Résumé
Objective: To design and synthesize a series of 2-aryl-4-(trans-4-hydroxycyclohexanolamine)-7H-pyrrolo[2, 3-d] pyrimidine derivatives and test their inhibitory activity against Mer tyrosine kinase(MerTK)and tumor cell proliferation. Methods: 2, 4-Dichloro-7H-pyrrolo[2, 3-d]pyrimidine(1)was used as starting material to synthesize the target compounds via iodination, protection with p- Tosyl(Ts), nucleophilic substitution, Stille coupling, vinyl reduction, Suzuki coupling and deprotection of Ts. The MerTK inhibitory activity was tested by the Kinase-Glo Plus luminescence method. The antiproliferation activity was assayed using MV- 4-11, A549, MDA-MB-231, KB, and KB-vin tumor cell lines by the CCK8 and SRB methods. Molecular docking of MerTK and 6h was conducted using the DS3.0 software. Results: Nine compounds were synthesized, and their structures were confirmed by 1H NMR and MS. Compound 6h exhibited certain inhibitory effect on MerTK, with the(6.7±0.3)μmol/L of IC50 value, and could selectively inhibit the growth of MV-4-11 tumor cells, with the(6.6±1.1)μmol/L of GI50 value that was approximately 3-fold to 6-fold more potent than the GI50 value of 6h on the other tested tumor cells. Molecular docking showed that 6h could interact with MerTK on the binding site of UNC569 and overlapped well with the original ligand UNC569, but its binding energy was higher than the binding energy of UNC569. Conclusion: Compound 6h showed a selective inhibitory effect on the MV-4-11 cell growth, which might be further investigated via more biological experiments to explore whether the inhibitory effect is related to the inhibition of MerTK by 6h. The molecular docking results in the present study have suggested that further structural modification on the 2 and 5 position of 7H-pyrrolo[2, 3-d] pyrimidine skeleton could likely improve the MerTK inhibitory activity.
Résumé
To investigate anti-hemolytic, antibacterial and anti-cancer activities of leaf and stem extracts fromPolygonum odoratum.Methods: Leaves and stems ofPolygonum odoratum were extracted using methanol and their anti-hemolytic activity was assessed using 2, 2′-Azobis (2-methylpropionamidine) dihydrochloride which is known to generate free radical damage on cell membranes of red blood cells. This damage, represented by hemolysis, was measured using spectrophotometry. Antibacterial activity was tested by using a broth microdilution method to find minimal inhibitory concentrations against eight bacterial strains. Anti-cancer activity of the extracts was evaluated against a human promyelocytic leukemic cell line (HL-60) by using MTT assay for cell viability and flow cytometry for apoptosis induction and cell cycle analysis.Results: Both leaf and stem extracts have anti-hemolytic activity. The results showed a significantly increased percentage of inhibition in a concentration-dependent manner. Interestingly, the leaf extract showed anti-hemolytic activity to a greater extent than the stem extract. Antibacterial activity of the extracts, as indicated by their minimal inhibitory concentration, using 12.5, 50, 25, 25 μg/mL, was measured againstStaphylococcus epidermidis, Enterococcus faecium,Enterococcus faecalisand Staphylococcus aureus. The leaf extracts also exhibited anti-cancer activity, demonstrated by significantly decreased cell viability of human promyelocytic cells (HL-60), with an IC50 of (350.00±1.85) μg/mL for 48 h and (38.00±0.92) μg/mL for 72 h. Additionally, HL-60 became apoptotic and accumulated in G1-phase after 48 hours of treatment.Conclusions: The extracts ofPolygonum odoratum exhibit potential anti-hemolytic activity. They also have antibacterial activity by inhibiting growth of Gram-positive bacteria. The leaf extract shows anti-cancer activity against HL-60 to a greater extent than the stem extract, causing decreased viability, increased G1-phase accumulation and apoptosis induction.
Résumé
Objective: To investigate anti-hemolytic, antibacterial and anti-cancer activities of leaf and stem extracts from Polygonum odoratum. Methods: Leaves and stems of Polygonum odoratum were extracted using methanol and their anti-hemolytic activity was assessed using 2, 2′-Azobis (2-methylpropionamidine) dihydrochloride which is known to generate free radical damage on cell membranes of red blood cells. This damage, represented by hemolysis, was measured using spectrophotometry. Antibacterial activity was tested by using a broth microdilution method to find minimal inhibitory concentrations against eight bacterial strains. Anti-cancer activity of the extracts was evaluated against a human promyelocytic leukemic cell line (HL-60) by using MTT assay for cell viability and flow cytometry for apoptosis induction and cell cycle analysis. Results: Both leaf and stem extracts have anti-hemolytic activity. The results showed a significantly increased percentage of inhibition in a concentration-dependent manner. Interestingly, the leaf extract showed anti-hemolytic activity to a greater extent than the stem extract. Antibacterial activity of the extracts, as indicated by their minimal inhibitory concentration, using 12.5, 50, 25, 25 μg/mL, was measured against Staphylococcus epidermidis, Enterococcus faecium, Enterococcus faecalis and Staphylococcus aureus. The leaf extracts also exhibited anti-cancer activity, demonstrated by significantly decreased cell viability of human promyelocytic cells (HL-60), with an IC
Résumé
Objective: To conduct systematic evaluation on the dermatologic toxicity caused by targeted anti-cancer drugs in children and teenager to provide reference for future studies and clinical practice.Methods: Pubmed(http:∥www.ncbi.nlm.nih.gov/pubmed/), American Society of Clinical Oncology Annual Meetings' Online Abstracts Database(http:∥www.asco.org/) and ClinicalTrials.gov(http:∥www.clinicaltrials.gov) were searched for the clinical trials on the use of targeted anti-cancer drugs (single or combination) in children and teenager complicated with dermatologic toxicity.Methodological quality assessment was performed for the included studies, using Cochrane's risk of bias assessment tool for randomized controlled trials and methodological index for non-randomized studies (MINORS).Meta-analysis was performed for the outcomes including adverse event rate of skin rash, xerosis, pruritis and mucositis.Results: A total of 24 studies with 960 patients were included in this study.Various solid tumors and leukemia were investigated in the studies.The quality assessment revealed that the majority of included studies were with high quality.According to the results of meta-analysis, the pooled event rate and 95% confidence interval were 0.19[0.12-0.28],0.24[0.06-0.51],0.12[0.04-0.24] and 0.21[0.07-0.39] for skin rash, xerosis, pruritis and mucositis, respectively.Publication bias analysis indicated potential reporting bias for skin rash (Egger's P=0.007).Conclusion: Dermatologic adverse events occur in a part of children and teenager with cancer treated with targeted therapy, which may cause impaired quality of life and disability.Adequate attention should be paid to these events during clinical trials and real life practice.