Dizajniranje i sinteza novih derivata tiofenkarbohidrazida, tienopirazola i tienopirimidina s antioksidativnim i antitumorskim djelovanjem

2-Amino-5-acetyl-4-methyl-thiophene-3-carboxylic acid ethyl ester (1) and 5-acetyl-2-amino-4-methylthiophene-3-carbohydrazide (2) were synthesized and used as starting materials for the synthesis of new series of 1-(5-amino-4-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-methylthiophen-2-yl) ethanone (3a), 1-(5-amino-4-(4-chloro-3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-methylthiophen-2-yl) ethanone (3b), 1-(4-methyl-2-amino-5-acetylthiophene-3-carbonyl) pyrazolidine-3,5-dione (4), (Z)-N\u27-(4-methyl-2-amino-5-acetylthiophene-3-carbonyl) formohydrazonic acid (5a), (Z)-ethyl-N\u27-(4-methyl-2-amino-5-acetylthiophene-3-carbonylformo hydrazonate (5b), 6-acetyl-3-amino-2,5-dimethylthieno2,3-dpyrimidin-4(3H)-one (8), 5-methyl-3-amino-2-mercapto-6-acetylthieno2,3-dpyrimidin-4(3H)-one (10) and 5-methyl-6-acetyl-2-thioxo-2,3-dihydrothieno2,3-dpyrimidin-4(1H)-one (12) as potential antioxidant and antitumor agents. Pharmacological results showed that compounds 6a, 6b, 8, 10 and 12 exhibited promising antitumor and antioxidant activity.Etilni ester 2-amino-5-acetil-4-metil-tiofen-3-karboksilne kiseline (1) i 5-acetil-2-amino-4-metiltiofen-3-karbohidrazid (2) sintetizirani su i upotrebljeni kao reaktanti u sintezi novih spojeva 1-(5-amino-4-(3,5-dimetil-1H-pirazol-1-karbonil)-3-metiltiofen-2-il) etanona (3a), 1-(5-amino-4-(4-klor-3,5-dimetil-1H-pirazol-1-karbonil)-3-metiltiofen-2-il) etanona (3b), 1-(4-metil-2-amino-5-acetiltiofen-3-karbonil) pirazolidin-3,5-diona (4), (Z)-N\u27-(4-metil-2-amino-5-acetiltiofen-3-karbonil) formohidrazonske kiseline (5a), (Z)-etil-N\u27-(4-metil-2-amino-5-acetiltiofen-3-karbonilformo hidrazonata (5b), 6-acetil-3-amino-2,5-dimetiltieno2,3-dpirimidin-4(3H)-one (8), 5-metil-3-amino-2-merkapto-6-acetiltieno2,3-dpirimidin-4(3H)-ona (10) i 5-metil-6-acetil-2-tiokso-2,3-dihidrotieno2,3-dpirimidin-4(1H)-ona (12) kao potencijalnih antioksidansa i citostatika. Farmakološka ispitivanja ukazuju na to da spojevi 6a, 6b, 8, 10 i 12 imaju značajno antitumorsko i antioksidativno djelovanje

Fusing Structural and Functional MRIs using Graph Convolutional Networks for Autism Classification

Geometric deep learning methods such as graph convolutional networks have recently proven to deliver generalized solutions in disease prediction using medical imaging. In this paper, we focus particularly on their use in autism classification. Most of the recent methods use graphs to leverage phenotypic information about subjects (patients or healthy controls) as additional contextual information. To do so, metadata such as age, gender and acquisition sites are utilized to define intricate relations (edges) between the subjects. We alleviate the use of such non-imaging metadata and propose a fully imaging-based approach where information from structural and functional Magnetic Resonance Imaging (MRI) data are fused to construct the edges and nodes of the graph. To characterize each subject, we employ brain summaries. These are 3D images obtained from the 4D spatiotemporal resting-state fMRI data through summarization of the temporal activity of each voxel using neuroscientifically informed temporal measures such as amplitude low frequency fluctuations and entropy. Further, to extract features from these 3D brain summaries, we propose a 3D CNN model. We perform analysis on the open dataset for autism research (full ABIDE I-II) and show that by using simple brain summary measures and incorporating sMRI information, there is a noticeable increase in the generalizability and performance values of the framework as compared to state-of-the-art graph-based models

Sinteza, in vitro antitumorsko ispitivanje i radiosenzitirajuće vrednovanje novih derivata 4-[3-(supstituiranih)tioureido]-N-(kinoksalin-2-il)benzensulfonamida

Sulfonamides and quinoxaline derivatives possess many types of biological activities and have been recently reported to show substantial antitumor activity. This paper reports the synthesis of novel thioureidosulfaquinoxaline derivatives. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against a human liver cell line (HEPG2) and showed higher activity than the reference drug doxorubicin. 4-(3-(4-Ethylbenzoate)thioureido)-N-(quinoxalin-2-yl)benzenesulfonamide (9) (IC50 = 15.6 µmol L1), N-(pyridin-2-yl)-4-(3-(4-(N-quinoxalin-2-yl-sulfamoyl)phenyl)thioureido)benzene-sulfonamide (10) (IC50 = 26.8 µmol L1) and N-(quinoxalin-2-yl)-4-(3-(4-(N-thiazol-2-ylsulfamoyl)phenyl)thioureido)benzenesulfonamide (11) (IC50 = 24.4 µmol L1) were the most potent compared to doxorubicin (IC50 = 71.8 µmol L1). The most potent compounds 9, 10 and 11 were evaluated as radiosensitizing agents by subjecting the compounds to γ-irradiation (8 kGy).Derivati sulfonamida i kinoksalina imaju raznoliko biološko djelovanje, između ostalog i antitumorsko djelovanje. U radu je opisana sinteza novih derivata tioureido sulfakinoksalina. Svim novim spojevima ispitano je antitumorsko djelovanje in vitro na humanoj staničnoj liniji jetre (HEPG 2). Svi ispitani spojevi pokazuju jači učinak nego referentni lijek doksorubicin. Najjači učinak imali su 4-(3-(4-etilbenzoat)tioureido)-N-(kinoksalin-2-il)benzen-sulfonamid (9) (IC50 = 15,6 µmol L1), N-(piridin-2-il)-4-(3-(4-(N-kinoksalin-2-il-sulfamoil)fenil)tioureido)-benzen-sulfonamid (10) (IC50 = 26,8 µmol L1) i N-(kinoksalin-2-il)-4-(3-(4-(N-tiazol-2-ilsulfamoil)fenil)tioureido)benzen-sulfonamid (11) (IC50 = 24,4 µmol L1), dok je IC50 vrijednost bila 71,8 µmol L1. Najaktivniji spojevi 9, 10 i 11 evaluirani su kao radziosenzitirajuća sredstva nakon izlaganja spojeva γ-zračenju (8 kGy)

Sinteza i vrednovanje analgetskog, protuupalnog i ulcerogenog djelovanja nekih triazolo- i 2-pirazolil-pirido[2,3-d]-pirimidina

New series of 2-hydrazino-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidines and its 1,7,8,9-tetrahydrocyclopenta[5,6]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine, 1,7,8,-9-tetrahydrocyclopenta[5,6]pyrido[2,3-d][1,2,3,4]tetrazolo[4,5-a]pyrimidine, 8,9-dihydro-7H-cyclopenta[5,6]pyrido[2,3-d]imidazolo[1,2-a]pyrimidine, 2-(pyrazol-1-yl)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine derivatives were prepared in order to obtain new compounds with potential anti-inflammatory and analgesic activity and low ulcerogenic effect. The compounds possessing potent anti-inflammatory activity were further tested for their analgesic and ulcerogenic activities. Compounds 3-amino-6-(4-aryl)-9-(4-arylmethylene)-cyclopenta[5,6]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(H)-one (4c), 1-amino-2-methyl-6-(4-aryl)-9-(4-aryl-methylene)-cyclopenta[5,6]pyrido[2,3-d]imidazolo[1,2-a]pyrimidin-5(H)-one (6a), 2-amino-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta[5,6]pyrido[2,3-d]pyrimidine-4(H)-one (9), 2-(3-amino-5-hydroxypyrazol-1-yl)-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta[5,6]-pyrido[2,3-d]pyrimidin-4(H)-one (10a) and 3-thioxo-6-(4-aryl)-9-(4-arylmethylene)-cyclopenta[5,6]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(H)-one (13) showed significant analgesic effects. Compound 2-(3-amino-5-hydroxypyrazol-1-yl)-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta[5,6]pyrido[2,3-d]pyrimidin-4(H)-one (10a) was evaluated as the lead compound having higher anti-inflammatory activity (82.8%) than ibuprofen (79.5%) and lower ulcerogenic effect.U radu je opisana sinteza serije 2-hidrazino-7,8-dihidro-6H-ciklopenta[5,6]pirido[2,3-d]pirimidina i njihovih 1,7,8,9-tetrahidrociklopenta[5,6]pirido[2,3-d][1,2,4]triazolo[4,3-a]pirimidinskih, 1,7,8,9-tetrahidrociklopenta[5,6]pirido[2,3-d][1,2,3,4]tetrazolo[4,5-a]pirimidinskih, 8,9-dihidro-7H-ciklopenta[5,6]pirido[2,3-d]imidazolo[1,2-a]pirimidinskih i 2-(pirazol-1-il)-7,8-dihidro-6H-ciklopenta[5,6]pirido[2,3-d]pirimidinskih derivata s potencijalnim protuupalnim i analgetskim te manjim ulcerogenim djelovanjem. Spojevima s izraženim protuupalnim djelovanjem testirano je analgetsko i ulcerogeno djelovanje. Spojevi 3-amino-6-(4-aril)-9-(4-arilmetilen)-ciklopenta[5,6]pirido[2,3-d][1,2,4]triazolo[4,3-a]pirimidin-5(H)-on (4c), 1-amino-2-metil-6-(4-aril)-9-(4-aril-metilen)-ciklopenta[5,6]pirido[2,3-d]imidazolo[1,2-a]pirimidin-5(H)-on (6a), 2-amino-5-(4-aril)-8-(4-arilmetilen)-ciklopenta[5,6]pirido[2,3-d]pirimidin-4(H)-on (9), 2-(3-amino-5-hidroksipirazol-1-il)-5-(4-aril)-8-(4-arilmetilen)- ciklopenta[5,6]-pirido[2,3-d]pirimidin-4(H)-on (10a) i 3-tiokso-6-(4-aril)-9-(4-arilmetilen)-ciklopenta[5,6]pirido[2,3-d][1,2,4]triazolo[4,3-a]pirimidin-5(H)-on (13) pokazali su značajno analgetsko djelovanje. Spoj 2-(3-amino-5-hidroksipirazol-1-il)-5-(4-aril)-8-(4-arilmetilen)-ciklopenta[5,6]pirido[2,3-d]pirimidin-4(H)-on (10a) je vodeći spoj s jačim protuupalnim djelovanjem (82,8%) od ibuprofena (79,5%), a slabijim ulcerogenim djelovanjem

Sinteza i protuupalno, analgetsko i ulcerogeno djelovanje derivata tieno[2,3-d]pirimidina

5-Methyl-6-phenyl-2-thioxothieno[2,3-d]pyrimidone derivative (2) reacted with hydrazonoyl chloride derivatives to afford triazolothienopyrimidones 4a-f. Also, acetone-1-(2-amino-5-isopropyl-thiophene-3-carbonitrile) (3) reacted with functional and bifunctional groups to yield the corresponding compounds 5-11. The new products showed anti-inflammatory, analgesic, and ulcerogenic activities comparable to that of indomethacin and acetylsalicylic acid, respectively.Reakcijom derivata 5-metil-6-fenil-2-tioksotieno[2,3-d]pirimidona (2) s hidrazonoil kloridima dobiveni su triazolotienopirimidoni 4a-f, a reakcijom aceton-1-(2-amino-5-izopropil-tiopen-3-karbonitrila (3) s funkcionalnim i bifunkcionalnim spojevima dobiveni su produkti 511. Novi spojevi imaju slično protuupalno, analgetsko i ulcerogeno djelovanje kao i indometacin, odnosno acetilsalicilna kiselina

Food Risk/Benefit Communication: A Systematic Review

A systematic review relevant to the following research questions was conducted (1) the extent to which different theoretical frameworks have been applied to food risk/benefit communication and (2) the impact such food risk/benefit communication interventions have had on related risk/benefit attitudes and behaviors. Fifty four papers were identified. The analysis revealed that (primarily European or US) research interest has been relatively recent. Certain food issues were of greater interest to researchers than others, perhaps reflecting the occurrence of a crisis, or policy concern. Three broad themes relevant to the development of best practice in risk (benefit) communication were identified: the characteristics of the target population; the contents of the information; and the characteristics of the information sources. Within these themes, independent and dependent variables differed considerably. Overall, acute risk (benefit) communication will require advances in communication process whereas chronic communication needs to identify audience requirements. Both citizen's risk/benefit perceptions and (if relevant) related behaviors need to be taken into account, and recommendations for behavioral change need to be concrete and actionable. The application of theoretical frameworks to the study of risk (benefit) communication was infrequent, and developing predictive models of effective risk (benefit) communication may be contingent on improved theoretical perspectives

Corporate boards and performance pricing in private debt contracts

This paper investigates the effects of corporate governance on the use of performance pricing in debt contracts on a sample of newly syndicated loans in the U.S. private debt market. While cross-sectional results provide no evidence for the predicted relation between corporate governance quality and the likelihood of using performance pricing in debt contracts, there is evidence for the predicted positive relation between corporate governance quality and the use of interest-increasing performance pricing provisions. Evidence also provides support for the predicted negative relation between corporate governance quality and the use of financial ratio as the measure of performance underlying the provisions. Overall, empirical evidence supports the hypothesis that debt-holders perceive aspects of corporate governance to be beneficial and factor them in their contracting decisions

Unlike for Human Monocytes after LPS Activation, Release of TNF-α by THP-1 Cells Is Produced by a TACE Catalytically Different from Constitutive TACE

Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine today identified as a key mediator of several chronic inflammatory diseases. TNF-α, initially synthesized as a membrane-anchored precursor (pro-TNF-α), is processed by proteolytic cleavage to generate the secreted mature form. TNF-α converting enzyme (TACE) is currently the first and single protease described as responsible for the inducible release of soluble TNF-α.Here, we demonstrated the presence on THP-1 cells as on human monocytes of a constitutive proteolytical activity able to cleave pro-TNF-α. Revelation of the cell surface TACE protein expression confirmed that the observed catalytic activity is due to TACE. However, further studies using effective and innovative TNF-α inhibitors, as well as a highly selective TACE inhibitor, support the presence of a catalytically different sheddase activity on LPS activated THP-1 cells. It appears that this catalytically different TACE protease activity might have a significant contribution to TNF-α release in LPS activated THP-1 cells, by contrast to human monocytes where the TACE activity remains catalytically unchanged even after LPS activation.On the surface of LPS activated THP-1 cells we identified a releasing TNF-α activity, catalytically different from the sheddase activity observed on human monocytes from healthy donors. This catalytically-modified TACE activity is different from the constitutive shedding activity and appears only upon stimulation by LPS