Discovery of Novel p53-MDM2 Inhibitor (RG7388)-Conjugated PlatinumIV Complexes as Potent Antitumor Agents.

While a number of p53-MDM2 inhibitors have progressed into clinical trials for the treatment of cancer, their progression has been hampered by a variety of problems, including acquired drug resistance, dose-dependent toxicity, and limited clinical efficiency. To make more progress, we integrated the advantages of MDM2 inhibitors and platinum drugs to construct novel PtIV-RG7388 (a selective MDM2 inhibitor) complexes. Most complexes, especially 5a and 5b, displayed greatly improved antiproliferative activity against both wild-type and mutated p53 cancer cells. Remarkably, 5a exhibited potent in vivo tumor growth inhibition in the A549 xenograft model (66.5%) without apparent toxicity. It arrested the cell cycle at both the S phase and the G2/M phase and efficiently induced apoptosis via the synergistic effects of RG7388 and cisplatin. Altogether, PtIV-RG7388 complex 5a exhibited excellent in vitro and in vivo antitumor activities, highlighting the therapeutic potential of PtIV-RG7388 complexes as antitumor agents.

Impact of Left Renal Vein Ligation on Renal Function Following En Bloc Resection of Segmental Inferior Vena Cava and Right Kidney.

BACKGROUND: Renal function after left renal vein (LRV) ligation following en bloc resection of segmental inferior vena cava (IVC) and right kidney is understudied. We assessed the impact of LRV ligation on postoperative renal function following en bloc resection of segmental IVC and right kidney. METHODS: We retrospectively reviewed 28 patients who underwent LRV ligation during en bloc resection of segmental IVC and right kidney. Patient demographics, tumor characteristics, intraoperative factors, complications, length of hospital and intensive care unit (ICU) stay, and patient survival were collected. Pre- and postoperative renal function was retrospectively analyzed. RESULTS: Twenty patients underwent robot-assisted surgery and eight patients underwent open surgery. The median operative time was 162 min and estimated blood loss was 350 mL. Ten patients had normal renal function and 12 patients had an initial increase in creatinine but improved gradually. Six patients developed acute renal failure; five patients gradually recovered in 5-32 days after temporary hemodialysis. Renal replacement therapy significantly correlated with maximal anterior-posterior diameter of the LRV (p = 0.001). Complications were observed in 11 cases, four of which were Clavien-Dindo grades I-II. Thirteen patients were alive with no recurrence, nine patients were alive with metastasis, and six cases died during the follow-up period. CONCLUSIONS: LRV ligation following en bloc resection of segmental IVC and right kidney is feasible, with no significant long-term impact on renal function. The maximum anterior-posterior diameter of the LRV is a reliable method for predicting renal replacement therapy in the absence of collateral circulation.

Discovery of PlatinumIV-Artesunate Multiaction Prodrugs as Potent Antitumor and Antimalarial Agents.

Recently, artemisinin and derivatives have been revealed to possess encouraging antitumor activity. Herein, we integrated the antitumor advantages of artesunate and platinum drugs to construct novel PtIV-artesunate dual-action and triple-action complexes. Most derivatives, especially 10f, displayed broad-spectrum and potent in vitro antitumor activities against a number of cancer cell lines. Compound 10f displayed potent antimetastasis and anticlonogenic activities, efficiently induced autophagic cell death and apoptosis, and arrested the cell cycle at both S and G2/M phases. More importantly, it displayed remarkable in vivo antitumor efficacy in the A549 xenograft model (TGI = 53.4%; 6 µmol/kg) with low toxicity. In addition to the antitumor application, 10f showed potent in vivo antimalarial activity in malarial-infected mice model and obviously alleviated malarial-related multiorgan injury. This conjugation greatly improved safety, especially reducing the platinum drugs' nephrotoxicity. Taken together, this study highlighted the therapeutic potential of PtIV-artesunate complexes as antitumor and antimalarial agents.

Inspired by bis-ß-carboline alkaloids: Construction and antitumor evaluation of a novel bis-ß-carboline scaffold as potent antitumor agents.

Bis-ß-carboline alkaloids are widely distributed in natural products and represent a promising drug-like scaffold for discovering drugs and bioactive molecules. In this study, we utilized the structural simplification strategy to construct a novel bis-ß-carboline scaffold via "one-pot" condensation-Mannich reaction. The simplified bis-ß-carboline derivatives were obtained in good yield. Antitumor evaluation revealed most compounds, especially 3m, displayed potent antitumor activity (IC50 values for 3m: 0.96 µM âˆ¼ 1.52 µM). More importantly, 3m displayed valuable antitumor properties including anti-migration and anti-invasion activity against cancer cells, antiangiogenic and vascular-disrupting properties. Mechanistic studies revealed 3m potently inhibited both Top1 and Top2 activity, thus interfering with DNA synthesis in cancer cells. Taken together, this study developed a new synthetic methodology to construct a novel bis-ß-carboline scaffold, which represents a promising lead structure for antitumor drug discovery.

Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation.

The colchicine binding site of tubulin is a promising target for discovering novel antitumour agents. Previously, we identified 2-aryl-4-amide-quinoline derivatives displayed moderate tubulin polymerisation inhibitory activity and broad-spectrum in vitro antitumour activity. In this study, structure based rational design and systematic structural optimisation were performed to obtain analogues C1∼J2 bearing diverse substituents and scaffolds. Among them, analogue G13 bearing a hydroxymethyl group displayed good tubulin polymerisation inhibitory activity (IC50 = 13.5 µM) and potent antiproliferative activity (IC50 values: 0.65 µM∼0.90 µM). G13 potently inhibited the migration and invasion of MDA-MB-231 cells, and displayed potent antiangiogenic activity. It efficiently increased intracellular ROS level and decreased MMP in cancer cells, and obviously induced the fragmentation and disassembly of the microtubules network. More importantly, G13 exhibited good in vivo antitumour efficacy in MDA-MB-231 xenograft model (TGI = 38.2%; i.p., 30 mg/kg).

Laparoscopic placement of left renal vein extravascular stenting in treatment of nutcracker syndrome: Techniques and long-term outcomes.

OBJECTIVES: We aimed to assess the feasibility and efficacy of laparoscopic extravascular stent in treatment of nutcracker syndrome by transperitoneal or retroperitoneal approach. METHODS: Seventy-six patients with nutcracker syndrome were retrospectively enrolled from a tertiary referral center, and underwent transperitoneal (63 patients) or retroperitoneal (13 patients) laparoscopic extravascular stent from March 2011 to December 2020. Surgical parameters, complications, imaging and clinical outcomes were collected and analyzed. RESULTS: All procedures were successfully carried out without open conversion. The median operation time, estimated blood loss, and postoperative hospital day were 120 (interquartile range [IQR]: 90-144) min, 20 (IQR: 10-30) ml, and 7 (IQR: 6-9) days. At a median follow-up of 52 (range: 9-127) months, 60 (79%) patients had complete symptom resolution, 14 (18%) patients had significant symptom improvement, and 2 (3%) patients reported no symptom improvement. Ninety-four percent (50/53) of hematuria, 91% (30/33) of proteinuria, and 89% (25/28) of flank/abdominal pain resolved after extravascular LRV stenting. No significant differences were detected in surgery parameters and recovery rates of clinical symptoms between two approaches (each p > 0.05). However, patients with transperitoneal approach need longer to achieve complete recovery compared with retroperitoneal approach (8.7 vs. 1.5 months, p = 0.016). CONCLUSIONS: Laparoscopic extravascular stent performed either transperitoneally or retroperitoneally is a feasible and effective option in treatment of nutcracker syndrome. Retroperitoneal laparoscopic extravascular stent required shorter time to achieve complete recovery, which should be considered whenever possible in surgical decision-making.

Fall Detection for Shipboard Seafarers Based on Optimized BlazePose and LSTM.

Aiming to avoid personal injury caused by the failure of timely medical assistance following a fall by seafarer members working on ships, research on the detection of seafarer's falls and timely warnings to safety officers can reduce the loss and severe consequences of falls to seafarers. To improve the detection accuracy and real-time performance of the seafarer fall detection algorithm, a seafarer fall detection algorithm based on BlazePose-LSTM is proposed. This algorithm can automatically extract the human body key point information from the video image obtained by the vision sensor, analyze its internal data correlation characteristics, and realize the process from RGB camera image processing to seafarer fall detection. This fall detection algorithm extracts the human body key point information through the optimized BlazePose human body key point information extraction network. In this section, a new method for human bounding-box acquisition is proposed. In this study, a head detector based on the Vitruvian theory was used to replace the pre-trained SSD body detector in the BlazePose preheating module. Simultaneously, an offset vector is proposed to update the bounding box obtained. This method can reduce the frequency of repeated use of the head detection module. The algorithm then uses the long short-term memory neural network to detect seafarer falls. After extracting fall and related behavior data from the URFall public data set and FDD public data set to enrich the self-made data set, the experimental results show that the algorithm can achieve 100% accuracy and 98.5% specificity for the seafarer's falling behavior, indicating that the algorithm has reasonable practicability and strong generalization ability. The detection frame rate can reach 29 fps on a CPU, which can meet the effect of real-time detection. The proposed method can be deployed on common vision sensors.

Discovery of novel tubulin inhibitors targeting the colchicine binding site via virtual screening, structural optimization and antitumor evaluation.

The colchicine binding site of tubulin is a promising target for discovering novel antitumor agents which exert the antiangiogenic effect and are not susceptible to multidrug resistance. For identifying novel tubulin inhibitors, structure-based virtual screening was applied to identify hit 9 which displayed moderate tubulin polymerization inhibition and broad-spectrum in vitro antitumor activity. Structural optimization was performed, and biological assay revealed analog E27 displayed the best antitumor activity with IC50 values ranging from 7.81 µM to 10.36 µM, and improved tubulin polymerization inhibitory activity (IC50 = 16.1 µM). It significantly inhibited cancer cell migration and invasion, induced cell apoptosis and arrested the cell cycle at G2/M phase. Moreover, the apoptotic effect of E27 is related to the increased ROS level, the decrease of MMP, and the abnormal expression of apoptosis-related proteins. Taken together, these results suggested E27 was a promising lead compound for discovering novel tubulin-targeted antitumor agents.

Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall.

Due to the limit of available treatments and the emergence of drug resistance in the clinic, invasive fungal infections are an intractable problem with high morbidity and mortality. The cell wall, as a fungi-specific structure, is an appealing target for the discovery and development of novel and low-toxic antifungal agents. In an attempt to accelerate the discovery of novel cell wall targeted drugs, this Perspective will provide a comprehensive review of the progress made to date on the development of fungal cell wall inhibitors. Specifically, this review will focus on the targets, discovery process, chemical structures, antifungal activities, and structure-activity relationships. Although two types of cell wall antifungal agents are clinically available or in clinical trials, it is still a long way for the other cell wall targeted inhibitors to be translated into clinical applications. Future efforts should be focused on the identification of inhibitors against novel conserved cell wall targets.

Resveratrol: Multi-Targets Mechanism on Neurodegenerative Diseases Based on Network Pharmacology.

Resveratrol is a natural polyphenol in lots of foods and traditional Chinese medicines, which has shown promising treatment for neurodegenerative diseases (NDs). However, the molecular mechanisms of its action have not been systematically studied yet. In order to elucidate the network pharmacological prospective effects of resveratrol on NDs, we assessed of pharmacokinetics (PK) properties of resveratrol, studied target prediction and network analysis, and discussed interacting pathways using a network pharmacology method. Main PK properties of resveratrol were acquired. A total of 13,612 genes related to NDs, and 138 overlapping genes were determined through matching the 175 potential targets of resveratrol with disease-associated genes. Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed to obtain more in-depth understanding of resveratrol on NDs. Accordingly, nodes with high degrees were obtained according using a PPI network, and AKT1, TP53, IL6, CASP3, VEGFA, TNF, MYC, MAPK3, MAPK8, and ALB were identified as hub target genes, which showed better affinity with resveratrol in silico studies. In addition, our experimental results demonstrated that resveratrol markedly enhanced the decreased levels of Bcl-2 and significantly reduced the increased expression of Bax and Caspase-3 in hippocampal neurons induced by glutamate exposure. Western blot results confirmed that resveratrol inhibited glutamate-induced apoptosis of hippocampal neurons partly by regulating the PI3K/AKT/mTOR pathway. In conclusion, we found that resveratrol could target multiple pathways forming a systematic network with pharmacological effects.

Pretreatment elevated prognostic nutritional index predicts a favorable prognosis in patients with prostate cancer.

BACKGROUND: The prognostic nutritional index (PNI), an immunity and nutrition based prognostic score, was correlated with clinical outcomes in different tumors. However, the prognostic significance of PNI has not been investigated in hormone sensitive prostate cancer (PCa). The objective of this study was to determine the prognostic significance of PNI in hormone sensitive PCa. METHODS: Two hundred eighty PCa patients undergoing androgen deprivation therapy (ADT) as first line therapy at three centers were enrolled. The serum albumin levels and peripheral lymphocyte count were measured at the time of diagnosis. PNI was calculated as 10 * serum albumin (g/dL) + 0.005 * total lymphocyte count (per mm3). Patients were categorized in two groups using a cut-off point of 50.2 as calculated by the receiver-operating curve analysis. Univariate and multivariate cox regression analyses were performed to evaluate PNI as a favorable prognostic factor for progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Prognostic accuracy was evaluated with the Harrell concordance index. RESULTS: Multivariate analyses identified PNI as an independent prognostic indicator with respect to PFS (hazard ratio (HR) = 0.521, p = 0.001), CSS (HR = 0.421, p = 0.002) and OS (HR = 0.429, p = 0.001). Patients with elevated PNI had better clinical outcomes. The addition of PNI to the final models improved predictive accuracy (c-index: 0.758, 0.830 and 0.782) for PFS, CSS and OS compared with the clinicopathological base models (c-index: 0.736, 0.801 and 0.752), which included Gleason score and incidence of metastasis. CONCLUSIONS: Elevated pretreatment PNI was a favorable prognostic indicator for PCa patients treated with ADT.

Structural simplification: an efficient strategy in lead optimization.

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding "molecular obesity". The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.

Antifungal Activity of Crude Extract from the Rhizome and Root of Smilacina japonica A. Gray.

This study aimed to investigate the antifungal activity of hydroalcoholic extract from Smilacina japonica A. Gray (SJA) against different fungi. The minimum inhibitory concentration (MIC) for SJA was determined by the broth microdilution method. The antifungal effects of SJA against Candida albicans were further confirmed by cell growth test and time-kill curve test. The effects of SJA on the fungal morphology and ultrastructure were also evaluated. SJA has a broad-spectrum antifungal activity. The MICs of SJA against different fungi, including fluconazole-sensitive and -resistant Candida albicans, other Candida species, and Cryptococcus neoformans, ranged from 208 µg/ml to 1665 µg/ml. Furthermore, SJA displayed fungicidal activity against varied fungi and obviously inhibited the hyphal growth of fungi. The mechanism study revealed that the antifungal activity of SJA might be associated with its effect on the cell morphology and ultrastructure.

Preoperative predictors of early death risk in bladder cancer patients treated with robot-assisted radical cystectomy.

BACKGROUND: Early identification of early death for bladder cancer patients undergoing radical cystectomy based on the laboratory findings at the time of diagnosis could improve the overall survival. The study aimed to explore preoperative factors associated with higher risk of early death (within 1 year after surgery) for bladder cancer patients. METHODS: A total of 186 bladder cancer patients who underwent robot-assisted radical cystectomy (RARC) were identified between October 2014 and May 2017. The probability of dying within 1 year after RARC was defined as the end point "early death." Predictive factors including clinical features and laboratory findings at diagnosis were retrospectively collected. RESULTS: Median follow-up time after RARC was 20.6 months (1.2-43.7 months). Fifty-one patients (27.4%) died during follow-up and 31 within 1 year from surgery (1-year mortality rate: 16.7%). All potentially prognostic factors were assessed on univariate analyses, which revealed the following factors as being associated with higher risk of early death within 1 year after RARC: older age (P = 0.004), advanced clinical stage (P = 0.005), presence of hydronephrosis (P = 0.021), higher fibrinogen (P = 0.007), higher PLR (P = 0.031), and lower PNI (P = 0.016). In a multivariate Cox proportional hazard regression model analysis, age >60 years (HR = 7.303, 95% CI 1.734-30.764; P = 0.007) and fibrinogen ≥3.295 g/L (HR = 2.396, 95% CI 1.138-5.045; P = 0.007) at diagnosis were independent prognostic factors of early death after RARC. CONCLUSION: Age and preoperative elevated plasma fibrinogen level were independent predictors for 1-year mortality after RARC. We believe that plasma fibrinogen levels may become a useful biomarker, which may help guide the treatment decision-making process for patients with bladder cancer.

Design, synthesis and biological evaluation of novel antitumor spirodihydrothiopyran-oxindole derivatives.

Sulfur containing spiroheterocyclic oxindoles are promising privileged scaffolds in medicinal chemistry and drug discovery. Previously, we identified a new class of spirodihydrothiopyran-oxindoles with good in vitro antitumor activity against A549 lung cancer cell line. Herein, various spirooxindole-dihydrothiopyrans with diverse substitutions were synthesized and assayed to investigate the structure-activity relationships. Among the derivatives, compounds 4b, 4i, 4m, 4n and 4q displayed superior or comparable antitumor activity than nutlin-3. Molecular mechanism study revealed this scaffold displayed moderate MDM2 inhibitory activity, significantly induced cancer cell apoptosis and arrested cell cycle at G0/G1 phase, which represented a good lead compound for antitumor drug discovery.

Structural Simplification of Natural Products.

Natural products (NPs) are important sources of clinical drugs due to their structural diversity and biological prevalidation. However, the structural complexity of NPs leads to synthetic difficulties, unfavorable pharmacokinetic profiles, and poor drug-likeness. Structural simplification by truncating unnecessary substructures is a powerful strategy for overcoming these limitations and improving the efficiency and success rate of NP-based drug development. Herein, we will provide a comprehensive review of the structural simplification of NPs with a focus on design strategies, case studies, and new technologies. In particular, a number of successful examples leading to marketed drugs or drug candidates will be discussed in detail to illustrate how structural simplification is applied in lead optimization of NPs.

Design, synthesis and evaluation of new classes of nonquaternary reactivators for acetylcholinesterase inhibited by organophosphates.

A new series of nonquaternary conjugates for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. It was found that substituted salicylaldehydes conjugated to aminobenzamide through piperidine would produce efficient reactivators for sarin, VX and tabun inhibited hAChE, such as L6M1R3, L6M1R5 to L6M1R7, L4M1R3 and L4M1R5 to L4M1R7. The in vitro reactivation experiment for pesticides inhibited hAChE of these new synthesized oximes were conducted for the first time. Despite they were less efficient than obidoxime, some of them were highlighted as equal or more efficient reactivators in comparison to 2-PAM. It was found that introduction of peripheral site ligands could increase oximes' binding affinity for inhibited hAChE in most cases, which resulted in greater reactivation ability.

Synthesis of spiro-tetrahydrothiopyran-oxindoles by Michael-aldol cascade reactions: discovery of potential P53-MDM2 inhibitors with good antitumor activity.

Using proline as the catalyst, an organocatalytic Michael-aldol cascade reaction was developed for the synthesis of spiro-tetrahydrothiopyran oxindoles. The highly functionalized scaffold was assembled in moderate to good yields (51-78%) and excellent diastereoselectivities (>20 : 1 dr). Interestingly, the oxindoles displayed moderate to good in vitro antitumor activities and were validated as p53-MDM2 inhibitors, which represented promising lead compounds for antitumor drug discovery.

Organocatalytic Asymmetric Synthesis of Spiro-Tetrahydrothiophene Oxindoles Bearing Four Contiguous Stereocenters by One-Pot Michael-Henry-Cascade-Rearrangement Reactions.

Asymmetric construction of tetrahydrothiophenes with four contiguous stereocenters remains a formidable challenge. Herein, the bottleneck was addressed by an unprecedented one-pot Michael-Henry-cascade-rearrangement reaction that could simultaneously create four consecutive stereogenic centers including two tetrasubstituted carbon stereocenters. The highly functionalized chiral spirotetrahydrothiophene scaffolds were assembled in moderate to good yields (≈54-79 %), excellent diastereo- (>20:1 d.r.) and enantio-selectivities (up to 93 % ee).