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

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

In vitro production of steroidal saponin, total phenols and antioxidant activity in callus suspension culture of Paris polyphylla Smith: an important Himalayan medicinal plant

Paris polyphylla Smith (Melanthiaceae) family, which is native to the Himalayan region, has received a lot of attention recently due to its extensive history of usage in traditional medicine. The production of steroidal saponin from callus suspension cultures of P. polyphylla was observed in the current study. The current study attempted to develop a P. polyphylla plant callus suspension culture through optimization of cultivation technique for callus suspension, quantification of total phenolic components and estimation of the extract’s antioxidant activity. A light-yellow callus was formed within six weeks of cultivating rhizomes on Murashige and Skoog (MS) media supplemented with Thidiazuron (TDZ). Furthermore, the effect of TDZ, Methyl Jasmonate (MeJA), and Yeast Extract (YE) on callus growth, steroidal saponin (dioscin and diosgenin), total phenolic content, total flavonoids, total tannin, and total antioxidant activity was also measured. The medium containing 0.5 μM TDZ depicted the maximum callus biomass (2.98 g fresh weight). Significantly high phenolic and tannin content was observed in the MS medium containing 50 μM MeJA, whereas, no significant increase was observed in total tannin production in any treatment. Three in vitro assays, DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,2′-azino-bis (3-ethylbenzothiazoline- 6-sulfonic acid)) and FRAP (ferric ion reducing antioxidant potential) and FC (Folin-Ciocalteu), were used to assess antioxidant potential of callus. Maximum antioxidant analysis reported in 1.0 μM TDZ (6.89 mM AAE/100 g) containing medium followed by 50 μM MeJA (6.44 mM AAE/100 g). The HPLC analysis showed a high presence of dioscin and diosgenin (5.43% and 21.09%, respectively) compared to the wild sample (2.56% and 15.05%, respectively). According to the results, callus produced on media supplemented with 50 μM MeJA have significant phenolic contents and elevated antioxidant activity; nevertheless, callus growth was greater in the presence of 0.5 μM TDZ. The findings of the current study have commercial implications since greater biomass production will result in active phytochemicals that the pharmaceutical and nutraceutical sectors are in need desperately

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

Value of Immunological Biomarkers in Early Prediction of Bacillus Calmette-Guerin Failure in High-Risk Non-muscle-invasive Bladder Cancer

Objectives To investigate the predictive value of different immunological markers on treatment outcomes after bacillus Calmette-Guerin (BCG) induction in high-risk non-muscle-invasive bladder cancer (NMIBC). Patients and Methods Patients who underwent transurethral resection of bladder tumors for NMIBC were assessed for study eligibility. Urine and blood samples were taken from patients at baseline (immediately before the first dose of induction). Urine samples were evaluated for interleukin (IL)-6, IL-8, IL-10, IL-11, and interferon- γ by solid-phase enzyme-linked immunosorbent assay (ELISA). Blood samples were evaluated for epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) using quantitative reverse transcriptase-polymerase chain reaction analysis. Each marker was assessed in relation to tumor recurrence. Results Between June 2016 and December 2019, 160 patients were included. Tumor recurrence occurred in 47 (29.38%) patients over a median (IQR) follow-up of 24 (12: 49) months. Using univariate analysis, the following urinary cytokines were associated with higher recurrence: urinary IL-6, 8, 10, 11, and interferon-γ. Also, serum EGFR and HER2 were associated with higher recurrence. On multivariate Cox regression analysis, significant variables include HER2 [HR (95%CI): 2.675 (1.367-5.233), p= 0.004], and IL-11 [HR (95%CI): 0.889 (0.825-0.957), p= 0.002]. Conclusions Serum HER2 and urinary IL-11 could be applied in clinical practice to predict BCG failure in patients with high-risk NMIBC, so those patients could be offered other modalities (radical cystectomy) early with better survival. Further studies are recommended to establish their exact role

Nigella sativa (Black Cumin) Seed Extract Alleviates Symptoms of Allergic Diarrhea in Mice, Involving Opioid Receptors

The incidence of food hypersensitivity and food allergies is on the rise and new treatment approaches are needed. We investigated whether N. sativa, one of its components, thymoquinone, or synthetic opioid receptor (OR)-agonists can alleviate food allergy. Hence, ovalbumin (OVA) -sensitized BALB/c-mice were pre-treated either with a hexanic N. sativa seed extract, thymoquinone, kappa- (U50'4889) or mu-OR-agonists (DAMGO) and subsequently challenged intra-gastrically with OVA. All 4 treatments significantly decreased clinical scores of OVA-induced diarrhea. N. sativa seed extract, thymoquinone, and U50'488 also decreased intestinal mast cell numbers and plasma mouse mast cell protease-1 (MMCP-1). DAMGO, in contrast, had no effect on mast cell parameters but decreased IFNγ, IL-4, IL-5, and IL-10 concentration after ex vivo re-stimulation of mesenteric lymphocytes. The effects on allergy symptoms were reversible by OR-antagonist pre-treatment, whereas most of the effects on immunological parameter were not. We demonstrate that N. sativa seed extract significantly improves symptoms and immune parameters in murine OVA-induced allergic diarrhea; this effect is at least partially mediated by thymoquinone. ORs may also be involved and could be a new target for intestinal allergy symptom alleviation. N. sativa seed extract seems to be a promising candidate for nutritional interventions in humans with food allergy