10-(Prop-2-yn-1-yl)-2,7-diaza­phenothia­zine1

In the title mol­ecule [systematic name: 10-(prop-2-yn-1-yl)dipyrido[3,4-b:3′,4′-e][1,4]thia­zine], C13H9N3S, the dihedral angle between the two pyridine rings is 146.33 (7)° and the angle between two halves of the thia­zine ring is 138.84 (8)°, resulting in a butterfly shape for the tricyclic system. The central thia­zine ring adopts a boat conformation, with the 2-propynyl substituent at the thia­zine N atom located in a pseudo-equatorial position and oriented to the concave side of the diaza­phenothia­zine system. In the crystal, mol­ecules are arranged via π–π inter­actions between the pyridine rings [centroid–centroid distances = 3.838 (1) and 3.845 (1) Å] into stacks extending along [001]. There are C—H⋯C and C—H⋯N inter­actions between mol­ecules of neighbouring stacks

Introduction to the 28th International Conference on Logic Programming Special Issue

We are proud to introduce this special issue of the Journal of Theory and Practice of Logic Programming (TPLP), dedicated to the full papers accepted for the 28th International Conference on Logic Programming (ICLP). The ICLP meetings started in Marseille in 1982 and since then constitute the main venue for presenting and discussing work in the area of logic programming

Dual action of dipyridothiazine and quinobenzothiazine derivatives : anticancer and cholinesterase-inhibiting activity

The inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of eeAChE (electric eel AChE) or eqBuChE (equine serum BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against eeAChE were in a submicromolar-to-micromolar range with $IC_{50}$ values from 0.78 to 19.32 $\mu$M, while their $IC_{50}$ values against eqBuChE ranged from 0.46 to 10.38 $\mu$M. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine 24, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine 23 was found to act as a selective inhibitor of eqBuChE with an $IC_{50}$ value of 0.46 $\mu$M. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives

Antioxidant, Wound Healing Potential and In Silico Assessment of Naringin, Eicosane and Octacosane

1. Diabetic chronic wounds, mainly foot ulcers, constitute one of the most common complications of poorly managed diabetes mellitus. The most typical reasons are insufficient glycemic management, latent neuropathy, peripheral vascular disease, and neglected foot care. In addition, it is a common cause of foot osteomyelitis and amputation of the lower extremities. Patients are admitted in larger numbers attributable to chronic wounds compared to any other diabetic disease. In the United States, diabetes is currently the most common cause of non-traumatic amputations. Approximately five percent of diabetics develop foot ulcers, and one percent require amputation. Therefore, it is necessary to identify sources of lead with wound-healing properties. Redox imbalance due to excessive oxidative stress is one of the causes for the development of diabetic wounds. Antioxidants have been shown to decrease the progression of diabetic neuropathy by scavenging ROS, regenerating endogenous and exogenous antioxidants, and reversing redox imbalance. Matrix metalloproteinases (MMPs) play vital roles in numerous phases of the wound healing process. Antioxidant and fibroblast cell migration activity of Marantodes pumilum (MP) crude extract has previously been reported. Through their antioxidant, epithelialization, collagen synthesis, and fibroblast migration activities, the authors hypothesise that naringin, eicosane and octacosane identified in the MP extract may have wound-healing properties. 2. The present study aims to identify the bioactive components present in the dichloromethane (DCM) extract of M. pumilum and evaluate their antioxidant and wound healing activity. Bioactive components were identified using LCMS, HPTLC and GCMS. Excision wound on STZ-induced diabetic rat model, human dermal fibroblast (HDF) cell line and colorimetric antioxidant assays were used to evaluate wound healing and antioxidant activities, respectively. Molecular docking and pkCMS software would be utilised to predict binding energy and affinity, as well as ADME parameters. 3. Naringin (NAR), eicosane (EIC), and octacosane (OCT) present in MP displayed antioxidant action and wound excision closure. Histological examination HDF cell line demonstrates epithelialization, collagen production, fibroblast migration, polymorphonuclear leukocyte migration (PNML), and fibroblast movement. The results of molecular docking indicate a substantial attraction and contact between MMPs. pkCMS prediction indicates inadequate blood-brain barrier permeability, low toxicity, and absence of hepatotoxicity. 4. Wound healing properties of (NEO) naringin, eicosane and octacosane may be the result of their antioxidant properties and possible interactions with MMP

The double Smiles rearrangement in neutral conditions leading to one of 10-(nitropyridinyl)dipyridothiazine isomers

© 2016 Elsevier B.V.Phenothiazines are reported to exhibit very promising anticancer, antibacterial, antifungal, anti-inflammatory activities, reversal of multidrug resistance and many other actions. Synthesis of phenotiazines is mostly carried cyclization of o-aminodiphenyl sulfides proceeded through the Smiles rearrangement. The modifications of the phenothiazine structure via the substitution of the benzene ring with the pyridine ring gave various pyridobenzothiazines and dipyridothiazines. The reaction of 3-amino-3’-nitro-2,2’-dipyridinyl sulfide with 4-chloro-3-nitropyridine in sole DMF led to one of four possible isomeric nitropyridinyldipyridothiazines. Two-dimensional 1H and 13C NMR experiments (COSY, ROESY, HSQC and HMBC) were used to reveal the right product structure as 10-(3'-nitro-4'-pyridinyl)dipyrido[2,3-b; 2',3’-e] [1,4]thiazine (10-(3'-nitro-4'-pyridinyl)-1,6-diazaphenothiazine). The final structure confirmation came from a single crystal X-ray analysis. This structure is the result of very rare reaction mechanism involving the double Smiles rearrangement of the S[sbnd]N type. The tricyclic dipyridothiazine system is unexpectedly almost planar, with the butterfly angle of 176.39(4)° between two pyridine rings and 174.17(6)° between the halves of the thiazine ring (the NCCS) planes. The pyridinyl substituent is rotated about N10[sbnd]C11 bond and oriented almost perpendicularly to the tricyclic ring system with the dihedral angle between the two planar systems of 94.93(3)°. The nitropyridinyl substituent is located quasi-equatorially with the S⋯N10‒C11 angle of 176.92(8)°. The nitro group is tilted from the pyridine ring by 128.44(8)°

Pharmacological Inhibition of CDK8 in Triple-Negative Breast Cancer Cell line MDA-MB-468 Increases E2F1 Protein, Induces Phosphorylation of STAT3 and Apoptosis

Cyclin-dependent kinase 8 (CDK8) has been identified as a colon cancer oncogene. Since this initial observation, CDK8 has been implicated as a potential driver of other cancers including acute myelogenous leukemia (AML) and some breast cancers. Here, we observed different biological responses to CDK8 inhibition among colon cancer cell lines and the triple-negative breast cancer (TNBC) cell line MDA-MB-468. When treated with CDK8 inhibitor 4, all treated cell lines responded with decreased cell viability and increased apoptosis. In the MDA-MB-468 cell line, the decrease in cell viability was dependent on increased phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is not observed in the colon cancer cell lines. Furthermore, increased STAT3 phosphorylation in 4 treated MDA-MB-468 cells was dependent on increased transcription factor E2F1 protein. These results are consistent with previous reports of exogenous expression of E2F1-induced apoptosis in MDA-MB-468 cells

The role of histone protein modifications and mutations in histone modifiers in pediatric b-cell progenitor acute lymphoblastic leukemia

While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis

AMPD1 gene mutations are associated with obesity and diabetes in Polish patients with cardiovascular diseases

Previous studies showed an association of the common functional polymorphism (C34T, Gln12Stop) in the adenosine monophosphate deaminase-1 (AMPD1) gene with survival in heart failure (HF) and/or coronary artery disease (CAD). The aim of the study was to search for other mutations in selected regions of the AMPD1 gene in Polish CAD and HF patients, and to analyze their associations with obesity and diabetes. Exons 2, 3, 5, and 7 of AMPD1 were scanned for mutations in 97 patients with CAD without HF (CAD+ HF−), 104 patients with HF (HF+), and 200 newborns from North-Western Poland using denaturing high-performance liquid chromatography (DHPLC), polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), and direct sequencing. Frequencies of AMPD1 C34T mutation, as well as novel A99G, G512A, IVS4-6delT, and C784T sequence alterations, were similar in the three groups, but 860T mutated allele was less frequent in the combined CAD+ HF− and HF+ groups than in the controls (1.7% vs. 4.3%, p = 0.040). Heterozygous 34CT genotype was associated with lower (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.13–0.81) and 860AT with higher (OR = 13.7, 95%CI = 1.6–118) prevalence of diabetes or hyperglycemia in relation to wild-type homozygotes. Abdominal obesity was more frequent in 860AT patients than in wild-type homozygotes and 34CT heterozygotes (86% vs. 40% vs. 29%, p < 0.05). Nine genes containing polymorphisms linked with AMPD1 C34T mutation were found in the HapMap database. AMPD1 C34T nonsense mutation is associated with reduced prevalence of diabetes and obesity in patients with CAD or HF, but A860T substitution seems to exert opposite metabolic effects and should always be accounted for in the studies of the AMPD1 genotype

Analisis potensi antidiabetik komponen bioaktif Daun Tulsi (Ocimum tenuiflorum L.) dengan pendekatan in silico

INDONESIA: Daun tulsi (Ocimum tenuiflorum L.) bersifat antiperglikemik yang berpotensi sebagai antidiabetes. Diabetes Mellitus (DM) merupakan suatu kondisi gangguan metabolisme tubuh kronis yang ditandai dengan kadar glukosa dalam darah di atas kadar normal. Penggunaan metformin dalam pengobatan diabetes menimbulkan efek samping pada pasien. Pengobatan dengan tanaman obat memiliki kelebihan dibandingkan metformin yakni minim efek samping yang ditimbulkan dan dapat digunakan untuk menjaga kesehatan. Penelitian ini termasuk penelitian deskripstif eksploratif. Senyawa bioaktif pada daun tulsi (Ocimum Tenuiflorum L.) diperoleh dari database dan pustaka. Protein yang digunakan dalam penelitian ini adalah IRS1, IRS2, PI3K, AMPK, MAPK, COX1, COX2, IGF, NADPH oxidase, IGFR, glycogen phosphorylase, lipoprotein lipase. Parameter yang diamati yaitu daya absorpsi dengan indikator persentase nilai HIA, neurotoksik dengan indikator nilai BBB, pendistribusian dengan indikator nilai Lipinski Rule of Five (Ro5), potensi antidiabetik dengan nilai Pa dan visualisasi interaksi senyawa dengan protein. Data yang diperoleh dianalisis secara deskriptif kuantitatif dan kualitatif. Hasil penelitian menunjukkan bahwa senyawa bioaktif tulsi memiliki daya absorpsi baik pada usus dengan persentase nilai HIA >80% kecuali senyawa kaempferol dan luteolin, bersifat neurotoksik rendah dengan nilai BBB >1.0, aktif sebagai obat oral, memiliki potensi sebagai antidiabetik dengan nilai Pa >7.0 kecuali senyawa caffeic acid. Senyawa bioaktif tulsi meliputi kaempferol, luteolin dan apigenin berpotensi sebagai antidiabetik dengan berikatan secara langsung pada protein AKT/PI3K, berfungsi melindungi kerusakan sel dari lipotoksisitas dengan menghambat FoxO1, yang menginduksi apoptosis sel pankreas. Senyawa apigenin berikatan secara tidak langsung dengan protein IRS2 yang dimediasi oleh protein IGF-1 untuk memicu pertumbuhan sel dan IRS2 memicu aksi insulin perifer. ENGLISH: Tulsi leaf (Ocimum tenuiflorum L.) is antiperglycemic which has potential as antidiabetic. Diabetes Mellitus (DM) is a chronic body metabolic disorder condition characterized by glucose levels in the blood above normal levels. The use of metformin in the treatment of diabetes causes side effects in patients. Treatment with medicinal plants has advantages over metformin, namely minimal side effects and can be used to maintain health. This research includes exploratory descriptive research. Bioactive compounds in tulsi leaves (Ocimum tenuiflorum L.) were obtained from databases and libraries. The proteins used in this study were IRS1, IRS2, PI3K, AMPK, MAPK, COX1, COX2, IGF, NADPH oxidase, IGFR, glycogen phosphorylase, lipoprotein lipase. Parameters observed were absorption power with HIA percentage indicator, neurotoxicity with BBB value indicator, distribution with Lipinski Rule of Five (Ro5) indicator value, antidiabetic potential with Pa value and visualization of compound interaction with protein. The data obtained were analyzed descriptively quantitatively and qualitatively. The results showed that the tulsi bioactive compound had good absorption in the intestine with a percentage HIA value > 80% except for kaempferol and luteolin compounds, low neurotoxicity with a BBB value > 1.0, active as an oral drug, has potential as an antidiabetic with a Pa value > 7.0 except caffeic acid compounds. Tulsi bioactive compounds including kaempferol, luteolin and apigenin have the potential as antidiabetic by binding directly to the AKT/PI3K protein, protecting cell damage from lipotoxicity by inhibiting FoxO1, which induces pancreatic cell apoptosis. Apigenin binds indirectly to IRS2 protein which is mediated by IGF-1 protein to trigger cell growth and IRS2 triggers the action of peripheral insulin. ARAB: أوراق تولسي (Ocimum tenuiflorum L) هي مادة مضادة للسكر في الدم ولها القدرة على أن تكون مضادة لمرض السكر. داء السكري (DM) هو اضطراب استقلابي مزمن في الجسم يتميز بمستويات الجلوكوز في الدم فوق المستويات الطبيعية. يتسبب استخدام الميتفورمين في علاج مرض السكري في حدوث آثار جانبية عند المرضى. يتفوق العلاج بالنباتات الطبية على الميتفورمين، وهو الحد الأدنى من الآثار الجانبية ويمكن استخدامه للحفاظ على الصحة. يشمل هذا البحث البحث الوصفي الاستكشافي. تم الحصول على المركبات النشطة بيولوجيا في أوراق التولسي (Ocimum Tenuiflorum L) من قواعد البيانات والمكتبات. كانت البروتينات المستخدمة في هذه الدراسة هي IRS1، IRS2، PI3K، AMPK، MAPK، COX1، COX2، IGF، NADPH أوكسيديز، IGFR، فوسفوريلاز الجليكوجين، ليباز البروتين الدهني. كانت المعلمات التي لوحظت هي قوة الامتصاص مع مؤشر النسبة المئوية لـ HIA، السمية العصبية بمؤشر قيمة BBB، التوزيع باستخدام قيمة مؤشر (Lipinski Rule of Five (Ro5، القدرة المضادة لمرض السكر مع قيمة Pa وتصور التفاعل المركب مع البروتين. تم تحليل البيانات التي تم الحصول عليها وصفيًا كماً ونوعاً. أظهرت النتائج أن مركب التولسي النشط بيولوجيًا يمتص جيدًا في الأمعاء بنسبة مئوية من HIA> 80 ٪ باستثناء مركبات الكايمبفيرول واللوتولين، سمية عصبية منخفضة بقيمة BBB> 1.0، نشط كدواء عن طريق الفم، لديه القدرة كمضاد لمرض السكر مع قيمة Pa> 7.0 باستثناء مركبات حمض الكافيين. تحتوي مركبات تولسي النشطة بيولوجيًا بما في ذلك الكايمبفيرول واللوتولين والأبيجينين على القدرة كمضاد لمرض السكر من خلال الارتباط مباشرة ببروتين AKT / PI3K، مما يحمي تلف الخلايا من السمية الدهنية عن طريق تثبيط FoxO1، الذي يحفز موت الخلايا المبرمج في البنكرياس. يرتبط Apigenin بشكل غير مباشر ببروتين IRS2 الذي يتوسطه بروتين IGF-1 لتحفيز نمو الخلايا ويطلق IRS2 عمل الأنسولين المحيطي