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.

Design, Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives Possessing a Trifluoromethyl Moiety as Potential Antitumor Agents.

A novel series of trifluoromethyl-containing quinazoline derivatives with a variety of functional groups was designed, synthesized, and tested for their antitumor activity by following a pharmacophore hybridization strategy. Most of the 20 compounds displayed moderate to excellent antiproliferative activity against five different cell lines (PC3, LNCaP, K562, HeLa, and A549). After three rounds of screening and structural optimization, compound 10 b was identified as the most potent one, with IC50 values of 3.02, 3.45, and 3.98 µM against PC3, LNCaP, and K562 cells, respectively, which were comparable to the effect of the positive control gefitinib. To further explore the mechanism of action of 10 b against cancer, experiments focusing on apoptosis induction, cell cycle arrest, and cell migration assay were conducted. The results showed that 10 b was able to induce apoptosis and prevent tumor cell migration, but had no effect on the cell cycle of tumor cells.

Efficacy and safety of platelet-rich plasma for acute nonarteritic anterior ischemic optic neuropathy: a prospective cohort study.

Background: As the most common acute optic neuropathy in older patients, nonarteritic anterior ischemic optic neuropathy (NAION) presents with varying degrees of visual acuity loss and visual field defect. However, there is no generally accepted treatment for NAION. Objectives: To evaluate the efficacy and safety of platelet-rich plasma (PRP) for patients with acute NAION within 2 months. Design: A prospective, nonrandomized controlled trial. Methods: Twenty-five eyes of 25 patients were enrolled. Of them, 13 received anisodine hydrobromide and butylphthalide-sodium chloride injection continuously for 10 days as basic treatment in the control group, and 12 received two tenon capsule injections of PRP on a 10 days interval as an additional treatment in the PRP group. We compared the best-corrected visual acuity (BCVA) and capillary perfusion density (CPD) of radial peripapillary capillaries and the moth-eaten eara of the peripapillary superficial capillary plexus and deep capillary plexus at 1 day (D1) before the first PRP treatment and 7 days (D7), 14 days (D14), and 30 days (D30) after the first PRP injection. Ocular and systemic adverse effects were assessed. Results: In the PRP group, a better BCVA occurred at D30 (adjusted p = 0.005, compared with D1, recovered from 0.67 ± 0.59 to 0.43 ± 0.59), and a significant improvement in CPD was observed at D30 (adjusted p < 0.001, p = 0.027, p = 0.027, compared with D1, D7, D14, in sequence, the value was 35.97 ± 4.65, 38.73 ± 4.61, 39.05 ± 5.26, 42.71 ± 4.72, respectively). CPD at D7 in the PRP group was better than that in the control group (p = 0.043). However, neither BCVA nor the moth-eaten area index were significantly different (all p > 0.5) between the two groups. The main adverse effect was local discomfort resolved within 1 week, and no other systemic adverse events occurred. Conclusion: Tenon capsule injection of PRP was a safe treatment for AION and could improve capillary perfusion of the optic nerve head and might be helpful in increasing short-term vision in patients with acute NAION.

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.

Trichromatic critical flicker frequency as potential visual test in cataract and macula disease patients.

PURPOSE: To investigate the capacity of critical flicker frequency (CFF) in discriminating cataract eyes with or without macula disease using trichromatic flickers, and to develop a model to predict postoperative best corrected visual acuity (BCVA). METHODS: Patients were divided into two groups based on the presence or absence of macular disease. CFF threshold measurements of red (R-CFF), green (G-CFF), and yellow (Y-CFF) flickers were conducted both preoperatively and postoperatively. A generalized estimating equations model (GEE) was employed to examine the relationship between CFF threshold and 3-month postoperative BCVA. RESULTS: A total of 115 eyes were enrolled, with 59 eyes in the cataract alone group and 56 eyes in the cataract with macular disease group completing the follow-up. R-CFF was found to be consistent before and after cataract removal (P = 0.06), even in cases where OCT was not performed successfully (P > 0.05). Y-CFF showed the highest AUC (0.798) for differentiating ocular comorbidities. According to the GEE model, in patients with a CFF threshold below 26 Hz, the odds ratios for achieving a postoperative VA of 20/40 or better were 34.8% for R-CFF, 26.0% for G-CFF, and 24.5% for Y-CFF. CONCLUSION: CFF emerges as a promising tool for predicting postoperative BCVA, providing valuable supplementary insights when fundus examination is obstructed. R-CFF demonstrates the best resistance to cataracts, while Y-CFF exhibits the highest sensitivity both in identifying macular diseases and predicting postoperative BCVA of 20/40 or better.

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.

The theory of critical flicker fusion frequency and its application in cataracts.

Background: Due to media opacity, it is usually difficult to accurately evaluate the postoperative visual acuity in cataracts patients. As a small and portable tool, the critical flicker fusion frequency (CFF) device reflects the temporal resolution of visual function and has been widely used in clinical research. However, poor understanding of the technique and equipment limitations have restricted its clinical application in China. Main text: There was a decrease in the CFF value in various ophthalmic diseases, indicating that the CFF is sensitive to detect visual functional changes. A number of studies have shown that the CFF test can accurately distinguish patients with simple cataracts from those with cataracts combined with fundus disease, and, as a visual test, it can more accurately predict postoperative visual acuity without being affected by media opacity. This study comprehensive reviews the basic principles of CFF and its application in ophthalmology, especially in cataracts. Conclusions: As one of the tools for dynamic visual function detection, the CFF test could help doctors to assess the possible presence of fundus disease in cataracts patients, especially in eyes with dense cataracts, and more precisely provide a reasonable visual prognosis than other available visual tests.

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.

Acute Retinal Necrosis Associated with Pseudorabies Virus Infection: A Case Report and Literature Review.

PURPOSE: To analyze a case of acute retinal necrosis (ARN) associated with pseudorabies virus (PRV) infection and discusses the clinical characteristics of PRV-induced ARN (PRV-ARN). METHODS: Case report and literature review of ocular features in PRV-ARN. RESULTS: A 52-year-old female diagnosed with encephalitis presented with bilateral vision loss, mild anterior uveitis, vitreous opacity, occlusive retinal vasculitis, and retinal detachment in her left eye. The result of metagenomic next-generation sequencing (mNGS) indicated that both cerebrospinal fluids and vitreous fluid tested positive for PRV. CONCLUSION: PRV, a zoonosis, can infect both humans and mammals. Patients affected with PRV may experience severe encephalitis and oculopathy, and the infection has been associated with high mortality and disability. ARN is the most common ocular disease, which develops rapidly following encephalitis and is characterized by five figures: bilateral onset, rapid progression, severe visual impairment, poor response to systemic antiviral drugs, and an unfavorable prognosis.

Research on Establishing Corneal Edema after Phacoemulsification Prediction Model Based on Variable Selection with Copula Entropy.

BACKGROUND: Corneal edema (CE) affects the outcome of phacoemulsification. Effective ways to predict the CE after phacoemulsification are needed. METHODS: On the basis of data from patients conforming to the protocol of the AGSPC trial, 17 variables were selected to predict CE after phacoemulsification by constructing a CE nomogram through multivariate logistic regression, which was improved via variable selection with copula entropy. The prediction models were evaluated using predictive accuracy, the area under the receiver operating characteristic curve (AUC), and decision curve analysis (DCA). RESULTS: Data from 178 patients were used to construct prediction models. After copula entropy variable selection, which shifted the variables used for prediction in the CE nomogram from diabetes, best corrected visual acuity (BCVA), lens thickness and cumulative dissipated energy (CDE) to CDE and BCVA in the Copula nomogram, there was no significant change in predictive accuracy (0.9039 vs. 0.9098). There was also no significant difference in AUCs between the CE nomogram and the Copula nomogram (0.9637, 95% CI 0.9329-0.9946 vs. 0.9512, 95% CI 0.9075-0.9949; p = 0.2221). DCA suggested that the Copula nomogram has clinical application. CONCLUSIONS: This study obtained a nomogram with good performance to predict CE after phacoemulsification, and showed the improvement of copula entropy for nomogram models.

Application of the Active-Fluidics System in Phacoemulsification: A Review.

The fluidics system is an indispensable and primary component of phacoemulsification. Both the gravity-fluidics system and active-fluidics system are commonly used in practice. The irrigation pressure of the gravity-fluidics system is determined by the bottle height, which is relatively constant, while the active-fluidics system is paired with a cassette that contains pressure sensors to monitor intraocular pressure changes. The active-fluidics system allows surgeons to preset a target intraocular pressure value, and it replenishes the fluids proactively; thus, the intraocular pressure is consistently maintained near the target value. Under such circumstances, stable intraocular pressure and anterior chamber volume values could be acquired. Research on surgical safety, efficiency and results have reported several strengths of the active-fluidics system. It is also advantageous in some complicated cataract surgeries. However, the system is not widely used at present, mainly due to its low penetration rate and high equipment cost. Some of its updates such as the new Active Sentry handpiece showed potential superiority in laboratory studies recently, but there is still further research to be conducted. This article gives an overview of the mechanism and performance of the active-fluidics system, and it is expected to provide clues for future research.

Mapping C-H⋠⋠⋠M Interactions in Confined Spaces: (α-ICyDMe )Au, Ag, Cu Complexes Reveal "Contra-electrostatic H Bonds" Masquerading as Anagostic Interactions*.

What happens when a C-H bond is forced to interact with unpaired pairs of electrons at a positively charged metal? Such interactions can be considered as "contra-electrostatic" H-bonds, which combine the familiar orbital interaction pattern characteristic for the covalent contribution to the conventional H-bonding with an unusual contra-electrostatic component. While electrostatics is strongly stabilizing component in the conventional C-H⋅⋅⋅X bonds where X is an electronegative main group element, it is destabilizing in the C-H⋅⋅⋅M contacts when M is Au(I), Ag(I), or Cu(I) of NHC-M-Cl systems. Such remarkable C-H⋅⋅⋅M interaction became experimentally accessible within (α-ICyDMe )MCl, NHC-Metal complexes embedded into cyclodextrins. Computational analysis of the model systems suggests that the overall interaction energies are relatively insensitive to moderate variations in the directionality of interaction between a C-H bond and the metal center, indicating stereoelectronic promiscuity of fully filled set of d-orbitals. A combination of experimental and computational data demonstrates that metal encapsulation inside the cyclodextrin cavity forces the C-H bond to point toward the metal, and reveals a still attractive "contra-electrostatic" H-bonding interaction.

The clinical application of critical flicker fusion frequency in demyelinating optic neuritis.

Purpose: To investigate the application of critical flicker fusion frequency (CFF) in demyelinating optic neuritis (DON). Methods: A cross-sectional study. A total of 127 eyes in 69 DON patients and 63 eyes in 33 healthy control (HC) groups were included between January 2021 to September 2021 from Department of Ophthalmology, PLA General Hospital. Patients underwent best-corrected visual acuity (BCVA), visual field, optical coherence tomography (OCT), flash visual evoked potential (F-VEP), and CFF examinations. The affected eyes were divided into aquaporins 4 (AQP4-), myelin oligodendrocyte glycoprotein (MOG-), and double negative DON according to serum antibody; mild, moderate, severe degree visual impairment according to BCVA ≥ 0.5, 0.1-0.5, < 0.1; and 4 groups: < 1, 1 ∼< 3, 3 ∼ < 6 and > 6 months according to time interval from onset to CFF examination. One-way ANOVA was used to perform above subgroup analysis. The correlations between CFF and F-VEP peak time, peak value, BCVA and mean visual filed defect (MD) were analyzed in order via Pearson correlation analysis. Results: he trichromatic values of red, green, and yellow in DON affected eyes were 21.83 ± 9.03, 23.66 ± 10.21, 24.09 ± 10.77 Hz, respectively, which was significantly reduced compared with the HC group (t = -14.82, -14.22, -14.00; P < 0.001). The subgroup analysis showed no significant difference between different antibody subtypes (P = 0.914 <0.848 <0.604), whereas, a significant decrease of CFF trichromatic value was found in severe visual acuity impairment group (P < 0.001). There was a significant difference in CFF- trichromatic values at different time points (P < 0.001), to be specific, CFF fluctuated under 20Hz within 3 months after onset and tended to be stable around 24-28Hz. Correlation analysis showed that the peak time of F-VEP (r = -0.486, -0.515, -0.526; P < 0.001), BVCA (r = -0.640, -0.659, -0.642; P < 0.001), were negatively correlated with CFF trichromatic values, MD and CFF were positively correlated (r = 0.486, 0.453, 0.476; P = 0.003, 0.006, 0.004). Conclusions: A significant decrease of CFF value was found in DON-affected eyes, and it has a good correlation with BCVA, MD and latency of F-VEP, and can better reflect the impairment of visual function.

Permethylated NHC-Capped α- and ß-Cyclodextrins (ICyDMe ) Regioselective and Enantioselective Gold-Catalysis in Pure Water.

A series of water-soluble encapsulated copper(I), silver(I) or gold(I) complexes based on NHC-capped permethylated cyclodextrins (ICyDMe ) were developed and used as catalysts in pure water for hydration, lactonization, hydroarylation and cycloisomerization reactions. ICyDMe ligands gave cavity-based high regioselectivity in hydroarylations, and high enantioselectivities in gold-catalyzed cycloisomerizations reactions giving up to 98 % ee in water. These ICyDMe are therefore useful ligands for selective catalysis in pure water.

Capturing the Monomeric (L)CuH in NHC-Capped Cyclodextrin: Cavity-Controlled Chemoselective Hydrosilylation of α,ß-Unsaturated Ketones.

The encapsulation of copper inside a cyclodextrin capped with an N-heterocyclic carbene (ICyD) allowed both to catch the elusive monomeric (L)CuH and a cavity-controlled chemoselective copper-catalyzed hydrosilylation of α,ß-unsaturated ketones. Remarkably, (α-ICyD)CuCl promoted the 1,2-addition exclusively, while (ß-ICyD)CuCl produced the fully reduced product. The chemoselectivity is controlled by the size of the cavity and weak interactions between the substrate and internal C-H bonds of the cyclodextrin.