Diversity-oriented synthesis of indole-fused scaffolds and bis(indolyl)methane from tosyl-protected tryptamine.

An efficient, diversity-oriented synthesis of indole-1,2-fused 1,4-benzodiazepines, tetrahydro-ß-carbolines, and 2,2'-bis(indolyl)methanes was established starting from tosyl-protected tryptamine. These diverse privileged skeletons were controllably constructed by adjusting different hydride donors and Brønsted acids. A variety of indole-1,2-fused 1,4-benzodiazepines were facilely accessed using benzaldehydes bearing cyclic amines as hydride donors via a cascade N-alkylation/dehydration/[1,5]-hydride transfer/Friedel-Crafts alkylation sequence. The reaction site could be switched when benzaldehydes bearing an alkoxy moiety as hydride donors were used for the generation of tetrahydro-ß-carbolines. On the other hand, the switchable synthesis of 2,2'-bis(indolyl)methanes could be achieved as well by applying p-TsOH·H2O as a catalyst. The reactions feature mild conditions, simple and practical operation, excellent efficiency and the use of EtOH as a green solvent. Using the concept of diversity-oriented, reagent-based synthesis, the inexpensive feedstock tryptamine was efficiently converted to three different types of privileged scaffolds, which facilitates rapid compound library synthesis for accelerating drug discovery.

Dearomatization of 3-Aminophenols for Synthesis of Spiro[chromane-3,1'-cyclohexane]-2',4'-dien-6'-ones via Hydride Transfer Strategy-Enabled [5+1] Annulations.

The Sc(OTf)3-catalyzed dearomative [5+1] annulations between readily available 3-aminophenols and O-alkyl ortho-oxybenzaldehydes were developed for synthesis of spiro[chromane-3,1'-cyclohexane]-2',4'-dien-6'-ones. The "two-birds-with-one-stone" strategy was disclosed by the dearomatization of phenols and direct α-C(sp3)-H bond functionalization of oxygen through cascade condensation/[1,5]-hydride transfer/dearomative-cyclization process. In addition, the antifungal activity assay and derivatizations of products were conducted to further enrich the utility of the structure.

Controllable Synthesis of N-Heterocycles via Hydride Transfer Strategy-Enabled Formal [5 + 1] and [5 + 2] Cyclizations.

The Brønsted acid-controlled switchable synthesis of indoline-fused tetrahydroquinolines and indole-fused benzazepines was developed through hydride transfer-enabled formal [5 + 1] and [5 + 2] cyclization reactions from indoles and N-alkyl o-aminobenzoketones. Indoline, furanone, and tetrahydroquinoline hybridized pentacyclic products were unprecedentedly accessed via a cascade condensation/hydride transfer/dearomatization-cyclization/deethylation/nucleophilic addition process. In addition, the undeveloped hydride transfer-involved [5 + 2] cyclizations were also realized for direct construction of indole-fused benzazepines.

Controllable Synthesis of N- and O-Containing Heterocycles via Formal [3 + 2] and [5 + 2] Cyclizations.

The controllable synthesis of spirooxindole-dihydrofurans and spirooxindole-benzazepines was developed through formal [3 + 2] and [5 + 2] cyclization reactions from 2-(2-oxoindolin-3-yl)malononitriles and ortho-aminobenzaldehydes, respectively. A variety of spirooxindole-benzazepines were facilely constructed via a furan ring-open-involved hydride transfer/cyclization process. It is noteworthy that the application of the hydride-transfer-involved [5 + 2] cyclization strategy for construction of spirobenzazepines was unprecedented. In addition, the spiro N- and O-containing heterocycles were highly functionalized by amino, amide, and cyano groups, which were conducive to late-stage functionalization.

Sulfur-containing marine natural products as leads for drug discovery and development.

Among the large series of marine natural products (MNPs), sulfur-containing MNPs have emerged as potential therapeutic agents for the treatment of a range of diseases. Herein, we reviewed 95 new sulfur-containing MNPs isolated during the period between 2021 and March 2023. In addition, we discuss that the widely used strategies and the emerging technologies including natural product-based antibody drug conjugates (ADCs), small-molecule-based proteolysis targeting chimeras (PROTACs), nanotechnology-based drug carriers, artificial intelligence (AI)-driven drug discovery have been used for improving the efficiency and success rate of NP-based drug development. We also provide perspectives regarding the challenges and opportunities in sulfur-containing MNPs based drug discovery and development and future research directions.

Analogues of natural products yaequinolones as potential inflammatory inhibitors: Design, synthesis and biological evaluation.

Inflammation is connected with a variety of diseases and there is still a need to develop more effective and safer anti-inflammatory drugs. Herein, we synthesized, resolved, and characterized eight enantiopure isomers of yaequinolone J1 (1), yaequinolone J2 (2), 4'-desmethoxyyaequinolone J1 (3), and 4'-desmethoxyyaequinolone J2 (4). The key synthetic steps were extended and 34 racemic analogues modified at the 4-aryl, the N-position, and the pyran ring were designed and synthesized. All the synthesized compounds were evaluated for their anti-inflammatory activities in RAW 264.7 cells of which 13 compounds showed significant inhibition of nitric oxide (NO) production at a concentration of 0.1 µM, which was more potent than that of indomethacin. Furthermore, compounds (-)-3, (-)-4, 5h, and 6g reduced the production of IL-6 in LPS-stimulated RAW 264.7 cells at a concentration of 50 nM. A preliminary SAR indicated that 3'-Br (5h), 4'-NO2 (6g) on 4-phenyl and 3-bromobenzyl (7f) on the N-position were the most effective substituents. This is the first report of the anti-inflammatory yaequinolone alkaloids and the present study provided evidence for exploiting this series of highly efficacious derivatives for new anti-inflammatory agents.

The Value of Left Internal Mammary Artery Flow Velocity in Predicting the Prognosis of Patients After Coronary Artery Bypass Grafting.

Background: The purpose of this study was to explore the value of the left internal mammary artery flow velocity (LIMAV) measured by ultrasound before coronary artery bypass grafting (CABG) in predicting the prognosis of patients after left internal mammary artery (LIMA) bypass grafting. Methods: One hundred and four patients who underwent CABG with LIMA as the bridge vessel in the cardiovascular surgery department of our hospital between May 2018 and June 2019 were selected. All patients underwent transthoracic Doppler ultrasonography to measure LIMAV preoperatively. Intraoperatively, mean graft flow (MGF) and pulsatility index (PI) of the LIMA bridge were measured using transit time flow measurement (TTFM). The primary endpoint event in this study was cardiac death within 18 months after surgery. Results: The Cox survival analysis showed that the MGF, the LIMAV and left ventricular ejection fraction (LVEF) were risk factors for death after CABG. The cut-offs of MGF, LIMAV and LVEF for the prediction of death after CABG were ≤ 14 mL/min (area under the curve (AUC): 0.830; sensitivity: 100%; specificity: 65.6%), ≤ 60 cm/s (AUC: 0.759; sensitivity: 65.5%; specificity: 85.3%), and ≤ 44% (AUC: 0.724; sensitivity: 50%; specificity: 88.5%), respectively. Compared with the use of MGF, MGF + LIMAV, combination of the MGF + LIMAV + LVEF (AUC: 0.929; sensitivity: 100%; specificity: 81.1%) resulted in a stronger predictive value (MGF vs. MGF + LIMAV + LVEF: P = 0.02). Conclusion: LIMAV measured by preoperative transthoracic ultrasound combined with intraoperative MGF and LVEF may have a greater value in predicting patients' risk of cardiac death after CABG.

Scalable total synthesis of (+)-aniduquinolone A and its acid-catalyzed rearrangement to aflaquinolones.

The strong antibacterial, antiviral and anticancer activities demonstrated by quinolones make them promising lead structures and important synthetic targets for drug discovery. Here, we report, to the best of our knowledge, the first scalable total synthesis of antiviral (+)-aniduquinolone A, possessing a 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one skeleton. This synthetic strategy explores E-stereoselective Horner-Wadsworth-Emmons (HWE) olefination as the key step to assemble isopropenyl substituted tetrahydrofuran onto the 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one core, which is built by highly diastereoselective intramolecular aldol reaction. Moreover, two sets of stereoisomers of aniduquinolone A with substantially overlapping NMR data were synthesized completely and assigned unambiguously by comprehensive analysis of both their spectroscopic and X-ray diffraction data. Unexpectedly, aflaquinolones A, C, and D that feature different 2,4-dimethyl cyclohexanone moieties were transformed successfully from (+)-aniduquinolone A by treating with TFA. The methodology delineated herein can be applied broadly to the synthesis of natural alkaloids containing the core structure of 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one.

Discovery, total syntheses and potent anti-inflammatory activity of pyrrolinone-fused benzoazepine alkaloids Asperazepanones A and B from Aspergillus candidus.

Natural products are well established as an important resource and play an important role in drug discovery. Here, two pyrrolinone-fused benzoazepine alkaloids, (+)-asperazepanones A (1) and B (2) with a 6/7/5 ring system, together with the artifact (-)-asperazepanone A (1), were isolated from the coral-derived Aspergillus candidus fungus. Their structures including absolute configurations were elucidated by extensive spectroscopic methods, single crystal X-ray diffraction, and ECD calculations. Furthermore, total syntheses of (±)-1 and (±)-2 have been achieved starting from the commercially L-aspartic acid diethyl ester hydrochloride and monoethyl malonate in 7 and 8 steps, respectively. The key step in the syntheses was an intramolecular Friedel-Crafts reaction to build the unique tricyclic skeleton. Interestingly, (+)-2 not only showed obviously inhibitory activity against NO production, but also inhibited potent LPS-induced expression of TNF-α and IL-6 at the concentration of 0.1 µM. It thus represents a potentially promising lead for anti-inflammatory drug discovery.

Two new polymorphs of cis-perinone: crystal structures, physical and electric properties.

The crystal structures of two polymorphs of cis-perinone (bisbenzimidazo[2,1-b:1',2'-j]benzo[lmn][3,8]phenanthroline-6,9-dione, Pigment Red 194) were solved from single crystals obtained solvothermally from 1,2-dichlorobenzene or n-butanol at 220°C. Both crystal structures (space group P21/c) derive from stacking of flat molecules arranged due to π-π interaction. The melting points of these two polymorphs are 471°C and 468°C and their respective optical bandgaps are 1.94 eV and 1.71 eV. One of the polymorphs demonstrates drift and hopping mechanisms of electric conductivity, whereas the other one is dominated by the drift conductivity. The direct current (DC) electric conductivity of the samples are 4.77 × 10-13 S m-1 and 6.84 × 10-10 S m-1 at room temperature. The significant difference in DC conductivities can be explained by the dependence of the mobility and concentration of charge carriers on the structure of the samples.

The influence of selective pulmonary perfusion on the inflammatory response and clinical outcome of patients with chronic obstructive pulmonary disease undergoing cardiopulmonary bypass.

OBJECTIVES: Patients undergoing cardiac surgery presenting with chronic obstructive pulmonary disease (COPD) have a higher 30-day mortality risk. In these patients, pulmonary dysfunction linked to an inflammatory response is frequent after cardiac operations using cardiopulmonary bypass (CPB), which causes pulmonary hypoperfusion. We hypothesize that selective pulmonary perfusion (sPP) of the lungs leads to a reduction of pulmonary inflammation and a better clinical outcome. METHODS: Fifty-nine COPD patients (forced expiratory volume in 1 s/vital capacity <70%) undergoing cardiac surgery procedures (coronary artery bypass grafting 64%, valve 14%) were block-randomized to sPP (venous blood, temperature 2°C, 4 l) or standard CPB (28/28). The primary end-point of the study was to evaluate the effect of pulmonary perfusion on gas exchange by measuring alveolar-arterial oxygen gradient. The surrogate end-points were inflammatory response, intensive care unit (ICU) stay, time on respirator (TOR) and major adverse cardiac and cerebrovascular events. A cytokine assay for interleukin-1ß, IL-6, IL-10, tumour necrosis factor-α (TNF-α) and polymorphonuclear elastase was performed with peripheral blood at different time-points [(t1) pre-CPB, (t2) end of CPB, (t3) 3 h, (t4) 24 h, (t5) 48 h postoperatively]. Repeated-measure analysis of variance and non-parametric statistics were used to assess the between-group and during time differences. RESULTS: The two groups proved comparable for perioperative variables. Serum cytokines were not different in the two groups throughout the study (P > 0.05 at single time-points), but as a function of time, the markers of the inflammatory response increased after CBP (P < 0.05 pre-CPB to 24 h). Clinical end-points were statistically comparable in both groups, but with a trend towards a shorter TOR (72 ± 159 h/106 ± 193 h) and ICU stay (3.9 ± 7.2 days/5.5 ± 9.2 days) in the sPP group despite a slightly longer time on extracorporeal circulation (120 vs 158 min). CONCLUSIONS: These results indicate a non-significant trend that repeated hypothermic lung perfusion with venous blood during CPB may have a protective effect on the lungs. A multicentre study design and larger cohort seem necessary to demonstrate the benefits of sPP more clearly.