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.

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 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.

Predicting visual outcomes in keratoprosthesis surgery with critical flicker fusion frequency, B-scan, visual electrophysiology and endoscopy.

PURPOSE: This study evaluates the predictive power of the critical flicker fusion frequency (CFF) test for visual outcomes in keratoprosthesis (KPro) candidates, comparing its accuracy with B-scan ultrasound, flash visual evoked potentials (fVEP) and endoscopy. METHODS: The study included 42 patients (42 eyes) scheduled for KPro surgery with a median follow-up period of 6 months. The receiver operating characteristic curve identified the cut-off threshold for CFF in the model development study (17 eyes). All patients in the comparison study (25 eyes) underwent preoperative assessments including trichromatic CFF (red, green and yellow), B-scan ultrasound, fVEP and perioperative endoscopy. Results were classified as either favourable or unfavourable predictors of visual outcomes based on predefined criteria. Sensitivity and specificity of each assessment were calculated based on postoperative best-corrected visual acuity (BCVA)≥20/200. The Bland-Altman test assessed the consistency between CFF-predicted BCVA and actual BCVA. RESULTS: Among the trichromatic CFF tests, the yellow-CFF (yCFF) exhibited the highest area under the curve value of 0.97 and a cut-off threshold at 10 Hz for predicting postoperative BCVA≥20/200 (p<0.05). yCFF achieved 90% sensitivity and 80% specificity in predicting satisfactory postoperative outcomes. Endoscopy had 80% sensitivity and 80% specificity, B-scan showed 70% sensitivity and 60% specificity, and fVEP had 75% sensitivity and 40% specificity. yCFF showed a mean bias of 0.091 logarithm of the minimum angle of resolution (logMAR) in postoperative prediction. CONCLUSIONS: The CFF test provides robust visual function evaluation in KPro candidates. It demonstrates superior predictive accuracy for visual prognosis compared with routine ophthalmologic examinations, such as B-scan ultrasonography, fVEP and endoscopy.