The Design and Development of Potent Small Molecules as Anticancer Agents Targeting EGFR TK and Tubulin Polymerization

Some novel anthranilate diamides derivatives 4a–e, 6a–c and 9a–d were designed and synthesized to be evaluated for their in vitro anticancer activity. Structures of all newly synthesized compounds were confirmed by infra-red (IR), high-resolution mass (HR-MS) spectra, 1H nuclear magnetic resonance (NMR) and 13C nuclear magnetic resonance (NMR) analyses. Cytotoxic screening was performed according to (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) assay method using erlotinib as a reference drug against two different types of breast cancer cells. The molecular docking study was performed for representative compounds against two targets, epidermal growth factor receptor (EGFR) and tubulin in colchicine binding site to assess their binding affinities in order to rationalize their anticancer activity in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticancer activity for these newly synthesized compounds. Biological data for most of the anthranilate diamide showed excellent activity with nanomolar or sub nanomolar half maximal inhibitory concentration (IC50) values against tumor cells. EGFR tyrosine kinase (TK) inhibition assay, tubulin inhibition assay and apoptosis analysis were performed for selected compounds to get more details about their mechanism of action. Extensive structure activity relationship (SAR) analyses were also carried out

Self Organizing Map-Based Classification of Cathepsin k and S Inhibitors with Different Selectivity Profiles Using Different Structural Molecular Fingerprints: Design and Application for Discovery of Novel Hits

The main step in a successful drug discovery pipeline is the identification of small potent compounds that selectively bind to the target of interest with high affinity. However, there is still a shortage of efficient and accurate computational methods with powerful capability to study and hence predict compound selectivity properties. In this work, we propose an affordable machine learning method to perform compound selectivity classification and prediction. For this purpose, we have collected compounds with reported activity and built a selectivity database formed of 153 cathepsin K and S inhibitors that are considered of medicinal interest. This database has three compound sets, two K/S and S/K selective ones and one non-selective KS one. We have subjected this database to the selectivity classification tool ‘Emergent Self-Organizing Maps’ for exploring its capability to differentiate selective cathepsin inhibitors for one target over the other. The method exhibited good clustering performance for selective ligands with high accuracy (up to 100 %). Among the possibilites, BAPs and MACCS molecular structural fingerprints were used for such a classification. The results exhibited the ability of the method for structure-selectivity relationship interpretation and selectivity markers were identified for the design of further novel inhibitors with high activity and target selectivity

A Novel Reverse Thermosensitive Polymer to Achieve Temporary Atraumatic Vessel Occlusion in Infra-popliteal Bypasses

AbstractObjectiveThe study aims to assess a novel thermosensitive polymer (LeGoo®) for distal vessel control during infra-popliteal (crural/pedal) bypass surgery in severe leg ischaemia.MethodRetrospective analysis of all distal bypasses from October 2009 to February 2012. Technical success, patency, limb salvage and amputation-free survival rates were analysed.ResultsFifty-four infra-popliteal bypasses using the polymer were performed in 46 patients. The distal anastomosis was at the anterior tibial (n = 15, 28%), posterior tibial (n = 12, 22%), peroneal (n = 8, 15%), tibio-peroneal trunk (n = 8, 15%) and dorsalis pedis arteries (n = 11, 20%). Technical success was achieved in 51/54 (94.4%; failures: two inadequate haemostasis, one un-dissolved polymer). In-hospital duplex of the distal anastomosis showed a significant stenosis in two cases (4.3%). Outflow angioplasty was performed in three cases (two distal anastomotic, one run-off vessel, 5.6%). The 1-year patency rate was 76.2% (standard error (SE) 6.7%), limb salvage rate 79.3% (SE 6.7%). Amputation-free survival was 93.5% at 30 days (SE 3.6%) and 67.5% at 1 year (SE 7.5%).ConclusionThis thermosensitive polymer is a potentially safe and useful atraumatic device to achieve a blood-less distal anastomotic field in infra-popliteal bypasses. The technique avoids other potentially traumatic methods of vessel control, which may be particularly important in patients with calcified distal vessels

Endovascular repair of a tuberculous mycotic thoracic aortic aneurysm with a custom-made device

Mycotic aortic aneurysms are rare and it is unlikely that any center will obtain extensive experience in their management. The aim of treatment is to repair the aorta and eradicate the infection with minimal operative and postoperative risk. We describe a case in which a custom-made endovascular stent graft provided the optimal treatment strategy and remained durable at 4 years of follow-up

Design, Synthesis, Cytotoxic Evaluation and Molecular Docking of New Fluoroquinazolinones as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects

A series of new fluoroquinazolinone 6–8 and 10a–g derivatives was designed, prepared and screened for their in vitro cytotoxic activity against human cancer cell lines MCF-7 and MDA-MBA-231. Compounds 6 (IC50 = 0.35 ± 0.01 µM), 10f (IC50 = 0.71 ± 0.01 µM), 10d (IC50 = 0.89 ± 0.02 µM) and 10a (IC50 = 0.95 ± 0.01 µM) displayed broad spectrum anticancer activity better than the reference drug gefitinib (IC50 = 0.97 ± 0.02 µM) against MCF-7. Compounds 10e (IC50 = 0.28 ± 0.02 µM), 10d (IC50 = 0.38 ± 0.01 µM), 7 (IC50 = 0.94 ± 0.07 µM) and 10c (IC50 = 1.09 ± 0.01 µM) showed better activity than the reference gefitinib (IC50 = 1.30 ± 0.04 µM) against MDA-MBA-231. Moreover, EGFR and tubulin inhibition assays were performed for the highest active derivatives and showed remarkable results comparing to the reference drugs. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated

Predictors of Outcome after Endovascular Repair for Chronic Type B Dissection

AbstractObjectivesTo assess the durability of endovascular repair (TEVAR) in chronic type B dissection (CD) and identify factors predictive of outcome.DesignRetrospective analysis of a prospective database.MaterialsPatients undergoing TEVAR for CD at a tertiary referral centre 2000–2010.MethodsAnalysis of pre-operative characteristics, operative outcome, false lumen thrombosis, aortic diameter and survival.Results58 consecutive patients were included (49 elective, 9 urgent, mean age 66 years). Mean aortic diameter was 6.4 cm (Standard deviation SD 1.3 cm). Three patients died perioperatively (5%, 1 urgent, 2 elective). Complications included retrograde type A dissection (n = 3), paraplegia (1), and transient ischaemic attack (1). Estimated survival (Kaplan–Meier) was 89% (1-year) and 64% (3-years). Forty-seven patients had mid-term imaging follow-up at mean 38 months. Reintervention rate was 15% at 1-year and 29% at 3-years. Aortic diameter decreased in 24, was stable in 15 and increased in 8. Mid-term survival was higher in patients with aortic remodelling (reduction of aortic diameter >0.5 cm; 3-year 89%) than without (54%; Log Rank p = 0.005). Remodelling occurred with extensive false lumen thrombosis.ConclusionSatisfactory mid-term outcome after TEVAR for CD remains a challenge. Survival is associated with aortic remodelling, which is related to persistence of flow in the false lumen

Predictors of Stroke and Paraplegia in Thoracic Aortic Endovascular Intervention

AbstractBackgroundEndoluminal repair of thoracic aortic pathology has become established in clinical practice, but is associated with significant neurological complications. The aim of this study was to identify factors that were predictive of stroke and paraplegia.MethodsProspective data was collected for a cohort of 293 consecutive patients having thoracic aortic endovascular repair between August 1997 and September 2009. Patient and procedural characteristics were related to the incidence of stroke and paraplegia using multivariate logistic regression analysis.ResultsThe median age was 68 years (18–87), there were 191 men and 102 women. Mortality was 5.1% for 195 elective and 13.4% for 98 urgent patients. Stroke affected 16 (5.5%) patients: 11 affected the anterior and 5 the posterior circulation. Coverage of the left subclavian artery with no revascularisation was the only significant factor predictive of stroke (OR 5.34 (1.42–20.40) P = 0.01). Paraplegia affected 16 patients (5.5%) but no independent risk factor was identified: 12 were identified perioperatively and 4 were delayed by up to 6 months.ConclusionCovering the left subclavian artery without revascularisation increases the risk of stroke following endoluminal repair of thoracic pathology. Paraplegia appears to be more complex and no independent precipitating factor was identified