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A series of 1-(2,3-dihydro-1H-indan-1-yl)-3-aryl urea/thiourea derivatives (4a-j) have been synthesized from the reaction of 2,3-dihydro-1H-inden-1-amine (2) with various aryl isocyanates/isothiocyanates (3a-j) by using N,N-DIPEA base (Hunig's base) catalyst in THF at reflux conditions. All of them are structurally confirmed by spectral (IR, 1H & 13C NMR and MASS) and elemental analysis and screened for their in-vitro antioxidant activity against DPPH and NO free radicals and found that compounds 4b, 4i, 4h & 4g are potential antioxidants. The obtained in vitro results were compared with the molecular docking, ADMET, QSAR and bioactivity study results performed for them and identified that the recorded in silico binding affinities were observed in good correlation with the in vitro antioxidant results. The Molecular docking analysis had unveiled the strong hydrogen bonding interactions of synthesized ligands with ARG 160 residue of protein tyrosine kinase (2HCK) enzyme and plays an effective role in its inhibition. Toxicology studies have assessed the potential risks of 4a-j and inferred that all of them were in the limits of potential drugs. The conformational analysis of 4a-j inferred that the urea/thiourea spacer linking 2,3-dihydro-1H-inden-1-amino and substituted aryl units has facilitated all these molecules to effectively bind with ARG 160 amino acid residue present on the α-helix of the protein tyrosine kinase (2HCK) enzyme specifically on chain A of hemopoetic cell kinase. Collectively this study has established a relationship between the antioxidant potentiality and ligands binding with ARG 160 amino acid residue of chain A of 2HCK enzyme to inhibit its growth as well as proliferation of reactive oxygen species in vivo. © 2019 Elsevier Inc. One of the authors Dr. Avula Vijay Kumar Reddy is thankful to Ural Federal University, Yekaterinburg, Russian Federation for providing Postdoctoral Fellowship.

Background Chronic myeloid leukaemia (CML) is very rare in children. The aim of the study is to report the experience within the I-CML-Ped study in children and adolescents presenting at diagnosis with advanced phase disease and to describe their characteristics and outcomes. Methods Of 479 children and adolescents enrolled in the international registry for childhood chronic myeloid leukaemia (I-CML-Ped Study; www.clinicaltrials.gov NCT01281735 ), 36 children (7.5%) presented at initial diagnosis with CML in advanced phase according to the European LeukemiaNet criteria. Results Nineteen (4%) patients were diagnosed in accelerated phase (CML-AP), and among the 17 patients (3.5%) diagnosed in blastic phase (CML-BP), 70% presented with lymphoid immunophenotype. Initial treatment of CML-AP/CML-BP consisted of tyrosine kinase inhibitors (TKIs) with or without chemotherapy, leading to complete haematologic response in 33 of 36 (92%) patients. Seventeen patients proceeded to haematopoietic stem cell transplantation. At the last follow-up, 18 of 19 patients with de novo CML-AP are alive in at least major molecular response (MMR) (n = 16), in progression (n = 1) or in molecular relapse (n = 1) and 13 of 17 patients with de novo CML-BP are alive in at least MMR. Five-year overall survival rates are 94% (95% confidence interval [CI]: 66%–99%) and 74% (95% CI: 44%–89%) for patients diagnosed in CML-AP and CML-BP, respectively. Conclusion Children with advanced phase at diagnosis of CML seem to have a better survival rate than that reported for advanced phases evolving under TKI treatment.

Structure novelty, chemical stability and synthetic feasibility attracted us to design 1,2,3-triazole compounds as potential inhibitors of VEGFR2 tyrosine kinase. Novel triazoles T1-T7 were proposed by oxazole (AAZ from PDB: 1Y6A)/1,2,3-triazole isosteric replacement, molecular modelling and docking. In order to enable synthesis of T1-T7 we developed a methodology for preparation of ynamide 22. Compound 22 was used for all Click chemistry reactions leading to triazoles T1-T3 and T6-T7. Among the obtained products, T1, T3 and T7 specifically bind VEGFR2 TK and modulate its activity by concentration dependent manner. Moreover predicted binding poses of T1-T7 in VEGFR2 TK were similar to the one known for the oxazole inhibitor AAZ (PDB: 1Y6A). Unfortunately the VEGFR2 inhibition by triazoles e.g. T3 and T7 is lower than that determined for their oxazole bioisosters T3-ox and AAZ, resp. Different electronic properties of 1,2,3-triazole/oxazole heterocyclic rings were proposed to be the main reason for the diminished affinity of T1-T3, T6 and T7 to an oxazole AAZ inhibitor binding site in VEGFR2 TK (PDB: 1Y6A or 1Y6B). Moreover T1-T3 and T6 were screened on cytotoxic activity against two human hepatocellular carcinoma cell lines. Selective cytotoxic activity of T2 against aggressive Mahlavu cells has been discovered indicating possible affinity of T2 to Mahlavu constitutionally active PI3K/Akt pathway. © 2015 Elsevier Masson SAS.

Marine environment is rich in structurally unique molecules and can be an inspiring source of novel drugs. Currently, six marine-derived drugs are in the market with FDA approval and several more are in the clinical pipeline. Structurally diverse and complex secondary metabolites have been isolated from the marine world and these include sulfated steroids. Biological activities of nearly 150 marine sulfated steroids reported from 1978 to 2017 are compiled and described, namely antimicrobial, antitumor, cardiovascular and antifouling activities. Structure–activity relationship for each activity is discussed. © 2018 Society for Endocrinology. This work was supported through national funds provided by FCT/MCTES – Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE – Programa Operacional Factores de Competitividade (POFC) programme, under the projects PTDC/ MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790; Project 3599 PPCDT – Promover a Produção Científica e Desenvolvimento Tecnológico e a Constituição de Redes Temáticas) and PTDC/AAG-TEC/0739/2014 (reference POCI-01-0145-FEDER-016793; Project 9471 RIDTI – Reforçar a Investigação, o Desenvolvimento Tecnológico e a Inovação) in the framework of the programme PT2020. The author acknowledges the Strategic Funding UID/Multi/04423/2013 provided by FCT – Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the programme PT2020.

The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression and/or death (whichever came first) occurred in 23 patients. For the entire cohort of patients the 5-year progression-free survival rate was 92% (95% CI: 87%-94%) and the 5-year survival accounting for chronic myeloid leukemia deaths was 97% (95% CI: 94%-99%). Of the 309 patients allocated to low (n=199), intermediate (n=68) and high (n=42) risk groups by the EUTOS Long-Term Survival score, events (progression and/or death) occurred in 6.0%, 8.8% and 26.2%, respectively. Estimates of the 5-year progression-free survival rates according to these three risk groups were 96% (95% CI: 92%-98%), 88% (95% CI: 76%-95%) and 67% (95% CI: 48%-81%), respectively. Differences in progression-free survival according to these risk groups were highly significant (P

Bioactivities of quinoides 1-5 and VEGFR2 TKIs 6-10 in hepatocellular cancer (HCC) and cancer stem cells (HCSCs) were studied. The compounds exhibited IC50 values in μM concentrations in HCC cells. Quinoide 3 was able to eradicate cancer stem cells, similar to the action of the stem cell inhibitor DAPT. However, the more cytotoxic VEFGR TKIs (IC50: 0.4-3.0 μM) including sorafenib, which is the only FDA approved drug for the treatment of HCC, enriched the hepatocellular cancer stem cell population by 2-3 fold after treatment. An aggressiveness factor (AF) was proposed to quantify the characteristics of drug candidates for their ability to eradicate the CSC subpopulation. Considering the tumour heterogeneity and marker positive cancer stem cell like subpopulation enrichment upon treatments in patients, this study emphasises the importance of the chemotherapeutic agent choice acting differentially on all the subpopulations including marker-positive CSCs.

Background Cervical cancer is the fourth most common cancer affecting women worldwide. Despite advances in screening and human papillomavirus (HPV) vaccination, a significant number of women present with or develop advanced disease. Palliative platinum-based chemotherapy (CT) is the standard first-line treatment for metastatic/recurrent cervical cancer. The prognosis remains poor and effective second line options are urgently needed. Methods We searched the English-language medical literature as well as relevant guideline databases, published from January 1981 to December 2015 and identified publications related to cervical cancer and its therapies. Our effort was to highlight the available treatment options in the setting of recurrent/metastatic disease. Results Although there have been important advances in the management of women with cervical cancer, the optimal treatment for patients with locally recurrent and metastatic disease after platinum failure is still problematic. Overall, there is a trend in terms of longer overall survival (OS) and better quality of life for the combination of cisplatin/paclitaxel (PC) as compared to the doublets of cisplatin/topotecan (TC), cisplatin/vinorelbine (VC), and cisplatin/gemcitabine (GC). Currently available single agents beyond first-line platinum-based therapy have limited efficacy in this setting and include topoisomerase inhibitors, vinca alkaloids, taxanes, alkylating agents and antimetabolites. Several targeted therapies have demonstrated activity in advanced cervical cancer. Bevacizumab has been evaluated in a phase III trial using doublets of cisplatin with paclitaxel or topotecan and has been approved in the first-line setting by the U. S. Food and Drug Administration. Selective targeting of angiogenic kinases by tyrosine kinase inhibitors (TKIs) may represent a novel therapeutic tool in this setting, but its use alone or in combination with CT is still investigational. Early reports have implicated PI3KCA somatic mutations suggesting that mTOR-targeted agents should be explored in this disease. Development of the immune checkpoint programmed cell death 1 (PD-1) and T-lymphocyte–associated molecule-4 (CTLA-4) inhibitors have been of considerable interest, leading to ongoing phase II studies in patients with advanced cervical cancer. Conclusions Progress in the management of recurrent and advanced cervical cancer patients has been slow and restricted to palliative intent. These patients should be considered for clinical trials of novel targeted agents and/or immunotherapy. © 2016 Elsevier Ireland Ltd 108 164 174

PubMed ID: 27501474, Objective: Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with chronic myeloid leukemia in chronic phase (CML-CP). This study was the first prospective evaluation of the efficacy and safety of nilotinib in Turkish patients with newly diagnosed CML-CP. The primary endpoint of the study was the rate of major molecular response (MMR; BCR-ABL1 ? 0.1% on the International Scale [BCR-ABL1IS]) by 12 months. Methods: Patients with newly diagnosed CML-CP were treated with nilotinib 300 mg twice daily. This analysis was based on the first 12 months of follow-up in a 24-month study. Results and Conclusions: Of 112 patients enrolled, 66.1% (80% CI, 59.7–72.0%) achieved MMR and 22.3% achieved a deep molecular response of MR4.5 (BCR-ABL1IS ? 0.0032%) by 12 months. During the first year of treatment, 1 patient progressed to blast crisis and 2 patients died. Safety results were consistent with previous studies. Most adverse events (AEs) were grade 1/2. Most frequently reported nonhematologic AEs of any grade were elevations in bilirubin, alanine aminotransferase, and triglycerides. These results support the use of nilotinib 300 mg twice daily as a standard-of-care treatment option for patients with newly diagnosed CML-CP. © 2016 Informa UK Limited, trading as Taylor & Francis Group., Novartis Pharmaceuticals Corporation, This study was funded by Novartis Pharmaceuticals Corporation.

Aims: We aimed to investigate whether older age leads to limitations in the starting dose of imatinib in daily treatment of chronic myeloid leukemia, and to determine the compliance of elderly patients with tyrosine kinase inhibitors (TKI) therapy. Methods: Data including the clinical characteristics, therapeutic outcomes and compliance with TKI therapy of elderly patients with chronic myeloid leukemia aged >65years were collected from 13 institutions in Turkey, retrospectively. Results: A total of 69 patients (27 [39%] men, 42 [61%] women) were evaluated retrospectively. The median age of the patients was 71years (range 66-85years). Of the patients, 66 (96%) were in the chronic phase and three (4.3%) were in the accelerated phase when diagnosed. A total of 63 (91.3%) patients were receiving imatinib as the first-line therapy. The initial dose of imatinib was 400mg/day in 59 patients (93.6%). Imatinib treatment induced 57 (90.5%) complete hematological responses at 3months, 29 (46%) complete cytogenetic responses at 6months and 49 (77.7%) major molecular responses at 12months. As a result, nilotinib and dasatinib were used in 14 patients as second-line therapy. Second-line TKI induced nine complete hematological responses (64.3%) at 3months, four complete cytogenetic responses (28.6%) at 12months and seven major molecular responses (50%) at 18months. A total of 56 of the patients (81.2%) are still alive. The median overall survival and progression-free survival rates were 35months (range 1-95months) and 17months (range 0.8-95months), respectively. Conclusion: Elderly patients should receive TKI according to the same guidelines that apply to younger patients. © 2014 Japan Geriatrics Society.

WOS: 000355733300008, PubMed ID: 25257190, AimsWe aimed to investigate whether older age leads to limitations in the starting dose of imatinib in daily treatment of chronic myeloid leukemia, and to determine the compliance of elderly patients with tyrosine kinase inhibitors (TKI) therapy. MethodsData including the clinical characteristics, therapeutic outcomes and compliance with TKI therapy of elderly patients with chronic myeloid leukemia aged >65years were collected from 13 institutions in Turkey, retrospectively. ResultsA total of 69 patients (27 [39%] men, 42 [61%] women) were evaluated retrospectively. The median age of the patients was 71years (range 66-85years). Of the patients, 66 (96%) were in the chronic phase and three (4.3%) were in the accelerated phase when diagnosed. A total of 63 (91.3%) patients were receiving imatinib as the first-line therapy. The initial dose of imatinib was 400mg/day in 59 patients (93.6%). Imatinib treatment induced 57 (90.5%) complete hematological responses at 3months, 29 (46%) complete cytogenetic responses at 6months and 49 (77.7%) major molecular responses at 12months. As a result, nilotinib and dasatinib were used in 14 patients as second-line therapy. Second-line TKI induced nine complete hematological responses (64.3%) at 3months, four complete cytogenetic responses (28.6%) at 12months and seven major molecular responses (50%) at 18months. A total of 56 of the patients (81.2%) are still alive. The median overall survival and progression-free survival rates were 35months (range 1-95months) and 17months (range 0.8-95months), respectively. ConclusionElderly patients should receive TKI according to the same guidelines that apply to younger patients. Geriatr Gerontol Int 2015; 15: 729-735.

The ruthenium(II)–cymene complexes [Ru(η 6 -cymene)(bha)Cl] with substituted halogenobenzohydroxamato (bha) ligands (substituents = 4-F, 4-Cl, 4-Br, 2,4-F 2 , 3,4-F 2 , 2,5-F 2 , 2,6-F 2 ) have been synthesized and characterized by elemental analysis, IR, 1 H NMR, 13 C NMR, cyclic voltammetry and controlled-potential electrolysis, and density functional theory (DFT) studies. The compositions of their frontier molecular orbitals (MOs) were established by DFT calculations, and the oxidation and reduction potentials are shown to follow the orders of the estimated vertical ionization potential and electron affinity, respectively. The electrochemical E L Lever parameter is estimated for the first time for the various bha ligands, which can thus be ordered according to their electron-donor character. All complexes exhibit very strong protein tyrosine kinase (PTK) inhibitory activity, even much higher than that of genistein, the clinically used PTK inhibitory drug. The complex containing the 2,4-difluorobenzohydroxamato ligand is the most active one, and the dependences of the PTK activity of the complexes and of their redox potentials on the ring substituents are discussed.

Imatinib has shown significant clinical and cytogenetic success in the treatment of chronic myeloid leukemia. Although resistance has been observed in a proportion of patients, sudden blastic crisis is a rare event during imatinib therapy. We describe a 24-year-old male patient with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase who developed sudden blastic crisis in the 24th month of imatinib therapy, with loss of complete cytogenetic response. At this time, the patient had splenomegaly, severe anemia, thrombocytopenia, and leukocytosis. Bone marrow aspirate revealed the presence of massive blastic infiltration with myeloid morphology. Flow cytometric analysis of the bone marrow cells showed positivity for CD45, CD34, CD13, CD33, CD19, CD41, C1361, and glycophorin-A. Trephine biopsy specimens showed 100% cellular marrow with diffuse infiltrate by blasts. A reticulin stain of the bone marrow biopsy section demonstrated severe diffuse fibrosis. Cytogenetic analysis by fluorescence in situ hybridization (FISH) revealed that 92% of the cells were positive for the BCR/ABL fusion signal and had increased copy numbers for chromosomes 8,13,19, and 21. The patient's prognosis was unfavorable. In conclusion, chronic myeloid leukemia remains complex and includes unanswered questions. The presented case with a rare event during imatinib therapy highlights the need for the continued monitoring of residual disease and the development of strategies to eliminate residual leukemia cells in patients showing a complete cytogenetic response. Novartis İlaç

Angiogenesis, the formation of new blood vessels, is essential for tumor growth, progression and metastasis. The development of agents that target tumor vasculature is ultimately dependent on the availability of appropriate preclinical screening assays. The chorioallantoic membrane (CAM) assay is well established and widely used as a model to examine angiogenesis, and anti-angiogenesis. This review 1) summarizes the currently used angiogenesis assays and the importance of CAM model among them; 2) summarizes the current knowledge about the development and structure of the CAM's capillary bed; 3) reports findings regarding the role played by molecular signaling pathways in angiogenesis process; 4) discusses the use, advantages and limitations of the CAM as a model for studying tumor angiogenesis and invasiveness, as well as development of angiogenic and/or anti-angiogenic agents; 5) discusses the importance of standardization of the major methodologies for all aspects of the use of the CAM in angiogenesis-related studies; 6) and finally, summarizes major findings regarding the agents developed by the use of CAM model in the study of tumor angiogenesis, invasion and development of anti-angiogenic agents. © 2005 Bentham Science Publishers Ltd.

Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization, as evaluated by angiography, is weak. In this study, we report an angiogenesis-independent effect of VEGF on ischemic skeletal muscle, ie, upregulation of myoglobin after VEGF treatment. Mice received intramuscular injection with adenoviral VEGF-A or either adenoviral LacZ or PBS as control, followed by surgical induction of acute hindlimb ischemia at day 3. At day 6, capillary density was increased in calf muscle of Ad. VEGF-treated versus control mice (P

Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization, as evaluated by angiography, is weak. In this study, we report an angiogenesis-independent effect of VEGF on ischemic skeletal muscle, ie, upregulation of myoglobin after VEGF treatment. Mice received intramuscular injection with adenoviral VEGF-A or either adenoviral LacZ or PBS as control, followed by surgical induction of acute hindlimb ischemia at day 3. At day 6, capillary density was increased in calf muscle of Ad. VEGF-treated versus control mice (P

We read with great interest the article by Ault et al1 in a recent issue of Journal of Clinical Oncology, describing the results of pregnancy among patients with chronic myeloid leukemia (CML) treated with imatinib. We would like to add some points and bring attention to some questions concerning imatinib and pregnancy. Tyrosine kinases (TKs) are one of the most critical groups of signaling molecules for the cellular regulation of proliferation, differentiation, survival, function, and motility, and various tumors overexpress TKs, leading to uncontrolled mitogenic signals to the neoplastic cells. Imatinib (Gleevec or Glivec; Novartis, Basel, Switzerland) is a small-molecule tyrosine kinase inhibitor active against BCR-ABL, c-ABL, ARG, PDGF-r, and c-KIT.2 Although imatinib has been used primarily for cancers such as CML, use of imatinib has demonstrated that tyrosine kinase inhibitors can have a wide therapeutic window and heralds the era of targeted cancer and noncancer disease therapy. Information about the effects of drugs on the developing embryo is derived primarily from animal experiments and case reports describing the outcomes of pregnancies complicated with drug. Some drugs can be teratogenic in some animal species, but not in humans. In preclinical studies imatinib was found to be teratogenic in rats, but not in rabbits, and impaired spermatogenesis was observed in rats, dogs, and monkeys; however, there was no evidence that imatinib was genotoxic. These observations lead to concerns that men treated with imatinib may have reduced sperm counts. Clinical experience has not shown this to be true because male patients who were receiving treatment of imatinib were partners in 18 pregnancies and four healthy infants. Owing to teratogenicity data in rats (causing exencephaly or encephalocele, and absent or reduced frontal and absent parietal bones), it is recommended that women treated with imatinib be aware of the potential teratogenicity of imatinib, and effective contraception should be used during imatinib therapy to prevent pregnancy.2 Hensley and Ford2 reported 26 pregnancies (15 in clinical trials, 11 in nonclinical trials) among women taking imatinib. Most of the patients opted for elective therapeutic abortions, and only three patients carried their pregnancies to term. Two infants were healthy, and one infant had hypospadias. Recently, eight patients with CML who became pregnant while receiving imatinib therapy were reported from different areas of the world.3-7 All of the fetuses had been exposed to imatinib during the first trimester, and four fetuses have also been exposed to imatinib during the second and third trimesters. Six of the reported eight pregnancies proceeded to term with healthy infants, and two were terminated with unsatisfactory outcomes—one had spontaneous abortion4 and the other had a dead fetus with meningocele.7 More recently, Ault et al1 reported their experience on 19 pregnancies involving 18 patients (10 female and eight male patients) who conceived while receiving imatinib for the treatment of CML. Three pregnancies (involving two female patients and one male patient) ended in spontaneous abortion, and one patient had an elective abortion. All other pregnancies were uneventful. Two of 16 infants had minor abnormalities at or shortly after birth (hypospadias in one and rotation of small intestine in another) that were surgically repaired.

Contact sensitivity to small molecular weight compounds is accompanied by the production of antigen-specific T-cell factors (TCF) shortly after skin application of the sensitizing agents. In this study, we show that macrophages can be activated by these TCF to generate large amounts of nitric oxide (NO). Incubation of the murine macrophage cell line J774 for 24 h with TCF raised against dinitrofluorobenzene (DNFB) or picryl chloride (PCL) resulted in a nitrite accumulation in the culture medium. Priming of J774 with rIFN-gamma synergistically enhanced stimulation of NO synthesis by DNFB-F and PCL-F. A possible contribution of lipopolysaccharide (LPS) as a contaminant of the TCF was excluded. The enhanced production of NO after stimulation with TCF was accompanied with an increased expression of inducible NO synthase. Inclusion of inhibitors of protein tyrosine kinase and protein kinase C inhibited the TCF-induced NO production by macrophages, indicating the involvement of both protein kinases in the signaling pathway activated by TCF. Since NO is an important biological mediator with many immunoregulatory properties, our results suggest a potential role for increased NO production by macrophages in the elicitation of contact sensitivity to small molecular weight compounds.