to evaluate the efficacy of EmboTrap II in terms of first-pass recanalization and to determine whether it could yield favorable outcomes. MATERIALS AND METHODS: In this multicenter, prospective study, we consecutively enrolled patients who underwent mechanical thrombectomy using EmboTrap II as a front-line device. The primary outcome was the first pass effect (FPE) rate defined by modified Thrombolysis In Cerebral Infarction (mTICI) grade 2c or 3 by the first pass of EmboTrap II. In addition, modified FPE (mFPE; mTICI grade 2b-3 by the first pass of EmboTrap II), successful recanalization (final mTICI grade 2b-3), and clinical outcomes were assessed. We also analyzed the effect of FPE on a modified Rankin Scale (mRS) score of 0-2 at 3 months. RESULTS: Two hundred-ten patients (mean age ± standard deviation, 73.3 ± 11.4 years; male, 55.7%) were included. Ninety-nine patients (47.1%) had FPE, and mFPE was achieved in 150 (71.4%) patients. Successful recanalization was achieved in 191 (91.0%) patients. Among them, 164 (85.9%) patients underwent successful recanalization by exclusively using EmboTrap II. The time from groin puncture to FPE was 25.0 minutes (interquartile range, 17.0-35.0 minutes). Procedure-related complications were observed in seven (3.3%) patients. Symptomatic intracranial hemorrhage developed in 14 (6.7%) patients. One hundred twenty-three (58.9% of 209 completely followed) patients had an mRS score of 0-2. Sixteen (7.7% of 209) patients died during the follow-up period. Patients who had successful recanalization with FPE were four times more likely to have an mRS score of 0-2 than those who had successful recanalization without FPE (adjusted odds ratio, 4.13; 95% confidence interval, 1.59-10.8; p = 0.004). CONCLUSION: Mechanical thrombectomy using the front-line EmboTrap II is effective and safe. In particular, FPE rates were high. Achieving FPE was important for an mRS score of 0-2, even in patients with successful recanalization.

Synthesis of Bridged Oxabicycles via Cascade Reactions involving O-Acyloxocarbenium Ion Intermediates.

Compared to related electrophilic species, O-acyloxocarbenium ions (AOIs) have been much less utilized in organic synthesis due to the lack of an efficient formation method. Here, we present a facile and simple approach for the generation of AOI from ester and acetal groups. Based on our AOI system with a pendant nucleophile, we obtained a unique bridged bicyclic system via an epoxonium-like transition state. The proposed mechanism is based on experimental and computational studies.

Total Syntheses of Pladienolide-Derived Spliceosome Modulators.

Pladienolides, an emerging class of naturally occurring spliceosome modulators, exhibit interesting structural features, such as highly substituted 12-membered macrocycles and epoxide-containing diene side chains. The potential of pladienolides as anti-cancer agents is confirmed by H3B-8800, a synthetic analog of this natural product class, which is currently under Phase I clinical trials. Since its isolation in 2004 and the first total synthesis in 2007, a dozen total syntheses and synthetic approaches toward the pladienolide class have been reported to date. This review focuses on the eight completed total syntheses of naturally occurring pladienolides or their synthetic analogs, in addition to a synthetic approach to the main framework of the natural product.

Synthesis of Cyclohexane-Angularly-Fused Triquinanes.

Cyclohexane-angularly-fused triquinanes, 6-5-5-5 tetracycles, have attracted the attention of synthetic chemists due to their highly congested core structures and multiple quaternary carbon centers. This review focuses on the six completed total synthesis of naturally occurring cyclohexane-angularly-fused triquinanes in addition to seven notable methodologies that have been developed for the synthesis of these structures.

Collective Asymmetric Total Synthesis of C-11 Oxygenated Cephalotaxus Alkaloids.

While numerous studies pertaining to the total synthesis of Cephalotaxus alkaloids have been reported, only two strategies have been reported to date for the successful synthesis of the C-11 oxygenated subset, due to the additional synthetic challenge posed by the remote C-11 stereocenter. Herein, we report the collective asymmetric total synthesis of C-11 oxygenated Cephalotaxus alkaloids using a chiral proline both as a starting material and as the only chirality source. A tetracyclic advanced intermediate was synthesized in a highly stereoselective manner from l-proline in 8 steps involving sequential chirality transfer steps such as a diastereoselective N-alkylation, stereospecific Stevens rearrangement and intramolecular Friedel-Crafts reaction via an unusual O-acyloxocarbenium intermediate. From a common intermediate, the asymmetric total synthesis of six C-11 oxygenated Cephalotaxus alkaloids was completed by a series of oxidation state adjustments.

Stereoselective Asymmetric Synthesis of Pyrrolidines with Vicinal Stereocenters Using a Memory of Chirality-Assisted Intramolecular SN2' Reaction.

An efficient strategy for the asymmetric synthesis of pyrrolidines with vicinal quaternary-tertiary or quaternary-quaternary stereocenters was established. A "memory of chirality" intramolecular SN2' reaction of α-amino ester enolates with allylic halides provided a functionalized pyrrolidine with excellent dia- and enantioselectivity. This method features construction of stereochemically enriched pyrrolidines in a single operation through the influence of a single chiral center presented in substrates.

Carotid Artery Stenting and Intracranial Thrombectomy for Tandem Cervical and Intracranial Artery Occlusions.

BACKGROUND: It remains controversial whether carotid artery stenting (CAS) is needed in cases of tandem cervical internal carotid artery occlusion (cICAO) and intracranial large vessel occlusion (LVO). OBJECTIVE: To investigate the efficacy and safety of CAS in combination with endovascular thrombectomy (CAS-EVT) in cICAO-LVO patients and to compare its outcomes with those of EVT without CAS (EVT-alone). METHODS: We identified all patients who underwent EVT for tandem cICAO-LVO from the prospectively maintained registries of 17 stroke centers. Patients were classified into 2 groups: CAS-EVT and EVT-alone. Clinical characteristics and procedural and clinical outcomes were compared between 2 groups. We tested whether CAS-EVT strategy was independently associated with recanalization success. RESULTS: Of the 955 patients who underwent EVT, 75 patients (7.9%) had cICAO-LVO. Fifty-six patients underwent CAS-EVT (74.6%), and the remaining 19 patients underwent EVT-alone (25.4%). The recanalization (94.6% vs 63.2%, P = .002) and good outcome rates (64.3% vs 26.3%, P = .007) were significantly higher in the CAS-EVT than in the EVT-alone. Mortality was significantly lower in the CAS-EVT (7.1% vs 21.6%, P = .014). There was no significant difference in the rate of symptomatic intracranial hemorrhage between 2 groups (10.7 vs 15.8%; P = .684) and according to the use of glycoprotein IIb/IIIa inhibitor (10.0% vs 12.3%; P = .999) or antiplatelet medications (10.2% vs 18.8%; P = .392). CAS-EVT strategy remained independently associated with recanalization success (odds ratio: 24.844; 95% confidence interval: 1.445-427.187). CONCLUSION: CAS-EVT strategy seemed to be effective and safe in cases of tandem cICAO-LVO. CAS-EVT strategy was associated with recanalization success, resulting in better clinical outcome.

Proline Ester Enolate Claisen Rearrangement and Formal Total Synthesis of (-)-Cephalotaxine.

A concise formal total synthesis of (-)-cephalotaxine was achieved via an ester enolate Claisen rearrangement (EECR). A series of EECRs of proline allyl esters were examined to obtain the desired relative stereochemistry of an azaspiranic tetracyclic backbone. An unexpected reversal or low diastereoselectivity of ( Z)-cinnamyl ester was observed. The diastereoselectivity was controlled by substitution patterns of a styrene region. This result represents a useful guide in aiding the prediction of stereochemical outcome of EECR of α-amino allylic esters.

Balloon Guide Catheter Is Beneficial in Endovascular Treatment Regardless of Mechanical Recanalization Modality.

Background and Purpose- Based on its mechanism, the use of balloon guide catheters (BGCs) may be beneficial during endovascular treatment, regardless of the type of mechanical recanalization modality used-stent retriever thrombectomy or thrombaspiration. We evaluated whether the use of BGCs can be beneficial regardless of the first-line mechanical endovascular modality used. Methods- We retrospectively reviewed consecutive acute stroke patients who underwent stent retriever thrombectomy or thrombaspiration from the prospectively maintained registries of 17 stroke centers nationwide. Patients were assigned to the BGC or non-BGC group based on the use of BGCs during procedures. Endovascular and clinical outcomes were compared between the BGC and non-BGC groups. To adjust the influence of the type of first-line endovascular modality on successful recanalization and favorable outcome, multivariable analyses were also performed. Results- This study included a total of 955 patients. Stent retriever thrombectomy was used as the first-line modality in 526 patients (55.1%) and thrombaspiration in 429 (44.9%). BGC was used in 516 patients (54.0%; 61.2% of stent retriever thrombectomy patients; 45.2% of thrombaspiration patients). The successful recanalization rate was significantly higher in the BGC group compared with the non-BGC group (86.8% versus 74.7%, respectively; P<0.001). Furthermore, the first-pass recanalization rate was more frequent (37.0% versus 14.1%; P<0.001), and the number of device passes was fewer in the BGC group (2.5±1.9 versus 3.3±2.1; P<0.001). The procedural time was also shorter in the BGC group (54.3±27.4 versus 67.6±38.2; P<0.001). The use of BGC was an independent factor for successful recanalization (odds ratio, 2.18; 95% CI, 1.54-3.10; P<0.001) irrespective of the type of first-line endovascular modality used. The use of BGC was also an independent factor for a favorable outcome (odds ratio, 1.40; 95% CI, 1.02-1.92; P=0.038) irrespective of the type of first-line endovascular modality used. Conclusions- Regardless of the first-line mechanical endovascular modality used, the use of BGC in endovascular treatment was beneficial in terms of both recanalization success and functional outcome.

Total Synthesis and Structural Elucidation of (-)-Cephalezomine G.

The first asymmetric synthesis and configurational elucidation of (-)-cephalezomine G was achieved. The highly functionalized Cα-substituted proline derivative was prepared from d-proline as the only chiral source via a C → N → C chirality transfer method consisting of stereoselective N-allylation and [2,3]-Stevens rearrangement. The azaspiranic tetracyclic backbone was constructed using ring-closing metathesis and the Friedel-Crafts reaction. Two contiguous hydroxyl groups were introduced in the later stages.

Expedient Synthesis of Alphitolic Acid and Its Naturally Occurring 2- O-Ester Derivatives.

The expedient synthesis of alphitolic acid (1) as well as its natural C-3-epimer and 2- O-ester derivatives was accomplished in a few steps from the readily commercially available betulin (9). A Rubottom oxidation delivered an α-hydroxy group in a stereo- and chemoselective manner. The diastereoselective reduction of the α-hydroxy ketone was key to accessing the 1,2-diol moiety of this class of natural products. Our concise and stereoselective synthetic protocol allowed the gram-scale synthesis of these natural products, which will facilitate future biological evaluations.

Asymmetric Synthesis of Cα-Substituted Prolines through Curtin-Hammett-Controlled Diastereoselective N-Alkylation.

Asymmetric synthesis of α-substituted proline derivatives has been accomplished by an efficient chirality-transfer method. High diastereoselectivity of the N-alkylation of the proline ester (C→N chirality transfer) was achieved when a 2,3-disubstituted benzyl group was used as the N-substituent. DFT calculations provided a mechanistic rationale for the high degree of stereoselectivity. The generated N-chirality of the quaternary ammonium salt was transferred back to the α-carbon through a stereoselective [2,3]-Stevens rearrangement (N→C chirality transfer) to give α-substituted proline ester.

Endovascular Coiling for a Wide-neck Bifurcated Aneurysm with Anterograde Horizontal Stenting via Microcatheter Looping: A Technical Case Report.

Technical advances with devices such as catheters, balloons, and stents have widened the indications for endovascular coiling for unfavorable aneurysms. The authors report two cases of coil embolization for a wide-neck bifurcated aneurysm with anterograde horizontal stenting via microcatheter looping. Two women, aged 56 and 38 years, respectively, had an undertall- and overwide-neck aneurysm with bifurcated branches at the basilar bifurcation and middle cerebral bifurcation, respectively. The delivery microcatheter was steamed so that it could be looped deliberately to the opposite vessel. The enterprise stent was first anchored to the vessel of the posterior cerebral artery on one side. The remaining portion was spanned into a looped microcatheter to the opposite branch while pushing the stent. The Neuroform Atlas stent was passed directly through the looped segment of the microcatheter at the M2 branch and spanned horizontally by unsheathing. Under horizontal stenting, complete coil embolization was achieved without immediate or delayed complications in both cases. This novel technique presents a viable option for stent-assisted coiling within an optimal anatomy.

Number of Stent Retriever Passes Associated With Futile Recanalization in Acute Stroke.

Background and Purpose- Stent retriever (SR) thrombectomy has become the mainstay of treatment of acute intracranial large artery occlusion. However, it is still not much known about the optimal limit of SR attempts for favorable outcome. We evaluated whether a specific number of SR passes for futile recanalization can be determined. Methods- Patients who were treated with a SR as the first endovascular modality for their intracranial large artery occlusion in anterior circulation were retrospectively reviewed. The recanalization rate for each SR pass was calculated. The association between the number of SR passes and a patient's functional outcome was analyzed. Results- A total of 467 patients were included. Successful recanalization by SR alone was achieved in 82.2% of patients. Recanalization rates got sequentially lower as the number of passes increased, and the recanalization rate achievable by ≥5 passes of the SR was 5.5%. In a multivariable analysis, functional outcomes were more favorable in patients with 1 to 4 passes of the SR than in patients without recanalization (odds ratio [OR] was 8.06 for 1 pass; OR 7.78 for 2 passes; OR 6.10 for 3 passes; OR 6.57 for 4 passes; all P<0.001). However, the functional outcomes of patients with ≥5 passes were not significantly more favorable than found among patients without recanalization (OR 1.70 with 95% CI, 0.42-6.90 for 5 passes, P=0.455; OR 0.33 with 0.02-5.70, P=0.445 for ≥6 passes). Conclusions- The likelihood of successful recanalization got sequentially lower as the number of SR passes increased. Five or more passes of the SR became futile in terms of the recanalization rate and functional outcomes.

Asymmetric Cα-Alkylation of Proline via Chirality Transfers of Conformationally Restricted Proline Derivative: Application to the Total Synthesis of (-)-Amathaspiramide F.

An efficient strategy for the asymmetric synthesis of Cα-tetrasubstituted proline derivatives from proline has been established. A nitrogen-fused bicyclic system was devised to control the stereodynamics of proline. Through N-quaternizations with allylic electrophiles followed by [2,3]-rearrangements, the bicyclic proline system delivered enantioenriched Cα-tetrasubstituted prolines. This strategy was applied to the concise total synthesis of (-)-amathaspiramide F.

Total Syntheses of Isowondonins Based on a Biosynthetic Pathway.

The first total syntheses of (-)-isowondonin A and (-)-isowondonin B, which are unusual imidazole marine alkaloids, has been accomplished through the development of methods for the selective formation of styryl sulfate group and regioselective alkylation of the imidazole. Application of the Noyori asymmetric hydrogenation of ketones allows the asymmetric synthesis. These results in conjunction with ECD calculations led to the determination of the absolute configuration of isowondonins.

Chemical assay-guided natural product isolation via solid-supported chemodosimetric fluorescent probe.

As a new model of chemical assay-guided natural product isolation, an effective chemodosimetric assay system was devised. Our chemical assay system features a fluorogenic chemodosimeter immobilized on a solid support, which offers advantages in identifying the desired compounds in complex natural product mixtures. To isolate only compounds with the target functional groups, the click chemistry concept was adopted. The model system presented here was developed for natural products with a terminal alkyne. Using our newly designed alkyne sensing beads with the aforementioned features, we have readily identified, quantified, and isolated compounds with a terminal alkyne group from plant extracts.