Real-time monitoring of abnormal mitochondrial viscosity in glioblastoma with a novel mitochondria-targeting fluorescent probe.

Glioblastoma is the most fatal and insidious malignancy, due to the existence of the blood-brain barrier (BBB) and the high invasiveness of tumor cells. Abnormal mitochondrial viscosity has been identified as a key feature of malignancies. Therefore, this study reports on a novel fluorescent probe for mitochondrial viscosity, called ZVGQ, which is based on the twisted intramolecular charge transfer (TICT) effect. The probe uses 3-dicyanomethyl-1,5,5-trimethylcyclohexene as an electron donor moiety and molecular rotor, and triphenylphosphine (TPP) cation as an electron acceptor and mitochondrial targeting group. ZVGQ is highly selective, pH and time stable, and exhibits rapid viscosity responsiveness. In vitro experiments showed that ZVGQ could rapidly recognize to detect the changes in mitochondrial viscosity induced by nystatin and rotenone in U87MG cells and enable long-term imaging for up to 12 h in live U87MG cells. Additionally, in vitro 3D tumor spheres and in vivo orthotopic tumor-bearing models demonstrated that the probe ZVGQ exhibited exceptional tissue penetration depth and the ability to penetrate the BBB. The probe ZVGQ not only successfully visualizes abnormal mitochondrial viscosity changes, but also provides a practical and feasible tool for real-time imaging and clinical diagnosis of glioblastoma.

Multifunctional Protein Hybrid Nanoplatform for Synergetic Photodynamic-Chemotherapy of Malignant Carcinoma by Homologous Targeting Combined with Oxygen Transport.

Photodynamic therapy (PDT) under hypoxic conditions and drug resistance in chemotherapy are perplexing problems in anti-tumor treatment. In addition, central nervous system neoplasm-targeted nanoplatforms are urgently required. To address these issues, a new multi-functional protein hybrid nanoplatform is designed, consisting of transferrin (TFR) as the multicategory solid tumor recognizer and hemoglobin for oxygen supply (ODP-TH). This protein hybrid framework encapsulates the photosensitizer protoporphyrin IX (PpIX) and chemotherapeutic agent doxorubicin (Dox), which are attached by a glutathione-responsive disulfide bond. Mechanistically, ODP-TH crosses the blood-brain barrier (BBB) and specifically aggregated in hypoxic tumors via protein homology recognition. Oxygen and encapsulated drugs ultimately promote a therapeutic effect by down-regulating the abundance of multidrug resistance gene 1 (MDR1) and hypoxia-inducible factor-1-α (HIF-1α). The results reveal that ODP-TH achieves oxygen transport and protein homology recognition in the hypoxic tumor occupation. Indeed, compared with traditional photodynamic chemotherapy, ODP-TH achieves a more efficient tumor-inhibiting effect. This study not only overcomes the hypoxia-related inhibition in combination therapy by targeted oxygen transport but also achieves an effective treatment of multiple tumors, such as breast cancer and glioma, providing a new concept for the construction of a promising multi-functional targeted and intensive anti-tumor nanoplatform.

A novel quinoline-based fluorescent probe for real-time monitoring of Cys in glioma.

Cysteine (Cys), a small-molecule biothiol, has recently been identified as a novel Glioblastoma (GBM) biomarker. The highly selective real-time monitoring and fluorescence imaging of Cys levels in vivo is of great significance for the early diagnosis and treatment of GBM. In this work, we reported a highly selective Cys fluorescent probe ZS-C1, based on quinoline according to the mechanism of the conjugate addition cyclization reaction. The Limit of Detection (LOD) of probe ZS-C1 was 1.97 µM, λex = 380 nm; λem = 531 nm. In vitro experiments showed that ZS-C1 could be distinguished from Hcy and GSH significantly, and the fluorescence quantum yield was reduced by 30 times. Further, biological imaging and 3D tumor sphere penetration assay showed that the ZS-C1 could monitor both exogenous and endogenous Cys in the living U87MG cells, and the fluorescence of probe ZS-C1 diffusely distributed inside the U87MG three-dimensional solid cell spheroid (up to 60 µM deep into the solid tumors). This work provided a potential tool for further investigations of Cys in biological samples and critical information for early diagnosis of glioma and guidance for clinical surgery.

A new mitochondria-targeted fluorescent probe for exogenous and endogenous superoxide anion imaging in living cells and pneumonia tissue.

As a precursor of all reactive oxygen species (ROS), superoxide anions play an important role in organisms. However, excessive superoxide anions can cause various diseases. Thus, it is highly urgent to develop efficient tools for in situ superoxide anion detection. In this work, a novel boric acid-based, mitochondria-targeted fluorescent probe Mito-YX for superoxide anion detection was designed by regulating its intramolecular charge transfer (ICT) effect. The probe exhibited turn-on fluorescence enhancement within 4 min of reaction with the superoxide anion. In addition, Mito-YX also exhibited high selectivity and a low detection limit down to 0.24 µM with good mitochondrial targeting characteristics, which provided a necessary basis for in vivo detection of superoxide anions. What is more, Mito-YX was successfully applied for the in situ monitoring of superoxide anions in living MCF-7 cells, RAW 264.7 cells and a mouse model of lung inflammation stimulated by LPS. This work provided an important and promising tool for rapid in situ diagnosis and research of the progression of pneumonia.

A new fluorescently labeled bisphosphonate for theranostics in tumor bone metastasis.

Bone metastasis of malignant solid tumors has become one of the most serious complications, especially in breast cancer, which was particularly challenging for early detection and treatment in clinical practice. In this work, we reported a new fluorescently labeled bisphosphonate for bone metastasis detection of breast cancer. The designed probes were based on Rhodamine B and bisphosphonate as recognition group, which can specifically target hydroxyapatite (HA) existed in bone tissue. After the osteoclasts were adsorbed on the bone surface, the surrounding microenvironment was acidified, causing the HA to locally dissolve. The probe bound to the HA was then released, and realized the fluorescence turn on under acidic conditions. In vitro experiments showed that G0 was more excellent than G2 owing to shorter connecting arm. Subsequently, we proved that G0 could combine with HA rapidly and exhibit excellent response in solid state. More importantly, we established a model of bone metastasis with MDA-MB-231 cells which was similar to the clinical cases and evaluated the theranostics value of G0 prospectively, which provide the potential application prospect in clinical.

A novel fast-response and highly selective AIEgen fluorescent probe for visualizing peroxynitrite in living cells, C. elegans and inflammatory mice.

Most of the ONOO- fluorescent probes have restricted applications because of their aggregation-caused quenching (ACQ) effect, long response time and low fluorescence enhancement. Herein, we developed a novel AIEgen fluorescent probe (PE-XY) based on a benzothiazole and quinolin scaffold with high sensitivity and selectivity for imaging of ONOO-. The results indicated that probe PE-XY exhibited fast response towards ONOO- with 2000-fold enhancement of fluorescence intensity ratio in vitro. Moreover, PE-XY exhibited a relatively high sensitivity (limit of detection: 8.58 nM), rapid response (<50 s), high fluorescence quantum yield (δ = 0.81) and excellent selectivity over other analytes towards ONOO-in vitro. Furthermore, PE-XY was successfully applied to detect endogenous ONOO- levels in living HeLa cells, C. elegans and inflammatory mice with low cytotoxicity. Overall, this work provided a novel fast-response and highly selective AIEgen fluorescent probe for real-time monitoring ONOO- fluctuations in living systems.

Glutathione-responsive prodrug conjugates for image-guided combination in cancer therapy.

Theranostic prodrug was highly desirable for precise diagnosis and anti-cancer therapy to decrease side effects. However, it is difficult to conjugate chemo-drug and molecular probe for combined therapy due to the complex pharmacokinetics of different molecules. Here, a novel anticancer theranostic prodrug (BTMP-SS-PTX) had been designed and synthesized by conjugating paclitaxel (PTX) with 2-(benzo[d]thiazol-2-yl)-4-methoxyphenol (BTMP) through a disulphide (-S-S-) linkage, which was redox-sensitive to the high concentration of glutathione in tumors. Upon activation with glutathione in weakly acid media, the BTMP-SS-PTX can be dissociated to release free PTX and visible BTMP, which realized the visual tracking of free drug. The cytotoxicity study demonstrated that soluble prodrug BTMP-SS-PTX displayed more outstanding anticancer activity in HepG2, MCF-7 and HeLa cells, lower toxicity to non-cancer cells (293 T) than free drugs. Furthermore, BTMP-SS-PTX was still able to induce apoptosis of HeLa cells and significantly inhibited tumor growth in HeLa-xenograft mouse model. On the basis of these findings, BTMP-SS-PTX could play a potential role in cancer diagnosis and therapy.

A DNA-based nanocarrier for efficient cancer therapy.

The study aimed to achieve enhanced targeted cytotoxicity and cell-internalization of cisplatin-loaded deoxyribonucleic acid-nanothread (CPT-DNA-NT), mediated by scavenger receptors into HeLa cells. DNA-NT was developed with stiff-topology utilizing circular-scaffold to encapsulate CPT. Atomic force microscopy (AFM) characterization of the DNA-NT showed uniformity in the structure with a diameter of 50-150 nm and length of 300-600 nm. The successful fabrication of the DNA-NT was confirmed through native-polyacrylamide gel electrophoresis analysis, as large the molecular-weight (polymeric) DNA-NT did not split into constituting strands under applied current and voltage. The results of cell viability confirmed that blank DNA-NT had the least cytotoxicity at the highest concentration (512 nM) with a viability of 92% as evidence of its biocompatibility for drug delivery. MTT assay showed superior cytotoxicity of CPT-DNA-NT than that of the free CPT due to the depot release of CPT after DNA-NT internalization. The DNA-NT exhibited targeted cell internalizations with the controlled intracellular release of CPT (from DNA-NT), as illustrated in confocal images. Therefore, in vitro cytotoxicity assessment through flow cytometry showed enhanced apoptosis (72.7%) with CPT-DNA-NT (compared to free CPT; 64.4%). CPT-DNA-NT, being poly-anionic, showed enhanced endocytosis via scavenger receptors.

A DNA-based nanocarrier for efficient cancer therapy / 药物分析学报

The study aimed to achieve enhanced targeted cytotoxicity and cell-internalization of cisplatin-loaded deoxyribonucleic acid-nanothread (CPT-DNA-NT),mediated by scavenger receptors into HeLa cells.DNA-NT was developed with stiff-topology utilizing circular-scaffold to encapsulate CPT.Atomic force microscopy (AFM) characterization of the DNA-NT showed uniformity in the structure with a diameter of 50-150 nm and length of 300-600 nm.The successful fabrication of the DNA-NT was confirmed through native-polyacrylamide gel electrophoresis analysis,as large the molecular-weight (polymeric) DNA-NT did not split into constituting strands under applied current and voltage.The results of cell viability confirmed that blank DNA-NT had the least cytotoxicity at the highest concentration (512 nM) with a viability of 92％ as evidence of its biocompatibility for drug delivery.MTT assay showed superior cyto-toxicity of CPT-DNA-NT than that of the free CPT due to the depot release of CPT after DNA-NT inter-nalization.The DNA-NT exhibited targeted cell internalizations with the controlled intracellular release of CPT (from DNA-NT),as illustrated in confocal images.Therefore,in vitro cytotoxicity assessment through flow cytometry showed enhanced apoptosis (72.7％) with CPT-DNA-NT (compared to free CPT;64.4％).CPT-DNA-NT,being poly-anionic,showed enhanced endocytosis via scavenger receptors.

Clinical evaluation of plasma coagulation parameters in patients with advanced-stage non-small cell lung cancer treated with palliative chemotherapy in China.

AIMS OF THE STUDY: Blood coagulation parameters are colossally important for clinical evaluation of palliative chemotherapy; however, this niche was not explored earlier for advanced-stage non-small cell lung cancer (NSCLC). Study focuses to explore the clinical relevancy of Coagulation parameters; prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), D-dimer and international normalised ratio (INR) and their response to palliative chemotherapy in advanced-stage NSCLC. METHODS: A retrospective study was conducted between 2013 and 2019 in Jiangsu Cancer hospital, Nanjing, PR. China. Medical records of 5445 patients were succinctly reviewed and classified accordingly to the inclusion and exclusion criteria. A total of 216 advanced NSCLC patients who used a first-line chemotherapy and antiangiogenic therapy regimen were enrolled in this study under ethical approval (JSCH-2020C-009). Blood samples were collected from these patients to measure the response levels of these coagulation parameters at time of admission to hospital and at the beginning of 4 cycles of Palliative therapy. We find the clinical value of all these coagulation parameters by using SPSS 24. Univariate Cox regression and Multivariate Cox regression models were used to identify the factors that were associated with progression-free survival (PFS) and the response to palliative chemotherapy. RESULTS: In the Kaplan-Meier survival analysis for overall median (95% CI) survival of high pre-treatment coagulation parameters showed shorter PFS compared with normal pre-treatment except TT and their overall median (95% CI) follow-up was 3.3 (3.12-3.47). Coagulation parameters have showed clinical relevance as a potential independent prognostic factor of PFS in the Univariate Cox regression. In multivariable model, Age (≥60 years vs < 60 years), cancer differentiation (Unknown vs Poor), PT (High vs Normal) range, FIB (High vs Normal) range and D-dimer (High vs Normal) range, (P = .025, P = .045, P = .029, P = .049 and P = .011, respectively) were associated as a prognostic factor of PFS in NSCLC. Patients on 3-drugs regimen found to have better PFS compared with the ones taking the 2-drugs treatment regimen (P = .043). CONCLUSION: The high range of PT, FIB and D-dimers was associated with poor prognosis of advanced-stage NSCLC. Our findings also confirmed that patients on 3-drugs regimen showed longer PFS compared with 2-drugs regimen.

Clinical Evaluation of Serum Tumor Markers in Patients With Advanced-Stage Non-Small Cell Lung Cancer Treated With Palliative Chemotherapy in China.

Aim: This study aims to analyze the prognostic value of seven tumor makers and also investigate the response of palliative chemotherapy in advanced NSCLC patients with advanced disease. Methods: Medical records of 278 advanced NSCLC Chinese patients who received six cycles of palliative chemotherapy were retrospectively reviewed under ethical approval (JSCH2019K-011). Univariate and multivariate Cox regression analyses were performed using SPSS 24 to find the clinical value of these tumor markers and to identify the factors that were associated with progression-free survival (PFS), as well as the response to palliative chemotherapy. Results: In baseline characteristic, the high levels of CEA, CA-125, CA-199, AFP, NSE, CYFRA21-1, and CA15-3 were detected in 209 (75.18%), 139 (50.0%), 62 (22.30%), 18 (6.47%), 155 (55.75%), 176 (63.30%), and 180 (64.74%) patients, respectively. Univariate analysis revealed that patients with high vs. normal levels of all tumor markers had an increased risk of poor prognosis. In the multivariable Cox regression model, the patient with (high vs. normal) CYFRA21-1 levels (HR = 1.454, P = 0.009) demonstrated an increased poor PFS. However, patients with (high vs. normal) CA19-9 levels (HR = 0.524, P < 0.0001) and NSE levels (HR = 0.584, P < 0.0001) presented a decreased risk of PFS. Also, patients receiving 3-drugs regimen had better PFS compared to those on 2-drugs regimen (P = 0.043). Conclusions: The high levels of CYFRA21-1 was correlated with a poor prognostic factor of PFS for Advanced NSCLC patients. However, the high levels of CA19-9 and NSE were associated with a better prognostic factor of PFS. Additionally, smoking habits and tumor status had a poor prognostic factor of PFS. Moreover, we found that antiangiogenic therapy has high efficacy with first-line chemotherapy and longer PFS of NSCLC patients.

Oxygen Self-Sufficient Core-Shell Metal-Organic Framework-Based Smart Nanoplatform for Enhanced Synergistic Chemotherapy and Photodynamic Therapy.

The abnormal angiogenesis and insufficient oxygen supply in solid tumors lead to intratumoral hypoxia, which severely limits the efficacy of traditional photodynamic therapy (PDT). Here, a multifunctional nanoplatform (ZDZP@PP) based on a zeolitic imidazolate framework-67 (ZIF-67) core as a hydrogen peroxide catalyst, a zeolitic imidazolate framework-8 (ZIF-8) shell with a pH-responsive property, and a polydopamine-poly(ethylene glycol) (PDA-PEG) layer for improving the biocompatibility is fabricated for not only relieving tumor hypoxia but also enhancing the efficacy of combination chemo-photodynamic therapy. The chemotherapy drug doxorubicin (DOX) and photosensitizer protoporphyrin IX (PpIX) are encapsulated in different layers independently; thus, a unique two-stage stepwise release becomes possible. Moreover, the nanoplatform can effectively decompose hydrogen peroxide to produce oxygen and thus relieve tumor hypoxia, which further facilitates the production of cytotoxic reactive oxygen species (ROS) by PpIX under laser irradiation. Both in vitro and in vivo experimental results confirm that the combination chemo-photodynamic therapy with the ZDZP@PP nanoplatform can provide more effective cancer treatment than chemotherapy or PDT alone. Consequently, the oxygen self-sufficient multifunctional nanoplatform holds promising potential to overcome hypoxia and treat solid tumors in the future.

Tubulin Inhibitors Binding to Colchicine-Site: A Review from 2015 to 2019.

Due to the three domains of the colchicine-site which is conducive to the combination with small molecule compounds, colchicine-site on the tubulin has become a common target for antitumor drug development, and accordingly, a large number of tubulin inhibitors binding to the colchicine-site have been reported and evaluated over the past years. In this study, tubulin inhibitors targeting the colchicine-site and their application as antitumor agents were reviewed based on the literature from 2015 to 2019. Tubulin inhibitors were classified into ten categories according to the structural features, including colchicine derivatives, CA-4 analogs, chalcone analogs, coumarin analogs, indole hybrids, quinoline and quinazoline analogs, lignan and podophyllotoxin derivatives, phenothiazine analogs, N-heterocycle hybrids and others. Most of them displayed potent antitumor activity, including antiproliferative effects against Multi-Drug-Resistant (MDR) cell lines and antivascular properties, both in vitro and in vivo. In this review, the design, synthesis and the analysis of the structure-activity relationship of tubulin inhibitors targeting the colchicine-site were described in detail. In addition, multi-target inhibitors, anti-MDR compounds, and inhibitors bearing antitumor activity in vivo are further listed in tables to present a clear picture of potent tubulin inhibitors, which could be beneficial for medicinal chemistry researchers.

Recent Progress in the Development of Small Molecule c-Met Inhibitors.

C-Met, also referred to as Hepatocyte Growth Factor Receptor (HGFR), is a heterodimeric receptor tyrosine kinase. It has been determined that c-Met gene mutations, overexpression, and amplification also occur in a variety of human tumor types, and these events are closely related to the aberrant activation of the HGF/c-Met signaling pathway. Meanwhile, high c-Met expression is closely associated with poor prognosis in cancer patients. The c-Met kinase has emerged as an attractive target for developing antitumor agents. In this review, we cover the recent advances on the small molecule c-Met inhibitors discovered from 2018 until now, with a main focus on the rational design, synthesis and structureactivity relationship analysis.

Synthesis, anticancer activity and molecular docking studies on 1,2-diarylbenzimidazole analogues as anti-tubulin agents.

Twenty-four 1,2-diarylbenzimidazole derivatives were designed, synthesized and biologically evaluated. It turned out that most of them were potential anticancer drugs. Among them, compound c24 showed the highest anti-tumor activity (GI50 = 0.71-2.41 µM against HeLa, HepG2, A549 and MCF-7 cells), and low toxicity to normal cells (CC50 > 100 µM against L02 cells). In the microtubule binding assay, c24 showed the most potent inhibition of microtubule polymerization (IC50 = 8.47 µM). The binding ability of compound c24 to tubulin crystal was verified by molecular docking simulation experiment. Further studies on HepG2 and HeLa cells showed that compound c24 could cause mitotic arrest of tumor cells to G2/M phase then inducing apoptosis. To sum up, compound c24 is a promising microtubule assembly inhibitor.

Design, synthesis and biological evaluation of 2-H pyrazole derivatives containing morpholine moieties as highly potent small molecule inhibitors of APC-Asef interaction.

Mutated adenomatous polyposis coli (APC) selectively combining with Asef has been reported to be implicated in promoting colon cancer proliferation, invasion and metastasis in several cancer biotherapy studies. However, there were universally resistance and harsh terms in disrupting APC-Asef interaction in biotherapy. Under the circumstances small-molecule inhibitors as the new APC interface could resolve the problems. In this research, a series of novel dihydropyrazole derivatives containing morpholine as high potent interaction inhibitors between APC and Asef were first synthesized after selection by means of docking simulation and virtual screening. Afterwards they were evaluated interaction inhibition of APC-Asef and pharmacological efficiency both in vitro and in vivo utilizing orthotopic transplantation model with multi-angle of view. Among them, compound 7g exhibited most excellent anti-proliferation activities against HCT116 cells with IC50 of 0.10 ±â€¯0.01 µM than Regorafenib (IC50 = 0.16 ±â€¯0.04 µM). The results favored our rational design intention and provides a new class of small-molecule inhibitors available for the development of colon tumor therapeutics targeting APC-Asef interaction inhibitions.

Dihydropyrazole Derivatives Containing Benzo Oxygen Heterocycle and Sulfonamide Moieties Selectively and Potently Inhibit COX-2: Design, Synthesis, and Anti-Colon Cancer Activity Evaluation.

Cyclooxygenase-2 (COX-2) as a rate-limiting metabolism enzyme of arachidonic acid has been found to be implicated in tumor occurrence, angiogenesis, metastasis as well as apoptosis inhibition, regarded as an attractive therapeutic target for cancer therapy. In our research, a series of dihydropyrazole derivatives containing benzo oxygen heterocycle and sulfonamide moieties were designed as highly potent and selective COX-2 inhibitors by computer-aided drug analysis of known COX-2 inhibitors. A total of 26 compounds were synthesized and evaluated COX-2 inhibition and pharmacological efficiency both in vitro and in vivo with multi-angle of view. Among them, compound 4b exhibited most excellent anti-proliferation activities against SW620 cells with IC50 of 0.86 ± 0.02 µM than Celecoxib (IC50 = 1.29 ± 0.04 µM). The results favored our rational design intention and provides compound 4b as an effective COX-2 inhibitor available for the development of colon tumor therapeutics.

Nanoscale Metal-Organic-Frameworks Coated by Biodegradable Organosilica for pH and Redox Dual Responsive Drug Release and High-Performance Anticancer Therapy.

Responsive nanocarriers with biocompatibility and precise drug releasing capability have emerged as a prospective candidate for anticancer treatment. However, the challenges imposed by the complicated preparation process and limited loading capacities have seriously impeded the development of novel multifunctional drug delivery systems. Here, we developed a novel and dual-responsive nanocarrier based on a nanoscale ZIF-8 core and an organosilica shell containing disulfide bridges in its frameworks through a facile and efficient strategy. The prepared ZIF-8@DOX@organosilica nanoparticles (ZDOS NPs) exhibited a well-defined structure and excellent doxorubicin (DOX) loading capability (41.2%) with pH and redox dual-sensitive release properties. The degradation of the organosilica shell was observed after 12 h incubation with a 10 mM reducing agent. Confocal imaging and flow cytometry analysis further proved that the nanocarriers can efficiently enter cells and complete intracellular DOX release under the low pH and high glutathione concentrations, which resulted in an enhanced cytotoxicity of DOX for cancer cells. Meanwhile, subcellular localization experiments revealed that the ZDOS NPs entered cells mainly by endocytosis and then escaped from lysosomes into the cytosol. Moreover, in vivo assays also demonstrated that the ZDOS NPs exhibited negligible systemic toxicity and significantly enhanced anticancer efficiencies compared with free DOX. In summary, our prepared pH and redox dual-responsive nanocarriers provide a potential platform for controlled release and cancer treatment.

Design, synthesis, and biological evaluation of 2,3-diphenyl-cycloalkyl pyrazole derivatives as potential tubulin polymerization inhibitors.

Several novel cycloalkyl-fused 2,3-diaryl pyrazole derivatives were designed, synthesized, and evaluated as potential anti-tubulin agents. Compound A10 exhibited the most potent antiproliferative activity against a panel of cancer lines (IC50  = 0.78-2.42 µM) and low cytotoxicity against 293T & L02 (CC50 values of 131.74 and 174.89 µM, respectively). Moreover, A10 displayed inhibition of tubulin polymerization in vitro, arrested the G2/M phase of the cell cycle, changed morphology of tubulin, increased intracellular reactive oxygen species, and induced apoptosis of HeLa cells. Docking simulation and 3D-QSAR models were performed to elaborate on the anti-tubulin mechanism of the derivatives. The inhibition of monoclonal colony formation provided more intuitional data to verify the possibility of A10 as a novel tubulin assembling inhibitor.

Design, synthesis and evaluation of novel diaryl-1,5-diazoles derivatives bearing morpholine as potent dual COX-2/5-LOX inhibitors and antitumor agents.

In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against cancer cell lines (IC50 = 6.43-10.97 µM for F10, HeLa, A549 and MCF-7 cells), lower toxicity to non-cancer cells than celecoxib (A33: IC50 = 194.01 µM vs.celecoxib: IC50 = 97.87 µM for 293T cells), and excellent inhibitory activities on COX-2 (IC50 = 0.17 µM) and 5-LOX (IC50 = 0.68 µM). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced apoptosis of F10 cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising candidate for cancer therapy.