Fragment-based design and synthesis of coumarin-based thiazoles as dual c-MET/STAT-3 inhibitors for potential antitumor agents.

c-MET and STAT-3 are significant targets for cancer treatments. Here, we describe a class of very effective dual STAT-3 and c-MET inhibitors with coumarin-based thiazoles (3a-o) as its scaffold. Spectroscopic evidence (NMR, HRMS, and HPLC) validated the structural discoveries of the new compounds. The cytotoxic activity of these compounds was also tested against a panel of cancer cells in accordance with US-NCI guidelines. Compound 3g proved to be active at 10 µM, thus it was automatically scheduled to be tested at five doses. Towards SNB-75 (CNS cancer cell line), compound 3g showed notable in vitro anti-cancer activity with GI50 = 1.43 µM. For the molecular targets, compound 3g displayed potent activity towards STAT-3 and c-MET having IC50 of 4.7 µM and 12.67, respectively, compared to Cabozantinib (IC50 = 15 nM of c-MET) and STAT-3-IN-3 (IC50 = 2.1 µM of STAT-3). Moreover, compound 3g significantly induced apoptosis in SNB-75 cells, causing a 3.04-fold increase in apoptotic cell death (treated cells exhibited 11.53 % overall apoptosis, against 3.04 % in reference cells) and a 3.58-fold increase in necrosis. Moreover, it arrests cells at the G2 phase. Dual inhibition of c-MET and STAT-3 protein kinase was further validated using RT-PCR. The target compound's binding mechanism was determined by the application of molecular docking.

Identification of 3-(5-cyano-6-oxo-pyridin-2-yl)benzenesulfonamides as novel anticancer agents endowed with EGFR inhibitory activity.

New 5-cyano-6-oxo-pyridine-based sulfonamides (6a-m and 8a-d) were designed and synthesized to potentially inhibit both the epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA), with anticancer properties. First, the in vitro anticancer activity of each target substance was tested using Henrietta Lacks cancer cell line and M.D. anderson metastasis breast cancer cell line cells. Then, the possible CA inhibition against the human CA isoforms I, II, and IX was investigated, together with the EGFR inhibitory activity, with the most powerful derivatives. The neighboring methoxy group may have had a steric effect on the target sulfonamides, which prevented them from effectively inhibiting the CA isoforms while effectively inhibiting the EGFR. The effects of the 5-cyanopyridine derivatives 6e and 6l on cell-cycle disruption and the apoptotic potential were then investigated. To investigate the binding mechanism and stability of the target molecules, thorough molecular modeling assessments, including docking and dynamic simulation, were performed.

Tailored horseshoe-shaped nicotinonitrile scaffold as dual promising c-Met and Pim-1 inhibitors: Design, synthesis, SAR and in silico study.

For the horseshoe tactic to succeed in inhibiting c-Met and Pim-1, the nicotinonitrile derivatives (2a-n) were produced in high quantities by coupling acetyl phenylpyrazole (1) with the proper aldehydes and ethyl cyanoacetate under basic conditions. Consistent basic and spectroscopic data (NMR, IR, Mass, and HPLC) supported the new products' structural findings. With IC50 potency in nanomolar ranges, these compounds had effectively repressed them, particularly compounds 2d and 2 h, with IC50 values below 200 nM. The most potent compounds (2d and 2 h) were tested for their antitumor effects against prostate (PC-3), colon (HCT-116), and breast (MDA-MB-231) and were evaluated in comparison to the anticancer drug tivantinib using the MTT assay. Similar to tivantinib, these compounds showed good antiproliferative properties against the HCT-116 tumor cells while having low cytotoxicity towards healthy fetal colon (FHC) cells. In the HCT-116 cell line, their ability to trigger the apoptotic cascade was also investigated by looking at the level of Bax and Bcl-2 as well as the activation of the proteolytic caspase cascade. When HCT-116 cells were exposed to compounds 2d and 2 h in comparison to the control, active caspase-3 levels increased. The HCT-116 cell line also upregulated Bcl-2 protein levels and downregulated Bax levels. Additionally, when treated with compound 2d, the HCT-116 cell cycle was primarily stopped at the S phase. Compared to the control, compound 2d treatment significantly inhibited the protein expression levels of c-Met and Pim-1 kinases in the treated HCT-116 cells. Thorough molecular modeling analyses, such as molecular docking and dynamic simulation, were performed to ascertain the binding mechanism and stability of the target compounds.

Discovery of novel enasidenib analogues targeting inhibition of mutant isocitrate dehydrogenase 2 as antileukaemic agents.

Mutant isocitrate dehydrogenase (IDH) 2 "IDH2m" acquires a neo-enzymatic activity reducing α-ketoglutarate to an oncometabolite, D-2-hydroxyglutarate (2-HG). Three s-triazine series were designed and synthesised using enasidenib as a lead compound. In vitro anticancer screening via National Cancer Institute "NCI" revealed that analogues 6a, 6c, 6d, 7g, and 7l were most potent, with mean growth inhibition percentage "GI%" = 66.07, 66.00, 53.70, 35.10, and 81.15, respectively, followed by five-dose screening. Compounds 6c, 6e, and 7c were established as the best IDH2R140Q inhibitors compared to enasidenib, reporting IC50 = 101.70, 67.01, 88.93, and 75.51 nM, respectively. More importantly, 6c, 6e, and 7c displayed poor activity against the wild-type IDH2, IC50 = 2928, 2295, and 3128 nM, respectively, which implementing high selectivity and accordingly safety. Furthermore, 6c was screened for cell cycle arrest, apoptosis induction, and western blot analysis. Finally, computational tools were applied to predict physicochemical properties and binding poses in IDH2R140Q allosteric site.

Does faecal calprotectin differentiate between inflammatory bowel disease colitis and non-inflammatory bowel disease colitides?

INTRODUCTION: Chronic colitis is a major problem worldwide with high morbidity. Causes of chronic colitis are heterogeneous. A cut-off level of faecal calprotectin to predict inflammatory bowel disease (IBD) as a cause of chronic colitis is lacking. AIM: To study the level of faecal calprotectin in different causes of colitis and to measure the cut-off level to differentiate between IBD and non-IBD colitides. MATERIAL AND METHODS: This prospective study was conducted from June 2018 to May 2019. The study included all patients aged 2 months up to 18 years who were confirmed to have chronic colitis endoscopically and histopathologically attending the Gastroenterology Clinic at Alexandria University Children's Hospital. Faecal calprotectin level was measured. RESULTS: We included 110 patients. Allergic colitis was the commonest cause followed by IBD followed by infectious colitis (50.9%, 38.1% and 6.3% respectively). Faecal calprotectin above 744 µg/g could predict IBD as a cause of chronic colitis with 86.8% specificity and 66.7% sensitivity. Significant elevation of faecal calprotectin was detected in IBD patients. Faecal calprotectin was significantly correlated with C-reactive protein level and erythrocyte sedimentation rate. CONCLUSIONS: Faecal calprotectin could predict the cause of colitis and could aid the paediatrician for early referral of patients with chronic colitis.

Role of Wrap-Crural Fixation and Minimal Dissection in Prevention of Transmigration After Laparoscopic Nissen Fundoplication in Children.

Background: Laparoscopic Nissen fundoplication is the gold standard antireflux procedure in pediatric age group. Intrathoracic migration of the fundic wrap is a common cause failure, leading to recurrence of gastroesophageal reflux disease (GERD) symptoms. Objectives: To investigate the impact of wrap-crural fixation and minimal esophageal dissection in prevention of wrap transmigration after laparoscopic Nissen fundoplication in children. Methods: Prospective randomized study of 46 pediatric patients with refractory GERD who underwent laparoscopic Nissen fundoplication divided into two equal groups. In Group A, wrap crural fixation was done, whereas in group B no fixation was done. Minimal esophageal dissection with preservation of the phrenoesophageal ligament was done in both groups. Approval of the Ethics Committee of our Faculty was obtained. Results: There was no difference between both groups regarding operative time, intraoperative complications, or length of hospital stay. Two patients in group B without wrap fixation suffered recurrence of GERD symptoms. On contrast study, they both showed intrathoracic wrap migration. One of them was reoperated. Whereas in group A, no recurrence of symptoms and no wrap transmigration were noticed in follow-up. Conclusion: In laparoscopic Nissen fundoplication, with minimal esophageal dissection and preservation of the phrenoesophageal ligament, there is no additional benefit from wrap-crural fixation in prevention of wrap transmigration.

Effects of Dual Sofosbuvir/Daclatasvir Therapy on Weight and Linear Growth in Adolescent Patients with Chronic Hepatitis C Virus Infection.

Negative effects on growth indices had been reported in children treated with interferon for chronic viral hepatitis. Forty chronic hepatitis C virus-infected adolescents, 12-17 years of age, were treated with sofosbuvir/daclatasvir therapy for 12 weeks. The intent-to-treat sustained virologic response rate at 12 weeks after end of treatment was 39/40 (97.5%). Unlike interferon-based therapy, we did not detect significant negative effects on linear growth or weight. Contrarily, a trend to increased appetite and insignificant weight gain was observed, but further larger studies are needed to confirm. See Video-Abstract, http://links.lww.com/ASAIO/A381.

High-resolution anorectal manometry in children with functional constipation: a single-centre experience before and after treatment.

INTRODUCTION: Constipation is a common disorder among children, and most of the cases are functional in aetiology. Few studies have reported the manometric data of normal and constipated children. AIM: To evaluate the manometric parameters in children with functional constipation and to assess any possible changes in these parameters after treatment. MATERIAL AND METHODS: A prospective descriptive study was conducted at a single centre, enrolling 50 children diagnosed with functional constipation based on Rome IV criteria. Their age ranged from 6 to 14 years with a mean of 7.31 ±1.72 years. High-resolution manometry was performed on all children at the initial presentation and after six months of treatment. RESULTS: The studied children showed markedly abnormal rectal sensation parameters (increased first sensation, first urge, intense urge, and maximum tolerable volume) during rectal balloon distension. These parameters were even higher in children with stool incontinence (p = 0.005). Manometric data after 6 months of treatment showed that the resting and squeeze pressures were increased when compared to pre-treatment recordings; however, both were statistically insignificant (p = 0.474 and p = 0.155, respectively). Abnormalities in rectal sensations and the manometric parameters reached near normal values following treatment. CONCLUSIONS: Anorectal manometry is sensitive in predicting improvement in patient condition even before complete clinical cure, and it has a prognostic role in the management of childhood constipation. More research is still needed before recommending anorectal manometry as a routine diagnostic or prognostic tool in paediatric constipation management.