Design, synthesis and antitumor activity of 2-substituted quinazoline-4-amine derivatives.

Werner (WRN) syndrome protein is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers. In this study, a series of new N-arylquinazoline-4-amine analogs were designed and synthesized based on structure optimization of quinazoline. The structures of the thirty-two newly synthesized compounds were confirmed by 1H NMR, 13C NMR and ESI-MS. The anticancer activity in vitro against chronic myeloid leukemia cells (K562), non-small cell lung cancer cells (A549), human prostate cancer cells (PC3), and cervical cancer cells (HeLa) of the target compounds was evaluated. Among them, the inhibition ratio of compounds 17d, 18a, 18b, 11 and 23a against four cancer cells at 5 µM concentration were more than 50 %. The IC50 values of compounds 18a and 18b were 0.3 ± 0.01 µM and 0.05 ± 0.02 µM in K562 cells respectively, compared with HeLa and A549 cells, 18a and 18b were more sensitive to K562 cells. In addition, the PC3 cells with WRN overexpression (PC3-WRN) was constructed, 18a and 18b and 23a were more sensitive to PC3-WRN cells compared with the control group cells (PC3-NC). Then, the cell viability of the novel WRN inhibitors were further assessed by colony formation assay. Compared with PC3-NC cells, 18b and 23a had obvious inhibitory effect on PC3-WRN cell at 1000 nM. In summary, these results indicated that the compounds 18b and 23a could be WRN protein inhibitor with potent anticancer properties in vitro.

Discovery of novel 4-trifluoromethyl-2-anilinoquinoline derivatives as potential anti-cancer agents targeting SGK1.

Given the critical necessity for the development of more potent anti-cancer drugs, a series of novel compounds incorporating trifluoromethyl groups within the privileged 2-anilinoquinoline scaffold was designed, synthesized, and subjected to biological evaluation through a pharmacophore hybridization strategy. Upon evaluating the in vitro anti-cancer characteristics of the target compounds, it became clear that compound 8b, which contains a (4-(piperazin-1-yl)phenyl)amino substitution at the 2-position of the quinoline skeleton, displayed superior efficacy against four cancer cell lines by inducing apoptosis and cell cycle arrest. Following research conducted in a PC3 xenograft mouse model, it was found that compound 8b exhibited significant anti-cancer efficacy while demonstrating minimal toxicity. Additionally, the analysis of a 217-kinase panel pinpointed SGK1 as a potential target for this compound class with anti-cancer capabilities. This finding was further verified through molecular docking analysis and cellular thermal shift assays. To conclude, our results emphasize that compound 8b can be used as a lead compound for the development of anti-cancer drugs that target SGK1.

Design and synthesis of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as potential Werner-dependent antiproliferative agents.

To discover new Werner (WRN) helicase inhibitors, a series of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives were designed and synthesized through a structural optimization strategy, and the anticancer activities of 25 new target compounds against PC3, K562, and HeLa cell lines were evaluated by the MTT assay. Some of these compounds exhibited excellent inhibitory activity against three different cancer cell lines. Compounds 6a, 8i, and 13a showed better antiproliferative activity against K562 cells, with IC50 values of 3871.5, 613.6 and 134.7 nM, respectively, than did paclitaxel (35.6 nM), doxorubicin (2689.0 nM), and NSC 617145 (20.3 nM). To further verify whether the antiproliferative activity of these compounds is dependent on WRN, PC3 cells overexpressing WRN (PC3-WRN) were constructed to further study their antiproliferative potency in vitro, and the inhibition ratio and IC20 values showed that compounds 6a, 8i, and 13a were more sensitive to PC3-WRN than were the control group cells (PC3-NC). The IC20 ratios of compounds 6a, 8i, and 13a to PC3-NC and PC3-WRN were 94.3, 153.4 and 505.5, respectively. According to the docking results, the compounds 6a, 8i, and 13a overlapped well with the binding pocket of 6YHR. Further study demonstrated that among the tested compounds, 13a was the most sensitive to PC3-WRN. In summary, our research identified a series of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as potential WRN-dependent anticancer agents.

Discovery of novel 2-(trifluoromethyl)quinolin-4-amine derivatives as potent antitumor agents with microtubule polymerization inhibitory activity.

In this work, a series of 2-(trifluoromethyl)quinolin-4-amine derivatives were designed and synthesized through structural optimization strategy as a microtubule-targeted agents (MTAs) and their cytotoxicity activity against PC3, K562 and HeLa cell lines were evaluated. The half maximal inhibitory concentration (IC50) of 5e, 5f, and 5o suggested that their potency of anti-proliferative activities against HeLa cell lines were better than the combretastatin A-4. Compound 5e showed the higher anti-proliferative activity against PC3, K562 and HeLa in vitro with IC50 values of 0.49 µM, 0.08 µM and 0.01 µM, respectively. Further mechanism study indicated that the representative compound 5e was new class of tubulin inhibitors by EBI competition assay and tubulin polymerization assays, it is similar to colchicine. Immunofluorescence staining revealed that compound 5e apparently disrupted tubulin network in HeLa cells, and compound 5e arrested HeLa cells at the G2/M phase and induced cells apoptosis in a dose-dependent manner. Molecular docking results illustrated that the hydrogen bonds of represented compounds reinforced the interactions in the pocket of colchicine binding site. Preliminary results suggested that 5e deserves further research as a promising tubulin inhibitor for the development of anticancer agents.

Lewis acid mediated cyclization: synthesis of 2 spirocyclohexylindolines.

Herein, we report the synthesis of 2-spirocyclohexylindolines based on a Lewis acid mediated cyclization. This diastereoselective procedure provides the target structures in a straightforward way via dual activation.

Catalytic asymmetric assembly of octahydroindolones: divergent synthesis of lycorine-type amaryllidaceae alkaloids (+)-α-lycorane and (+)-lycorine.

We report the first catalytic asymmetric approach to octahydroindolones and a divergent enantioselective synthesis of perhydroindole alkaloids, as exemplified by lycorine-type Amaryllidaceae alkaloids (+)-α-lycorane and (+)-lycorine, from a common intermediate by using a highly concise route. The assembly of octahydroindolones employs a catalytic enantioselective 1,4-conjugate addition of nitro dienynes, followed by a TsOH-catalyzed cascade synthesis of highly functionalized enones, and a diastereoselective intramolecular Michael addition.

Design, synthesis and bioevaluation of novel prenylated chalcones derivatives as potential antitumor agents.

A series of novel prenylated chalcone derivatives with broad spectrum anticancer potential were designed and synthesized. Some of the synthesized target compounds showed potent anti-proliferative activities toward LNCaP (prostate cancer cell line), K562 (human leukemia cells), A549 (human lung carcinoma cell line) and HeLa (cervical cancer cell line) cell lines. Among of the active compounds, (E)-1-(4-(2-(diethylamino)ethoxy)-2-hydroxy-6-methoxy-3-(3-methylbut-2-en-1-yl)phenyl)-3-(pyridin-3-yl)prop-2-en-1-one (C36) was directly interacted with protein kinase B (PKB), also known as AKT, significantly inhibited the pPI3K, pAKT(Ser473) protein levels to repress the growth of cancer cells by inducing apoptosis, arresting cell cycle. Our studies provide support for prenylated chalcone derivatives potential applications in cancer treatment as a potential AKT inhibitor.

Trifluoromethyl quinoline derivative targets inhibiting HDAC1 for promoting the acetylation of histone in cervical cancer cells.

Cervical cancer is the leading cause of death among gynecological malignant tumors, especially due to the poor prognosis of patients with advanced tumors due to recurrence, metastasis, and chemotherapy resistance. Therefore, exploring new antineoplastic drugs with high efficacy and low toxicity may bring new expectations in patients with cervical cancer. Natural products and their derivatives exert an antitumor activity. Therefore, in this work, combined with network pharmacology analysis and experimental validation, we investigated the anti-cervical cancer activity and molecular mechanism of a new trifluoromethyl quinoline (FKL) derivative in vivo and in vitro. FKL117 inhibited the proliferation of cervical cancer cells in a dose and time-dependent manner, induced apoptosis in HeLa cells, arrested the cell cycle in the G2/M phase, and regulated the expression of the apoptotic and cell cycle-related proteins Bcl-2, Bax, cyclin B1, and CDC2. We used online databases to obtain HDAC1 as one of the possible targets of FKL117 and the target binding and binding affinity were modeled by molecular docking. The results showed that FKL117 formed a hydrogen bond with HDAC1 and had good binding ability. We found that FKL117 targeted to inhibit the expression and function of HDAC1 and increased the acetylation of histone H3 and H4, which was also confirmed in vivo. The migration of HMGB1 from the nucleus to the cytoplasm further verified the above results. In conclusion, our study suggested that FKL117 might be used as a novel candidate for targeting the inhibition of HDAC1 against cervical cancer.

Discovery of novel N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as the inhibitors of tubulin polymerization in leukemia cells.

A series of new N-aryl-2-trifluoromethylquinazoline-4-amine analogs were designed and synthesized based on structure optimization of quinazoline by introducing a trifluoromethyl group into 2-position. The structures of the twenty-four newly synthesized compounds were confirmed by 1H NMR, 13C NMR and ESI-MS. The in vitro anti-cancer activity against chronic myeloid leukemia cells (K562), erythroleukemia cells (HEL), human prostate cancer cells (LNCaP), and cervical cancer cells (HeLa) of the target compounds was evaluated. Among them, compounds 15d, 15f, 15h, and 15i showed the significantly (P < 0.01) stronger growth inhibitory activity on K562 than those of the positive controls of paclitaxel and colchicine, while compounds 15a, 15d, 15e, and 15h displayed significantly stronger growth inhibitory activity on HEL than those of the positive controls. However, all the target compounds exhibited weaker growth inhibition activity against K562 and HeLa than those of the positive controls. The selectivity ratio of compounds 15h, 15d, and 15i were significantly higher than those of other active compounds, indicating that these three compounds had the lower hepatotoxicity. Several compounds displayed strong inhibition against leukemia cells. They inhibited tubulin polymerization, disrupted cellular microtubule networks by targeting the colchicine site, and promoted cell cycle arrest of leukemia cells at G2/M phase and cell apoptosis, as well as inhibiting angiogenesis. In summary, our research provided that novel synthesized N-aryl-2-trifluoromethyl-quinazoline-4-amine active derivatives as the inhibitors of tubulin polymerization in leukemia cells, which might be a valuable lead compounds for anti-leukemia agents.

Design, synthesis and bioevaluation of novel trifluoromethylquinoline derivatives as tubulin polymerization inhibitors.

Aim: A series of novel trifluoromethylquinoline derivatives were designed, synthesized and evaluated for antitumor activities. Methodology: All compounds were evaluated for antiproliferative activity against four human cancer cell lines. Results: Among them, 5a, 5m, 5o and 6b exhibited remarkable antiproliferative activities against all the tested cell lines at nanomolar concentrations. Mechanism of action studies demonstrated that 6b targeted the colchicine binding site, potentially inhibiting tubulin polymerization, and further studies indicated that 6b could arrest LNCaP cells in the G2/M phase and induce cell apoptosis. Molecular docking confirmed that 6b could bind to the colchicine binding site. Conclusion: Results suggested that 6b could serve as a promising lead compound for the development of novel tubulin polymerization inhibitors and cancer therapy.

Cardiovascular effects of wearing respirators against particulate matter: A randomized crossover trial.

Fine particles (PM2.5) are implicated as an important risk to cardiovascular health. N95 respirators had been widely used to provide protection by filtering particles. Yet the practical effects of wearing respirators have not been fully understood. This study aimed to evaluate the cardiovascular effects of respirator wearing against PM2.5 and underpin the understanding of the mechanisms of cardiovascular responses triggered by PM2.5. We conducted a randomized, double-blind crossover trial among 52 healthy adults in Beijing, China. Participants were exposed to outdoor PM2.5 for 2 h in alterations wearing true respirators (with membranes) or sham ones (without membranes). We measured ambient PM2.5 and tested the filtration efficiency of the respirators. We compared the heart rate variability (HRV), blood pressure and arterial stiffness indicators between the true respirator group and the sham respirator group. Concentrations of ambient PM2.5 during the 2-h exposure ranged from 4.9 to 255.0 µg/m3. The filtration efficiency of true respirators was 90.1 % and that of sham ones was 18.7 %. Between-group differences varied by pollution levels. On less polluted days (PM2.5< 75 µg/m3), participants wearing true respirators showed lower levels of HRV and higher levels of heart rate compared with those wearing sham respirators. These between-group differences were inconspicuous on heavily polluted days (PM2.5≥ 75 µg/m3). We found that a 10 µg/m3 increase in PM2.5 was associated with a 2.2 % to 6.4 % decrease in HRV, prominent at 1 h after the start of exposure. N95 respirators have good performance in reducing PM2.5 exposure. Short-term exposure to PM2.5 can induce very acute responses in autonomic nervous function. However, the overall effects of wearing respirators might be not always favorable to human health in terms of their inherent adverse effects, which seem dependent on the levels of air pollution. Precise individual protection recommendations warrant to be developed.

A Wireless Fully-Passive Acquisition of Biopotentials.

Biopotential signals contain essential information for assessing the functionality of organs and diagnosing diseases. We present a flexible sensor, capable of measuring biopotentials, in real time, in a wireless and fully-passive manner. The flexible sensor collects and transmits biopotentials to an external reader without wire, battery, or harvesting/regulating element. The sensor is fabricated on a 90 µm-thick polyimide substrate with a footprint of 18 × 15 × 0.5 mm3. The wireless fully-passive acquisition of biopotentials is enabled by the RF (Radio Frequency) microwave backscattering effect where the biopotentials are modulated by an array of varactors with incoming RF carrier that is backscattered to the external reader. The flexile sensor is verified and validated by emulated signal and electrocardiogram (ECG), electromyogram (EMG), and electrooculogram (EOG), respectively. A deep learning algorithm analyzes the signal quality of wirelessly acquired data, along with the data from commercially available wired sensor counterparts. Wired and wireless data shows <3% discrepancy in deep learning testing accuracy for ECG and EMG up to the wireless distance of 240 mm. Wireless acquisition of EOG further demonstrates accurate tracking of horizontal eye movement with deep learning training and testing accuracy reaching up to 93.6% and 92.2%, respectively, indicating successful detection of biopotentials signal as low as 250 µVPP. These findings support that the real-time wireless fully-passive acquisition of on-body biopotentials is indeed feasible and may find various uses for future clinical research.

Application of a bacteriophage lysin to disrupt biofilms formed by the animal pathogen Streptococcus suis.

Bacterial biofilms are crucial to the pathogenesis of many important infections and are difficult to eradicate. Streptococcus suis is an important pathogen of pigs, and here the biofilm-forming ability of 32 strains of this species was determined. Significant biofilms were completely formed by 10 of the strains after 60 h of incubation, with exopolysaccharide production in the biofilm significantly higher than that in the corresponding planktonic cultures. S. suis strain SS2-4 formed a dense biofilm, as revealed by scanning electron microscopy, and in this state exhibited increased resistance to a number of antibiotics (ampicillin, amoxicillin, ciprofloxacin, kanamycin, and rifampin) compared to that of planktonic cultures. A bacteriophage lysin, designated LySMP, was used to attack biofilms alone and in combination with antibiotics and bacteriophage. The results demonstrated that the biofilms formed by S. suis, especially strains SS2-4 and SS2-H, could be dispersed by LySMP and with >80% removal compared to a biofilm reduction by treatment with either antibiotics or bacteriophage alone of less than 20%; in addition to disruption of the biofilm structure, the S. suis cells themselves were inactivated by LySMP. The efficacy of LySMP was not dose dependent, and in combination with antibiotics, it acted synergistically to maximize dispersal of the S. suis biofilm and inactivate the released cells. These data suggest that bacteriophage lysin could form part of an effective strategy to treat S. suis infections and represents a new class of antibiofilm agents.

The health effects of wearing facemasks on cardiopulmonary system of healthy young adults: A double-blinded, randomized crossover trial.

BACKGROUND: Facemask had increasingly been utilized as a personal protective measure to reduce exposure to ambient particulate matter (PM) during heavily-polluted days and routine life. However, evidence on the potential effects on cardiovascular system by wearing particulate-filtering facemask was limited. METHODS: We conducted a double-blinded randomized crossover trial (RCT) to evaluate the effects of wearing N95 facemasks on the molecular responses of cardiopulmonary system among 52 healthy college students in Beijing, China. We measured cardiopulmonary health indicators and collected biological samples before and after (up to 5 h at multiple time points) a 2-h walk to examine the changes in lung function, biomarkers of respiratory and systemic oxidative stress/inflammation. We applied linear mixed-effect models to evaluate the effect of the facemask-intervention on the health of cardio-pulmonary system. RESULTS: In the trial wearing real facemasks, FEV1 increased by 2.05% (95% CI: 0.27%-3.87%), 2.80% (95% CI: 1.00%-4.63%), and 2.87% (95% CI: 1.07%-4.70%) at V1 (30-min), V2 (3-h), and V3 (5-h) after the 2-h walk outsides, respectively. Compared with participants wearing the sham mask, the percentage change of nitrate in EBC was lower among those wearing the real mask. After the 2-h exposure, urinary MDA levels increased compared to the baseline in both trials. Real trial was lower than sham trial for 6 cytokines (i.e., IL-6, IL-10, IL-13, IL-17A, IFN-γ and TNF-α) in serum at 5-h post-exposure. Wearing facemasks on polluted days produced better improvement, however, on cleaner days, the improvement was weaker. CONCLUSIONS: Short-term use of N95 facemasks appeared to effectively reduce the levels of lung function declines, the respiratory oxidative stress, and the systemic inflammation/oxidative stress which may be induced by short-term exposure to PM. Wearing facemasks on polluted days (PM2.5 > 75 µg/m3) presented larger beneficial effects on the cardiopulmonary health than in clean days (PM2.5 < 75 µg/m3).

A wireless fully-passive acquisition of biopotentials.

Biopotential signals contain essential information for assessing functionality of organs and diagnosing diseases. We present a flexible sensor, capable of measuring biopotentials, in real time, in wireless and fully-passive manner. The flexible sensor collects and transmits biopotentials to an external reader without wire, battery, or harvesting/regulating element. The sensor is fabricated on a 90 µm-thick polyimide substrate with footprint of 18 × 15 × 0.5 mm3. The wireless fully-passive acquisition of biopotentials is enabled by the RF (Radio Frequency) microwave backscattering effect where the biopotentials are modulated by an array of varactors with incoming RF carrier that is backscattered to the external reader. The flexile sensor is verified and validated by emulated signal and Electrocardiogram (ECG), Electromyogram (EMG), and Electrooculogram (EOG), respectively. A deep learning algorithm analyzes the signal quality of wirelessly acquired data, along with the data from commercially-available wired sensor counterparts. Wired and wireless data shows <3% discrepancy in deep learning testing accuracy for ECG and EMG up to the wireless distance of 240 mm. Wireless acquisition of EOG further demonstrates accurate tracking of horizontal eye movement with deep learning training and testing accuracy reaching up to 93.6% and 92.2%, respectively, indicating successful detection of biopotentials signal as low as 250 µVPP. These findings support that the real-time wireless fully-passive acquisition of on-body biopotentials is indeed feasible and may find various uses for future clinical research.

Rh(II)/Brønsted Acid Catalyzed General and Highly Diastereo- and Enantioselective Propargylation of in Situ Generated Oxonium Ylides and C-Alkynyl N-Boc N,O-Acetals: Synthesis of Polyfunctional Propargylamines.

The first metal/organo cooperatively catalyzed asymmetric reaction of C-alkynyl N-Boc-protected N,O-acetals with in situ generated oxonium ylides has been developed. This new type of propargylation allows for the efficient synthesis of structurally diverse unreported chiral propargylamines bearing oxa-quaternary stereocenters. The reaction features unprecedented substrate scope and high diastereo- and enantioselectivity. Theoretical studies suggest a novel cooperative catalysis model and the unique transfer of R2OH.

Wireless Passive Stimulation of Engineered Cardiac Tissues.

We present a battery-free radio frequency (RF) microwave activated wireless stimulator, 25 × 42 × 1.6 mm3 on a flexible substrate, featuring high current delivery, up to 60 mA, to stimulate engineered cardiac tissues. An external antenna shines 2.4 GHz microwave, which is modulated by an inverted pulse to directly control the stimulating waveform, to the wireless passive stimulator. The stimulator is equipped with an on-board antenna, multistage diode multipliers, and a control transistor. Rat cardiomyocytes, seeded on electrically conductive gelatin-based hydrogels, demonstrate synchronous contractions and Ca2+ transients immediately upon stimulation. Notably, the stimulator output voltage and current profiles match the tissue contraction frequency within 0.5-2 Hz. Overall, our results indicate the promising potential of the proposed wireless passive stimulator for cardiac stimulation and therapy by induction of precisely controlled and synchronous contractions.

Asymmetric catalytic conjugate addition of acetaldehyde to nitrodienynes/nitroenynes: applications to the syntheses of (+)-α-lycorane and chiral ß-alkynyl acids.

The catalytic enantioselective conjugate addition of acetaldehyde to polyconjugated substrates, nitrodienynes and nitroenynes, has been accomplished using organocatalysis. Various functionalized 1,3-enynes and propargylic compounds were obtained in moderate to good yields with high enantioselectivity. The synthetic utilities of the conjugate addition reactions have been highlighted in the concise total synthesis of (+)-α-lycorane and the metal-free synthesis of chiral ß-alkynyl acids.