Biclustering analysis on tree-shaped time-series single cell gene expression data of Caenorhabditis elegans.

BACKGROUND: In recent years, gene clustering analysis has become a widely used tool for studying gene functions, efficiently categorizing genes with similar expression patterns to aid in identifying gene functions. Caenorhabditis elegans is commonly used in embryonic research due to its consistent cell lineage from fertilized egg to adulthood. Biologists use 4D confocal imaging to observe gene expression dynamics at the single-cell level. However, on one hand, the observed tree-shaped time-series datasets have characteristics such as non-pairwise data points between different individuals. On the other hand, the influence of cell type heterogeneity should also be considered during clustering, aiming to obtain more biologically significant clustering results. RESULTS: A biclustering model is proposed for tree-shaped single-cell gene expression data of Caenorhabditis elegans. Detailedly, a tree-shaped piecewise polynomial function is first employed to fit non-pairwise gene expression time series data. Then, four factors are considered in the objective function, including Pearson correlation coefficients capturing gene correlations, p-values from the Kolmogorov-Smirnov test measuring the similarity between cells, as well as gene expression size and bicluster overlapping size. After that, Genetic Algorithm is utilized to optimize the function. CONCLUSION: The results on the small-scale dataset analysis validate the feasibility and effectiveness of our model and are superior to existing classical biclustering models. Besides, gene enrichment analysis is employed to assess the results on the complete real dataset analysis, confirming that the discovered biclustering results hold significant biological relevance.

Development and Validation of a Post-Radiotherapy Prediction Model for Bowel Dysfunction After Rectal Cancer Resection.

BACKGROUND & AIMS: The benefit of radiotherapy for rectal cancer is based largely on a balance between a decrease in local recurrence and an increase in bowel dysfunction. Predicting postoperative disability is helpful for recovery plans and early intervention. We aimed to develop and validate a risk model to improve the prediction of major bowel dysfunction after restorative rectal cancer resection with neoadjuvant radiotherapy using perioperative features. METHODS: Eligible patients more than 1 year after restorative resection following radiotherapy were invited to complete the low anterior resection syndrome (LARS) score at 3 national hospitals in China. Clinical characteristics and imaging parameters were assessed with machine learning algorithms. The post-radiotherapy LARS prediction model (PORTLARS) was constructed by means of logistic regression on the basis of key factors with proportional weighs. The accuracy of the model for major LARS prediction was internally and externally validated. RESULTS: A total of 868 patients reported a mean LARS score of 28.4 after an average time of 4.7 years since surgery. Key predictors for major LARS included the length of distal rectum, anastomotic leakage, proximal colon of neorectum, and pathologic nodal stage. PORTLARS had a favorable area under the curve for predicting major LARS in the internal dataset (0.835; 95% CI, 0.800-0.870, n = 521) and external dataset (0.884; 95% CI, 0.848-0.921, n = 347). The model achieved both sensitivity and specificity >0.83 in the external validation. In addition, PORTLARS outperformed the preoperative LARS score for prediction of major events. CONCLUSIONS: PORTLARS could predict major bowel dysfunction after rectal cancer resection following radiotherapy with high accuracy and robustness. It may serve as a useful tool to identify patients who need additional support for long-term dysfunction in the early stage. CLINICALTRIALS: gov, number NCT05129215.

Efficacy and influencing factors of cervical perivascular sympathectomy in children with cerebral palsy.

BACKGROUND: There is a lack of research to determine the efficacy of cervical perivascular sympathectomy (CPVS) in children with cerebral palsy (CP). OBJECTIVE: This study aimed to evaluate the efficacy of CPVS in children with CP and analyze the associated influential factors. METHODS: Using the method of retrospective cohort studies, children who underwent CPVS were included in the CPVS group, whereas those who underwent selective posterior rhizotomy (SPR) were included in the SPR group. The Communication Function Classification System (CFCS) and Teacher Drooling Scale (TDS) were used to evaluate the communication function and salivation in the two groups before and 12 months after surgery and compare the surgical efficiency between the two groups, and the factors affecting the efficacy were screened by binary logistic regression. RESULTS: The study included 406 patients, 202 in the CPVS group and 204 in the SPR group. No significant differences were observed in the baseline characteristics (p > 0.05). The surgical efficacy of the CPVS group (47.01%) was significantly higher than that in the SPR group (9.81%) (χ2 = 71.08, p < 0.001). Binary logic regression analysis showed that preterm birth and Gross Motor Function Classification System (GMFCS) grade were influencing factors of surgical efficacy. Eighteen patients developed postoperative complications. CONCLUSION: CPVS is a safe and effective surgery for cerebral palsy. Preterm birth and GMFCS grade are independent factors affecting the efficacy of surgery.

Development and validation of a predictive model for poor prognosis of communication disorders in children with cerebral palsy after cervical perivascular sympathectomy.

Cervical perivascular sympathectomy (CPVS) can improve communication disorders in children with cerebral palsy (CP); however, there are no research reports on the factors affecting surgical efficacy. This study aimed to establish a nomogram for poor prognosis after CPVS. We collected data from 313 CP patients who underwent CPVS at the Neurosurgery Cerebral Palsy Center of the Second Affiliated Hospital of Xinjiang Medical University from January 2019 to January 2023. Among them, 70% (n = 216) formed the training cohort and 30% (n = 97) the validation cohort. The general data and laboratory examination data of both groups were analyzed. In training cohort, 82 (37.96%) showed improved postoperative communication function. Logistic analysis identified motor function, serum alkaline phosphatase, serum albumin, and prothrombin activity as the prognostic factors. Using these four factors, a prediction model was constructed with an area under the curve (AUC) of 0.807 (95% confidence interval [CI], 0.743-0.870), indicating its ability to predict adverse outcomes after CPVS. The validation cohort results showed an AUC of 0.76 (95% CI, 0.650-0.869). The consistency curve and Hosmer-Lemeshow test (χ2 = 10.988 and p = 0.202, respectively) demonstrated good consistency between the model-predicted incidence and the actual incidence of poor prognosis. Motor function, serum alkaline phosphatase, serum albumin, and prothrombin activity are independent risk factors associated with the prognosis of communication disorders after CPVS. The combined prediction model has a good clinical prediction effect and has promising potential to be used for early prediction of prognosis of CPVS.

Isolation, identification and transcriptome analysis of triadimefon-degrading strain Enterobacter hormaechei TY18.

Triadimefon, a type of triazole systemic fungicide, has been extensively used to control various fungal diseases. However, triadimefon could lead to severe environmental pollution, and even threatens human health. To eliminate triadimefon residues, a triadimefon-degrading bacterial strain TY18 was isolated from a long-term polluted site and was identified as Enterobacter hormaechei. Strain TY18 could grow well in a carbon salt medium with triadimefon as the sole nitrogen source, and could efficiently degrade triadimefon. Under triadimefon stress, a total of 430 differentially expressed genes (DEGs), including 197 up-regulated and 233 down-regulated DEGs, were identified in strain TY18 using transcriptome sequencing (RNA-Seq). Functional classification and enrichment analysis revealed that these DEGs were mainly related to amino acid transport and metabolism, carbohydrate transport and metabolism, small molecule and pyrimidine metabolism. Interestingly, the DEGs encoding monooxygenase and hydrolase activity acting on carbon-nitrogen were highly up-regulated, might be mainly responsible for the metabolism in triadimefon. Our findings in this work suggest that strain E. hormaechei TY18 could efficiently degrade triadimefon for the first time. They provide a great potential to manage triadimefon biodegradation in the environment successfully.

A novel tubulin inhibitor, 6h, suppresses tumor-associated angiogenesis and shows potent antitumor activity against non-small cell lung cancers.

Tumor angiogenesis is closely associated with the metastasis and progression of non-small cell lung cancer (NSCLC), a highly vascularized solid tumor. However, novel therapeutics are lacking for the treatment of this cancer. Here, we developed a series of 2-aryl-4-(3,4,5-trimethoxy-benzoyl)-5-substituted-1,2,3-triazol analogs (6a-6x) as tubulin colchicine-binding site inhibitors, aiming to find a novel promising drug candidate for NSCLC treatment. We first identified 2-(2-fluorophenyl)-3-(3,4,5-trimethoxybenzoyl)-5-(3-hydroxyazetidin-1-yl)-2H-1,2,3-triazole (6h) as a hit compound, which inhibited angiogenesis induced by NSCLC cells both in vivo and in vitro. In addition, our data showed that 6h could tightly bind to the colchicine-binding site of tubulin and inhibit tubulin polymerization. We also found that 6h could effectively induce G2/M cell cycle arrest of A549 and H460 cells, inhibit cell proliferation, and induce apoptosis. Furthermore, we showed 6h had the potential to inhibit the migration and invasion of NSCLC cells, two basic characteristics of tumor metastasis. Finally, we found 6h could effectively inhibit tumor progression in A549 xenograft mouse models with minimal toxicity. Taken together, these findings provide strong evidence for the development of 6h as a promising microtubule colchicine-binding site inhibitor for NSCLC treatment.

Chalcogen bond-assisted syn-locked scaffolds: DFT analysis and biological implications of novel tubulin inhibitors.

A series of new tubulin inhibitors containing chalcogen bonds have been discovered. Density functional theory (DFT) analysis of the O-C-C-S torsion profile shows a preference of 0.8 kcal/mol for the syn-conformer over the anti-conformer. Besides, the O-S natural bond orbital (NBO) analysis reveals that the OLP âˆ¼ C-SBD∗ energy potential is 0.62 kcal/mol. Further pharmacochemical screening of several series of (4-arylthiophen-2-yl)(3,4,5-trimethoxyphenyl)methanones identified IPO-10 as a highly effective tubulin inhibitor with an IC50 of 23 nm for MCF-7.

Halomonas dongshanensis sp. nov., isolated from the seawater of Dongshan Island.

A taxonomic study was carried out on strain yzlin-01T, isolated from Dongshan Island seawater. The bacterium was Gram-stain-negative, catalase-positive, oxidase-negative, rod-shaped, and motile by polar flagella. Growth was observed at temperatures of 10-40 °C, at salinities of 0.5-18 %, and at pH of 6-10. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain yzlin-01T belonged to the genus Halomonas, with the highest sequence similarity to Halomonas malpeensis YU-PRIM-29T (96.7 %), followed by Halomonas johnsoniae T68687T (96.4 %) and Halomonas gomseomensis M12T (96.4 %), and other species of the genus Halomonas (93.4-96.3 %). The ANI and digital DNA-DNA hybridization estimate values between strain yzlin-01T and the closest type strain Halomonas malpeensis YU-PRIM-29T were 77.44 and 21.6 %, respectively. The principal fatty acids were summed feature 8 (consisting of C18 : 1 ω7c and/or C18 : 1 ω6c; 55.7 %), C16 : 0 (20.6 %), C12 : 0 3-OH (6.8 %), summed feature 3 (consisting of C16 : 1 ω7c and/or C16 : 1 ω6c; 5.1 %). The G+C content of the chromosomal DNA was 60.0 mol %. The respiratory quinone was identified as Q-9 (100 %). Phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, aminophospholipid, and three unidentified phospholipids were present. Combined genotypic and phenotypic data suggest that strain yzlin-01T represents a novel species within the genus Halomonas, for which the name Halomonas dongshanensis sp. nov. is proposed, with the type strain yzlin-01T (=GDMCC 1.3202T=KCTC 92467T).

SERS detection of foodborne pathogens in beverage with Au nanostars.

The aim of this study is to develop a simple but rapid method for the determination of foodborne pathogens in complex matrices (beverages) by surface enhanced Raman spectroscopy (SERS) combined with Au nanostar solid-phase substrates. The star-shaped singlet Au nanostructure was formed on the surface of a stainless steel sheet by chemical replacement reaction. Rhodamine 6G verified the sensitivity and reproducibility of this substrate, and the relative standard deviations of the SERS intensity at 1312 cm-1, 1364 cm-1, and 1510 cm-1 displacements were 3.40%, 5.64%, and 3.48%, respectively. By detecting four pathogens in beverage samples on Au nanostar substrates, the utility of the SERS assay was demonstrated, while the combination of principal component analysis (PCA) and hierarchical cluster analysis (HCA) further enabled the isolation and identification of pathogens. The results of spiked beverages were validated in conventional culture identification and Vitek 2 Compact biochemical identification system experiments. Thus, this research demonstrated that Au nanostar substrates can be effectively utilized for the recognition of pathogenic bacteria and have immense promise to advance the progress of quick detection of foodborne pathogens and food safety.

Aculebiphenyl A-B, new biphenyl derivatives from Ruscus aculeatus.

The investigation of chemical constituents from the rhizomes of Ruscus aculeatus resulted in the isolation of two new biphenyl derivatives, aculebiphenyls A and B (1-2), together with two known analogs (3-4). Their chemical structures were elucidated based on extensive spectroscopic interpretation and HR-ESI-MS analysis. Compounds 3-4 were isolated from the Ruscus genus for the first time. The isolated compounds were tested for anti-inflammatory activities and antibacterial activities. Compound 1 exhibited significant inhibitory effects on LPS-induced NO production and COX-2 with IC50 values of 10.8 µM and 0.4 µM. Compound 1 also significantly down-regulated the levels of inflammatory cytokines IL-1ß, IL-6, and TNF-α. Compound 1 showed moderate antibacterial activities.

Novel microtubule inhibitor SQ overcomes multidrug resistance in MCF-7/ADR cells by inhibiting BCRP function and mediating apoptosis.

The occurrence of multidrug resistance (MDR) is one of the impediments in the clinical treatment of breast cancer, and MDR breast cancer has abnormally high breast cancer resistance protein (BCRP/ABCG2) expression. However, there are currently no clinical drugs that inhibit this target. Our previous study found that 2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol (SQ0814061/SQ), a small molecule drug with low toxicity to normal tissues, could target microtubules, inhibit the proliferation of breast cancer, and reduce its migration and invasion abilities. However, the effect and the underlying mechanism of SQ on MDR breast cancers are still unknown. Therefore, in this study, we investigated the effect of SQ on adriamycin-resistant MCF-7 (MCF-7/ADR) cells and explored the underlying mechanism. The MTT assay showed that SQ had potent cytotoxicity to MCF-7/ADR cells. In particular, the results of western blot and flow cytometry proved that SQ could effectively inhibit the expression of BCRP in MCF-7/ADR cells to decrease its drug delivery activity. In addition, SQ could block the cell cycle at G2/M phase in parental and MCF-7/ADR cells, thereby mediating cell apoptosis, which was related with the inhibition of PI3K-Akt-MDM2 pathway. Taken together, our findings indicate that SQ overcomes multidrug resistance in MCF-7/ADR cells by inhibiting BCRP function and mediating apoptosis through PI3K-Akt-MDM2 pathway inhibition.

Nematicidal activity of volatile organic compounds produced by Bacillus altitudinis AMCC 1040 against Meloidogyne incognita.

The application of nematicidal microorganisms and their virulence factors provides more opportunities to control root-knot nematodes. Bacillus altitudinis AMCC 1040, previously isolated from suppressive soils, showed significant nematicidal activity, and in this study, nematicidal substances produced by Bacillus altitudinis AMCC 1040 were investigated. The results of the basic properties of active substances showed that these compounds have good thermal stability and passage, are resistant to acidic environment and sensitive to alkaline conditions. Further analysis showed that it is a volatile component. Using HS-SPME-GC/MS, the volatile compounds produced by Bacillus altitudinis AMCC 1040 were identified and grouped into four major categories: ethers, alcohols, ketone, and organic acids, comprising a total of eight molecules. Six of them possess nematicidal activities, including 2,3-butanedione, acetic acid, 2-isopropoxy ethylamine, 3-methylbutyric acid, 2-methylbutyric acid and octanoic acid. Our results further our understanding of the effects of Bacillus altitudinis and its nematicidal metabolites on the management of Meloidogyne incognita and may help in finding less toxic nematicides to control root knot nematodes.

Impact of acetaminophen product labelling changes in Canada on hospital admissions for accidental acetaminophen overdose: a population-based study.

BACKGROUND: Accidental acetaminophen overdoses are associated with substantial morbidity and health care costs. In Canada, updated labelling standards were implemented in October 2009 and September 2016, with the intent of communicating risks of overdose and facilitating product identification and safe use, respectively. Full compliance with the 2016 standards was expected by March 2018. We sought to explore whether these changes affected rates of hospital admission for accidental acetaminophen overdose. METHODS: We conducted a population-based study of hospital admissions for accidental acetaminophen overdose in 9 Canadian provinces and 3 Canadian territories between Apr. 1, 2014, and Mar. 31, 2020. We used interventional autoregressive integrated moving average (ARIMA) models to evaluate the impact of the updated labelling standards on rates of hospital admission for accidental acetaminophen overdose. In secondary analyses, we studied intensive care unit (ICU) admissions and hospital admissions for accidental acetaminophen overdose involving opioids. RESULTS: Monthly rates of hospital admission for accidental acetaminophen overdose were essentially unchanged over the study period (0.21 and 0.22 cases per 100 000 population in April 2004 and March 2020, respectively). We found no association between changing labelling standards and trends in rates of hospital admission for accidental acetaminophen overdose (October 2009 p = 0.2, September 2016 p = 0.7 and March 2018 p = 0.2). Similarly, labelling changes did not have an impact on admissions involving ICU admission and concomitant opioid poisoning. INTERPRETATION: Modifications to product labels did not reduce the rate of acetaminophen-related harm. Additional measures to reduce the burden of accidental acetaminophen overdose are required.

Design, synthesis and biological evaluation of colchicine glycoconjugates as tubulin polymerization inhibitors.

A series of new colchicine glycoconjugates as tubulin polymerization inhibitors were designed by targeting strategy based on Warburg effect. All of the colchicine glycoconjugates were synthesized and then evaluated for their antiproliferative activities against three human cancer lines HT-29, MCF-7 and Hep-3B. Among them, 1e exhibited greater than 10 times selectivity between GLUT1 highly expressed cells (HT-29 and MCF-7) and GLUT1 lowly expressed cells (Hep-3B), and also showed lower cytotoxicity against HUVECs compared with colchicine. Moreover, 1e significantly inhibited tubulin polymerization and disrupted microtubule networks. GLUT1 inhibitor-dependent cytotoxicity assay demonstrated that the uptake of 1e was regulated via GLUT1. Molecular docking studies showed that 1e could be a substrate of GLUT1 and bind to the colchicine site of tubulin.

2-Methoxy-5((3,4,5-trimethosyphenyl) seleninyl) phenol causes G2/M cell cycle arrest and apoptosis in NSCLC cells through mitochondrial apoptotic pathway and MDM2 inhibition.

Nonsmall cell lung cancer (NSCLC) is one of the most common malignancies and needs novel and effective chemotherapy. In this study, our purpose is to explore the anticancer effects of 2-methoxy-5((3,4,5-trimethosyphenyl) seleninyl) phenol (SQ) on human NSCLC (A549 and H460) cells. We found that SQ suppressed the proliferation of NSCLC cells in time- and dose-dependent manners, and blocked the cells at G2/M phase, which was relevant to microtubule depolymerization. Additionally, SQ induced A549 and H460 cell apoptosis by activating the mitochondrial apoptotic pathway. Further, we demonstrated that SQ enhanced the generation of reactive oxygen species (ROS), and pretreatment with N-acetyl- L-cysteine (NAC) attenuated SQ-induced cell apoptosis. Meanwhile, SQ mediated-ROS generation caused DNA damage in A549 and H460 cells. Our data also revealed that SQ-induced apoptosis was correlated with the inhibition of mouse double minute 2 (MDM2) in A549 and H460 cells. In summary, our research indicates that the novel compound SQ has great potential for therapeutic treatment of NSCLC in future.

Design, synthesis, and biological evaluation of biotinylated colchicine derivatives as potential antitumor agents.

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovering new anti-tumour drugs to improve tumour targeting effects and reduce off-target toxicities. Colchicine is one of the most prominent and historically microtubule-targeting drugs, but its clinical applications are hindered by notorious adverse effects. In this study, we presented a novel tumour-specific conjugate 9 that consists of deacetylcolchicine (Deac), biotin, and a cleavable disulphide linker. 9 was found to exhibit potent anti-tumour activity and exerted higher selectivity between tumour and nontarget cells than Deac. The targeting moiety biotin might enhance the transport capability and selectivity of 9 to tumour cells via biotin receptor-mediated endocytosis. The tubulin polymerisation activity of 9 (with DTT) was close to the parent drug Deac. These preliminary results suggested that 9 is a high potency and reduced toxicity antitumor agent and worthy of further investigation.

Asymmetric optical links using monolithic III-nitride diodes.

Multiple-quantum well (MQW) III-nitride diodes can both emit and detect light. In particular, a III-nitride diode can absorb shorter-wavelength photons generated from another III-nitride diode that shares an identical MQW structure because of the spectral overlap between the emission and detection spectra of the III-nitride diode, which establishes a wireless visible light communication system using two identical III-nitride diodes. Moreover, a wireless light communication system using a modulating retro-reflector (MRR) enables asymmetric optical links, which forms a two-way optical link using a single transmitter and receiver. Here, in association with an MRR, we propose, fabricate, and characterize asymmetric optical links using monolithic III-nitride diodes, where one III-nitride diode functions as a transmitter to emit light, an MRR reflects light with the encoded information, another monolithically integrated III-nitride diode serves as a receiver to absorb the reflected light to convert optical signals into electrical ones, and the encoded information is finally decoded. Advanced monolithic III-nitride asymmetric optical links can be developed toward Internet of Things (IoT) deployment based on such multifunction devices.

W436, a novel SMART derivative, exhibits anti-hepatocarcinoma activity by inducing apoptosis and G2/M cell cycle arrest in vitro and in vivo and induces protective autophagy.

Hepatocellular carcinoma (HCC) is considered one of the most common primary liver cancers and the second leading cause of cancer-associated mortality around the world annually. Therefore, it is urgent to develop novel drugs for HCC therapy. We synthesized a novel 4-substituted-methoxybenzoyl-aryl-thiazole (SMART) analog, (5-(4-aminopiperidin-1-yl)-2-phenyl-2H-1,2,3-triazol-4-yl) (3,4,5-trimethoxyphenyl) methanone (W436), with higher solubility, stability, and antitumor activity than SMART against HCC cells in vivo. The purpose of this study was to investigate the mechanisms by which W436 inhibited cell growth in HCC cells. We observed that W436 inhibited the proliferation of HepG2 and Hep3B cells in a dose-dependent manner. Importantly, the anticancer activity of W436 against HCC cells was even higher than that of SMART in vivo. In addition, the antiproliferative effects of W436 on HCC cells were associated with G2/M cell cycle arrest and apoptosis via the activation of reactive oxygen species-mediated mitochondrial apoptotic pathway. W436 also induced protective autophagy by inhibiting the protein kinase B/mammalian target of rapamycin pathway. At the same time, W436 treatment inhibited the cell adhesion and invasion as well as the process of epithelial-to-mesenchymal transition Taken together, our results showed that W436 had the promising potential for the therapeutic treatment of HCC with improved solubility, stability, and bioavailability.

The effect of radioiodine treatment on the characteristics of TRAb in Graves' disease.

BACKGROUND: Graves' disease (GD) is one of the most common autoimmune thyroid diseases (AITDs) in humans, and thyrotropin receptor antibody (TRAb) is a characterized autoantibody in GD. The use of radioactive iodine therapy (RAI) for GD treatment is increasing. OBJECTIVES: We studied the biological properties of TRAb and evaluated the effect of RAI therapy on TRAb in GD patients. METHODS: In total, 225 patients (22 onset GD patients without 131I therapy, 203 GD patients treated with 131I therapy) and 20 healthy individuals as normal controls were included in this study. Clinical assessments were performed, and we examined in vitro the biological properties of TRAb in the 22 onset GD patients and 20 controls as well as 84 GD patients with 131I therapy. RESULTS: Serum TRAb and thyroid peroxidase antibody (TPOAb) levels increased in the initial year of RAI treatment, and both antibodies decreased gradually after one year. After 5 years from radioiodine treatment, TRAb and TPOAb levels decreased in 88% and 65% of GD patients, respectively. The proportion of patients positive for thyroid-stimulatory antibody (TSAb) was significantly higher in the 7-12-month group, and thyroid-blocking antibody (TBAb) levels were elevated after one year in half of the patients who received 131I treatment. CONCLUSIONS: Treatment of GD patients with radioiodine increased TPOAb and TRAb (their main biological properties were TSAbs) within the first year after therapy, and the main biological properties of elevated TRAb were TBAbs after 1 year.

Design, synthesis and anticancer activity of 5-aryl-4-(4-arylpiperazine-1-carbonyl)-1,2,3-thiadiazoles as microtubule-destabilizing agents.

Hereby, we report our efforts on discovery and optimization of a new series of 5-aryl-4-(4-arylpiperazine-1-carbonyl)-1,2,3-thiadiazoles as new microtubule-destabilizing agents along our previous study. Guided by docking model analysis, we introduced the 1,2,3-thiadiazole moiety containing the hydrogen-bond acceptors as B-ring of XRP44X analogues. Extensive structure modifications were performed to investigate the detailed structure and activity relationships (SARs). Some compounds exhibited potent antiproliferative activities against three human cancer cell lines (SGC-7901, A549 and HeLa). The compound 5m exhibited the highest potency against the three cancer cell lines. The tubulin polymerization experiments indicated that compound 5m effectively inhibited the tubulin polymerization, and immunostaining assay revealed that it significantly disrupted microtubule dynamics. Moreover, cell cycle studies revealed that compound 5m dramatically arrested cell cycle progression at G2/M phase.