Palladium-Catalyzed [3 + 2] Cycloaddition of 4-Vinyl-4-Butyrolactones with Alkenes: Synthesis of Spirocyclopentane Compounds.

A palladium-catalyzed [3 + 2] cycloaddition of 4-vinyl-4-butyrolactones (VBLs) with alkenes has been developed to afford various spirocyclopentane products in high yields with excellent diastereoselectivities. The scale-up reaction and further derivations of the product worked well, demonstrating the potential application of the current reaction in organic synthesis.

Fluorine assembly nanocluster breaks the shackles of immunosuppression to turn the cold tumor hot.

Clinical investigations have shown that a nonimmunogenic "cold" tumor is usually accompanied by few immunopositive cells and more immunosuppressive cells in the tumor microenvironment (TME), which is still the bottleneck of immune activation. Here, a fluorine assembly nanocluster was explored to break the shackles of immunosuppression, reawaken the immune system, and turn the cold tumor "hot." Once under laser irradiation, FS@PMPt produces sufficient reactive oxygen species (ROS) to fracture the ROS-sensitive linker, thus releasing the cisplatin conjugated PMPt to penetrate into the tumors and kill the regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Meanwhile, ROS will induce potent immunogenic cell death (ICD) and further promote the accumulation of dendritic cells (DCs) and T cells, therefore not only increasing the infiltration of immunopositive cells from the outside but also reducing the immunosuppressive cells from the inside to break through the bottleneck of immune activation. The FS@PMPt nanocluster regulates the immune process in TME from negative to positive, from shallow to deep, to turn the cold tumor into a hot tumor and provoke a robust antitumor immune response.

[Connotation of Baimai disease and analysis of compatibility and usage of Baimai Ointment: based on Tibetan medicine theory].

Baimai is a complex of structure and function with the characteristics of wide distribution, complex structure, and multi-dimensional functions. Baimai, consisting of the channels in brain, the internal hidden channels connecting the viscera, and the external channels linking the limbs, governs the sensory, motor, and information transmission functions of human. According to Tibetan medicine, Baimai functions via "Long"(Qi) which moves in Baimai. "Long" is rough, light, cold, tiny, hard, and dynamic. The dysfunction of Baimai is manifested as numbness, swelling and pain, stiffness, atrophy, contracture, disability, hyperactivity, etc. The clinical manifestations of Baimai disease are facial paralysis, limb numbness, hemiplegia, contracture and rigidity, pain, opistho-tonos, paralysis, unconsciousness, head tremor, aphasia and tongue stiffness, and other abnormalities in facial consciousness, limb movement, and tactile sensation. Baimai Ointment for external use is used for the treatment of Baimai disease. It is mainly composed of medicinals which are spicy and bitter, warm, soft, mild, heavy, moist, and stable, and thus it is effective for the rough, light, cold, tiny, hard, and dynamic "Long" of Baimai disease. In clinical practice, it is mainly used for musculoskeletal diseases, such as osteoarthritis, scapulohumeral periarthritis, cervical spondylosis, low back pain, myofascitis, and tenosynovitis, nervous system diseases, such as paralysis and shoulder-hand syndrome, and limb stiffness caused by stroke, spastic cerebral palsy, trigeminal neuralgia, and facial neuritis, and limb motor and sensory dysfunction caused by trauma. According to the main symptoms of Baimai disease such as stiffness, rigidity, contraction, numbness, sensory disturbance and pain, clinicians should apply the Baimai Ointment via the inunction treatment of Tibetan medicine and in combination with Huo'ermai therapy and physiotherapy.

Synthesis of gadolinium-based Bi2S3 nanoparticles as cancer theranostics for dual-modality computed tomography/magnetic resonance imaging-guided photothermal therapy.

Development of a safe, efficient and inexpensive multifunctional nanoplatform using a facile approach for multimodal imaging and therapeutic functions becomes more and more practically relevant but challenging. In this work, we demonstrated a novel nanocomposites (Bi2S3-Gd) for computed tomography (CT)/magnetic resonance (MR) imaging-guided photothermal therapy (PTT) for cancer in vitro. It was achieved by modification of hydrophobic Bi2S3 with a smart amphiphilic gadolinium-chelated ligand. The as-prepared nanocomposites composed of low-cost Bi2S3 and gadolinium complexes, showed high stability, excellent biocompatibility and good photostability. It was observed that Bi2S3-Gd nanocomposites can efficiently convert the NIR light into heat, and then suppressed the growth of tumor cells under NIR laser irradiation. Apart from serving as an effective photothermal agent, the as-prepared nanomaterials could induce an efficient contrast enhancement for both CT and MR imaging at low concentrations of Bi and Gd, rendering more accurate diagnosis. This work suggests the potential of Bi2S3-Gd nanomaterials as a novel multifunctional nanoplatform for CT/MR imaging-guided PTT for cancer.

Synthesis, molecular properties prediction and biological evaluation of indole-vinyl sulfone derivatives as novel tubulin polymerization inhibitors targeting the colchicine binding site.

Twenty-two novel indole-vinyl sulfone derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors. The physicochemical and drug-likeness properties of all target compounds were predicted by Osiris calculations. All compounds were evaluated for their antiproliferative activities, among them, compound 7f exhibited the most potent activity against a panel of cancer cell lines, which was 2-7 folds more potent than our previously reported compound 4. Especially, 7f displayed about 8-fold improvement of selective index as compared with compound 4, indicating that 7f might have lower toxicity. Besides, 7f inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further investigations showed that compound 7f effectively disrupted microtubule network, caused cell cycle arrest at G2/M phase and induced cell apoptosis in K562 cells. Moreover, 7f reduced the cell migration and disrupted capillary-like tube formation in HUVEC cells. Importantly, the in vivo anti-tumor activity of 7f was validated in H22 liver cancer xenograft mouse model without apparent toxicity, suggesting that 7f is a promising anti-tubulin agent for cancer therapy.

Metal-Free Synthesis of N-(Pyridine-2-yl)amides from Ketones via Selective Oxidative Cleavage of C(O)-C(Alkyl) Bond in Water.

The TBHP/TBAI-mediated synthesis of N-(pyridine-2-yl)amides in water from ketones and 2-aminopyridine via direct oxidative C-C bond cleavage has been developed. A series of ketones, including more challenging inactive aromatic ketones substituted with diverse long-chain alkyl groups, were selectively converted to N-(pyridine-2-yl)amides. Furthermore, the protocol can be applied to aryl alkyl carbinols to afford the corresponding amides in moderate to good yields.

Redox modulation with a perfluorocarbon nanoparticle to reverse Treg-mediated immunosuppression and enhance anti-tumor immunity.

Tumor hypoxia and high glutathione (GSH) expression promote regulatory T cell (Treg) infiltration and maintain its immunosuppressive function, which significantly reduces the response rate of cancer immunotherapy. Here, we developed an immunomodulatory nano-formulation (FEM@PFC) to reverse Treg-mediated immunosuppression by redox regulation in the tumor microenvironment (TME). Oxygen carried in perfluorocarbon (PFC) was delivered to the TME, thus relieving the hypoxic condition and inhibiting Treg infiltration. More importantly, GSH depletion by the prodrug efficiently restricted the Foxp3 expression and immunosuppressive function of Tregs, thus breaking the shackles of tumor immunosuppression. Additionally, the supplement of oxygen cooperated with the consumption of GSH to enhance the irradiation-induced immunogenic cell death and subsequent dendritic cell (DC) maturation, thereby efficiently promoting the activation of effector T cells and restricting the immunosuppression of Tregs. Collectively, the FEM@PFC nano-formulation reverses Treg-mediated immunosuppression and regulates the redox balance in the TME to boost anti-tumor immunity and prolong the survival of tumor-bearing mice, which provides a new immunoregulatory strategy from the perspective of redox modulation.

Hyaluronic acid immobilized polyacrylamide nanoparticle sensors for CD44 receptor targeting and pH measurement in cells.

Our ability to design receptor-targeted nanocarriers aimed at drug release after endocytosis is limited by the current knowledge of intracellular nanoparticle (NP) trafficking. It is not clear if NP size, surface chemistry, and/or targeting of cell surface receptors changes the intracellular fate of NPs; i.e., will all NPs enter acidic compartments and eventually end up in lysosomes or are there escape mechanisms or receptor-specific signaling that can be induced to change the cellular processing of an internalized NP? To give new insight into the intracellular trafficking of NPs that target the CD44 receptor, which is overexpressed on the surface of a broad variety of cancer cells, we have synthesized an NP pH sensor system that targets CD44. We used a polyacrylamide nanoparticle matrix bearing hyaluronic acid (HA) on the surface as a CD44 targeting ligand. The HA-coated NPs were prepared by radical polymerization followed by post functionalization with sensor fluorophores and physically absorbed or chemically conjugated HA. Cell uptake studies showed significant uptake of HA-coated nanosensors in HeLa cells and no uptake under the same conditions without the HA targeting ligand. The pH distribution profile in cells was measured for nanosensors with HA, cationic, and noncharged NP surface coatings giving a clear indication of the intracellular pH environment that the different NPs experience after internalization. The pH profile of cationic nanosensors in comparison to HA conjugated nanosensors indicates that the intracellular trafficking is aimed at lysosomes regardless of whether CD44 receptor-specific or unspecific uptake is induced.

Crosslinked Protein Delivery Strategy with Precise Activity Regulation Properties for Cancer Therapy and Gene Editing.

Protein drugs hold tremendous promise for therapeutic applications due to their direct and superior pharmacological effects. However, protein drugs can be degraded in blood stream and unable to cross many physical barriers to exert therapeutic effect. Degradable synthetic crosslinking is a versatile strategy to enhance the stability of the nanoparticle in a complex physiological medium and is helpful to get through physical barriers. Herein, crosslinked polypeptide (PABP) composed of poly-amino acids including cystine, tyrosine, lysine, ketal bridge, and polyethylene glycol (PEG) is modularly explored and synthesized for protein delivery. Notably, plasma membrane V-ATPase is the particular pathway which induces the macropinocytosis of the inner peptide analogous core (PAB/protein) after the outer PEG shell disassociation at tumor intercellular sites. In addition, PABP/protein achieves proteins' activity shielding in systemic circulation and recovery in tumor cytoplasm precisely. In application, PABP/RNase-A shows satisfying tumor accumulation and antineoplastic efficacy. More importantly, PABP/Cas9 + small guide RNA displays obvious gene editing efficiency. The crosslinked protein delivery strategy not only makes the accurate protein transport and activity regulation possible but also is promising in paving the way for clinical translation of protein drugs.

A Potential Link Between Polycystic Ovary Syndrome and Asthma: a Meta-Analysis.

While there exists some evidence indicating a higher prevalence of asthma in polycystic ovary syndrome (PCOS) patients, whether PCOS is an independent risk factor for asthma remains debatable. In this report, a systematic review and meta-analysis were performed to assess the association between PCOS and asthma. Using of the terms "PCOS," "polycystic ovary syndrome," "polycystic ovarian syndrome," "Stein Leventhal Syndrome," "asthma," and "wheezing," PubMed, Embase, Web of Science, Scopus, Cochrane Trial Register, China National Knowledge Infrastructure (CNKI), and Wanfang databases were searched for studies published from their inceptions to February 2021. The data were extracted and a meta-analysis was conducted under the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A random-effects model was used to calculate the odds ratios (OR) and 95% confidence intervals (95% CI). A total of 6 articles involving 26,876 PCOS women and 156,143 healthy controls were included in this survey. Our results indicate that PCOS patients showed an increased risk of asthma (OR = 1.75, 95% CI = 1.40-2.19, I2 = 91.2%, P = 0.000, random-effects model). No statistically significant differences were obtained when these data were stratified by region, diagnostic criteria for asthma, and study design. PCOS is associated with a higher risk of asthma, a relationship which is independent of region, diagnostic criteria for bronchitis, and study design.

Quantifying the Carbon Reduction Potential of Recycling Construction Waste Based on Life Cycle Assessment: A Case of Jiangsu Province.

The recycling of construction waste is key to reducing waste generation and CO2 emissions. This study aimed to develop a quantitative model for analyzing the carbon reduction potential of recycling construction, demolition, and renovation waste (CDRW) in Jiangsu province. The waste generation rate calculation method and nonlinear autoregressive artificial neural network model were used to estimate and predict CDRW generation. The life cycle assessment was performed to calculate the carbon reduction potential of recycling CDRW. In quantifying the carbon reduction potential, not only construction and demolition waste, but also renovation waste was considered for the first time. The results showed that the total carbon reduction potential of recycling CDRW increased from 3.94 Mt CO2e in 2000 to 58.65 Mt CO2e in 2020. Steel and concrete were the main contributors. By scenario analysis, the carbon reduction potential of fully recycling CDRW in 2020 increased by 37.79 Mt CO2e, a growth rate of 64%. The study further predicts future CDRW generation and the corresponding carbon reduction potential. Our conclusions indicate that 245.45 Mt of CDRW will be generated in 2030, and carbon reduction potential may reach 82.36 Mt CO2e. These results will help the government manage construction waste better and reach early achievement of the carbon peak target.

Site-Specific Polyplex on CCR7 Down-Regulation and T Cell Elevation for Lymphatic Metastasis Blocking on Breast Cancer.

Tumor metastasis contributes to high cancer mortality. Tumor cells in lymph nodes (LNs) are difficult to eliminate but underlie uncontrollable systemic metastasis. The CC chemokine receptor 7 (CCR7) is overexpressed in tumor cells and interacts with CC chemokine ligand 21 (CCL21) secreted from LNs, potentiating their lymphatic migration. Here, a site-specific polyplex is developed to block the CCR7-CCL21 signal and kill tumor cells toward LNs, greatly limiting their lymphatic infiltration. A CCR7-targeting small interfering RNA (siCCR7) is condensed by mPEG-poly-(lysine) with chlorin e6 (Ce6) modification (PPLC) to form PPLC/siCCR7. The knockdown of CCR7 by siCCR7 in tumor cells significantly reduced their response on CCL21 and LN tropism. Additionally, photodynamic therapy-mediated immune activation precisely targets and kills tumor cells released from the primary foci before they reaches the LNs, reducing the number of tumor cells entering the LNs. Consequently, the PPLC/siCCR7 polyplexes inhibited up to 92% of lung metastasis in 4T1 tumor bearing mice and reduced tumor cell migration to LNs by up to 80%. This site-specific strategy optimized anti-metastasis efficacy and promotes the clinical translational development of anti-metastatic therapy.

A Novel Preparation of Special-Shaped Phosphors-in-Glass by Gel Casting with Isobam for High-Power WLEDs Lighting.

Phosphors-in-glass (PiGs) regarded as a promising phosphor-converter for white light emitting diodes (WLEDs) is being researched widely. However, there are few reports on the effect of changing the shape of PiGs on the color rendering index (CRI) and heat dissipation of WLEDs. In this paper, gel casting with Isobam was first attempted in preparing special-shaped PiGs successfully. It exhibited that 76 wt.% was the optimum solid content based on the rheological properties of slurry and the shrinkage of green bodies. The sintering rate should be kept at a low speed and glass transition temperature (Tg) of glass powders must be higher than sublimation temperatures (Ts) of APS and Isobam. The CRI of PiGs was increased by about 27% after changing the shape of PiGs from cylinder to dome. Most importantly, operating temperature also reduced effectively the increase of the surface area of PiGs. Therefore, changing the shape of PiGs by gel casting with Isobam is a creative way for high-power WLEDs lighting.

Metabolic intervention liposome for targeting glutamine-addiction of breast cancer.

The growth and rapid proliferation of tumor cells depend on both glycolysis and glutamine metabolism, leading to metabolic compensation. Here, dual inhibition on the metabolic plasticity by Glucose oxidase and Telaglenastat loaded liposome (Lip@GOx&Tel) were studied for intervening metabolic pathway on energy and material against breast cancer. Lip@GOx&Tel targeting inhibited the two nutrient supply mechanisms employed by tumor cells, reducing the supply of ATP production and biosynthesis precursors essential necessary for tumor, thereby eliciting anti-tumor and anti-metastasis effect. Meanwhile, Lip@GOx&Tel ingeniously amplify the therapeutic effect by up-regulating ROS and down-regulating GSH to disrupt redox homeostasis, thus resulting in inspiring 82% tumor suppression rate on 4 T1 tumor model. Moreover, our study solved the limitation of combination between protein drugs and small molecule drugs in vivo by using liposome nanoparticles with clinical translation value. In short, this work provides a unique perspective of nanomedicine for treating diseases from metabolic intervention.

Identification and immune characteristics of molecular subtypes related to protein glycosylation in Alzheimer's disease.

Background: Protein glycosylation has been confirmed to be involved in the pathological mechanisms of Alzheimer's disease (AD); however, there is still a lack of systematic analysis of the immune processes mediated by protein glycosylation-related genes (PGRGs) in AD. Materials and methods: Transcriptomic data of AD patients were obtained from the Gene Expression Omnibus database and divided into training and verification datasets. The core PGRGs of the training set were identified by weighted gene co-expression network analysis, and protein glycosylation-related subtypes in AD were identified based on k-means unsupervised clustering. Protein glycosylation scores and neuroinflammatory levels of different subtypes were compared, and functional enrichment analysis and drug prediction were performed based on the differentially expressed genes (DEGs) between the subtypes. A random forest model was used to select important DEGs as diagnostic markers between subtypes, and a line chart model was constructed and verified in other datasets. We evaluated the differences in immune cell infiltration between the subtypes through the single-sample gene set enrichment analysis, analyzed the correlation between core diagnostic markers and immune cells, and explored the expression regulation network of the core diagnostic markers. Results: Eight core PGRGs were differentially expressed between the training set and control samples. AD was divided into two subtypes with significantly different biological processes, such as vesicle-mediated transport in synapses and neuroactive ligand-receptor interactions. The high protein glycosylation subtype had a higher level of neuroinflammation. Riluzole and sulfasalazine were found to have potential clinical value in this subtype. A reliable construction line chart model was constructed based on nine diagnostic markers, and SERPINA3 was identified as the core diagnostic marker. There were significant differences in immune cell infiltration between the two subtypes. SERPINA3 was found to be closely related to immune cells, and the expression of SERPINA3 in AD was found to be regulated by a competing endogenous RNA network that involves eight long non-coding RNAs and seven microRNAs. Conclusion: Protein glycosylation and its corresponding immune process play an important role in the occurrence and development of AD. Understanding the role of PGRGs in AD may provide a new potential therapeutic target for AD.

Ovarian reserve and IVF outcomes in patients with inflammatory bowel disease: A systematic review and meta-analysis.

Background: Inflammatory bowel disease (IBD) mainly affects people during reproductive age. However, it is unclear whether IBD might be associated with impaired ovarian reserve in female patients or with in vitro fertilization (IVF) outcomes. Methods: This systematic review and meta-analysis included articles from inception to May, 2022. Random-effect model was applied to calculate the standardized mean differences (SMDs) and odds ratios (ORs) and their 95% confidence intervals (95%CIs). Studies comparing the ovarian reserve or IVF outcomes of patients with IBD with the population were considered. To be included in this study, necessary measurements such as OR, relative risk (RR), SMD or hazard ratio (HR) or any necessary information to calculate them were provided in the articles. Letters, case reports, review articles including meta-analyses and expert opinions were excluded. For different articles studying the same population, the article with larger scale was selected. Findings: We included in our analysis 9 studies and data from 2386 IBD records and matched controls. Comparing with women without IBD, women with IBD had lower anti-mullerian hormone (AMH) levels (SMD = -0.38, 95%CI: -0.67, -0.09); (I2 = 79.0%, p = 0.000). Patients with IBD of different ages showed distinct ovarian reserves, with patients below 30 years old not showing any decline in ovarian reserve compared to the control group (SMD = -0.56, 95%CI: -2.28, 1.16); (I2 = 96.3%; p = 0.000), while patients with IBD over 30 years old (SMD = -0.75, 95%CI: -1.07, -0.43); (I2 = 0.0%; p = 0.608) showed a decline compared to control group. Patients with IBD in remission stage had similar ovarian reserves to population (SMD = -0.10, 95%CI: -0.32, 0.12); (I2 = 0.0%; p = 0.667), while patients in active stage showed an impaired ovarian reserve (SMD = -1.30, 95%CI: -1.64, -0.96); (I2 = 0.0%; p = 0.318). Patients with IBD showed a pregnancy rate after receiving IVF treatment comparable to the control population (OR = 0.87, 95%CI: 0.55, 1.37); (I2 = 70.1%, p = 0.035). Interpretation: The result of this study suggest that IBD may reduce reproductive age women's ovarian reserve and IVF treatment might help pregnancy outcomes in patients with impaired fertility. These results should be further validated in additional studies given the heterogeneity and quality of the studies included. Funding: This study was supported by the National Natural Science Foundation of China (No. 81671423), National Key Research and Development Program of China (No. 2016YFC1000603), 2020 Shenyang Science and Technology Plan Program (No. 20-205-4-006), Scientific and Technological Talents Applied Technology Research Program of Shenyang (No. 18-014-4-56).

Design, synthesis and biological evaluation of vinyl selenone derivatives as novel microtubule polymerization inhibitors.

A series of novel vinyl selenone derivatives were designed, synthesized and evaluated as the tubulin polymerization inhibitors using a bioisosteric strategy. Among them, the representative compound 11k exhibited satisfactory anti-proliferative activities with IC50 values ranging from 0.287 to 0.621 µM against a panel of cancer cell lines. Importantly, 11k displayed more potent in vivo antitumor activity than the positive control paclitaxel, CA-4 and parent compound 4 without apparent toxicity, which was presumably ascribed to the antiangiogenic, antiproliferative and selective effects of selenium, along with the unique physiological activity of indole skeleton, which were both introduced into the structure of target compounds. Further mechanism study demonstrated that compound 11k showed potent activity in tubulin polymerization inhibition with IC50 value of 1.82 µM. Moreover, cellular mechanism studies disclosed that 11k blocked cell cycle arrest at G2/M phase, induced cell apoptosis and depolarized mitochondria of K562 cells. Meanwhile, 11k reduced the cell migration and had potent vascular disrupting activity. In summary, 11k could serve as a promising lead for the development of more efficient microtubule polymerization inhibitors for cancer therapy.

Simple preparation of photothermal nanomaterial GNR@SiO2 with enhanced drug loading content.

With the rising threat of cancers, gold nanorods (GNRs) based photothermal-chemotherapy is becoming an increasingly important strategy to cure cancers. There are some challenges faced by GNRs system including complicated synthesis process and low drug loading capacity. In this study, GNRs assisted mesoporous silica nanoparticles (GNR@SiO2 NPs) are fabricated by a simple method. The mesoporous SiO2 can not only prevent the aggregation of GNRs but also provide large hollow mesoporous structure to enhance drug loading capacity. Moreover, GNRs absorb near-infrared (NIR) light and convert it into heat. The temperature of the GNR@SiO2 solution was increased to ∼60 (2 W) and 90°C (3 W) after NIR radiation. The photothermal conversion efficiency was 32.60% of GNR@SiO2 under NIR light irradiation at 2 W, while 39.01% under NIR light irradiation at 3 W. The drug loading content of GNR@SiO2 was 22.3 ± 2.5%, which was higher than that of most reported GNR drug delivery systems. The authors also found that the GNR@SiO2@ doxorubicin may have a higher drug release rate under the conditions of the tumour microenvironment. The in vitro cytotoxity of GNR@SiO2 was demonstrated on HeLa cells. The experimental results indicate that GNR@SiO2 has great potential for synergistic treatment to kill cancer cells.

Design, synthesis and biological evaluation of quinoline-indole derivatives as anti-tubulin agents targeting the colchicine binding site.

A series of novel isocombretastatin A-4 (isoCA-4) analogs were designed and synthesized by replacing 3,4,5-trimethoylphenyl and isovanillin of isoCA-4 with quinoline and indole moieties, respectively. The structure activity relationships (SARs) of these synthesized quinoline-indole derivatives have been intensively investigated. Two compounds 27c and 34b exhibited the most potent activities against five cancer cell lines with IC50 values ranging from 2 to 11 nM, which were comparable to those of Combretastatin A-4 (CA-4, 1). Further mechanism investigations revealed that 34b effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further cellular mechanism studies elucidated that 34b disrupted cell microtubule networks, arrested the cell cycle at G2/M phase, induced apoptosis and depolarized mitochondria of K562 cells. Moreover, 34b displayed potent anti-vascular activity in both wound healing and tube formation assays. Importantly, 27c and 34b significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, suggesting that 27c and 34b deserve further research as potent antitumor agents for cancer therapy.

Discovery of Novel Quinoline-Chalcone Derivatives as Potent Antitumor Agents with Microtubule Polymerization Inhibitory Activity.

A series of novel quinoline-chalcone derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Among them, compound 24d exhibited the most potent activity with IC50 values ranging from 0.009 to 0.016 µM in a panel of cancer cell lines. Compound 24d also displayed a good safety profile with an LD50 value of 665.62 mg/kg by intravenous injection, and its hydrochloride salt 24d-HCl significantly inhibited tumor growth in H22 xenograft models without observable toxic effects, which was more potent than that of CA-4. Mechanism studies demonstrated that 24d bound to the colchicine site of tubulin, arrested the cell cycle at the G2/M phase, induced apoptosis, depolarized mitochondria, and induced reactive oxidative stress generation in K562 cells. Moreover, 24d has potent in vitro antimetastasis and in vitro and in vivo antivascular activities. Collectively, our findings suggest that 24d deserves to be further investigated as a potent and safe antitumor agent for cancer therapy.