Synthesis, antiproliferative activity evaluation and structure–activity relationships of novel aromatic urea and amide analogues of N-phenyl- N′-(2-chloroethyl)ureas

Purpose : This study aimed to evaluate the possible cytotoxic activity of the essential oil of the Eugenia uniflora leaves on normal and tumoral human cells by colorimetric cell viability assay, based on the use of tetrazolium salt (XTT). Methods : To achieve the cytotoxicity it was used normal human lung fibroblast cell line GMO7492A and the evaluation of antiproliferative activity was performed on three tumor cell lines, as follows: human glioblastoma (MO59J), human cervical adenocarcinoma (HeLa) and human breast adenocarcinoma (MCF-7). For the determination of cytotoxic concentration to the normal line, 12 concentrations were evaluated being from 2.44 to 5000 µg/mL. In the evaluation of antiproliferative activity were tested 8 different concentrations of the extract (3.91 to 500 µg/mL). Results : The results in the normal line GM07492A showed that concentrations higher or equal to 39.1 µg/mL are significantly different of the negative control. In the evaluation of antiproliferative activity on tumor cell lines MO59J, HeLa and MCF-7 was observed that the concentration of 125 µg/mL showed a cytotoxic effect on these lines being significantly different from the negative control. The results from the evaluation of the antiproliferative activity in different tumor cell lines of E. uniflora oil was not selective for the tested cell types. Conclusion : E. uniflora oil did not show cytotoxic activity in concentrations lower than 39.1 µg/mL, however, the values found to IC 50 for tumor cells were superior, concluding that the oil has no selectivity for tumor cells tested.

Synthesis, characterization, and investigation of antiproliferative activities against human cancer cell lines (MV4-11, MCF-7, and A549) and Toxoplasma gondii parasite of twelve novel 2,4-diaminotriazine-thiazoles are presented. The toxicity of the compounds was studied at three different cell types, normal mouse fibroblast (Balb/3T3), mouse fibroblast (L929), and human VERO cells. The structures of novel compounds were determined using 1H and 13C NMR, FAB(+)-MS, and elemental analyses. Among the derivatives, 4a–k showed very high activity against MV4-11 cell line with IC50 values between 1.13 and 3.21 µg/ml. Additionally, the cytotoxic activity of compounds 4a–k against normal mouse fibroblast Balb/3T3 cells is about 20–100 times lower than against cancer cell lines. According to our results, compounds 4a, 4b, 4d, and 4i have very strong activity against human breast carcinoma MCF-7, with IC50 values from 3.18 to 4.28 µg/ml. Moreover, diaminotriazines 4a–l showed significant anti-Toxoplasma gondii activity, with IC50 values 9–68 times lower than those observed for sulfadiazine. Molecular docking studies indicated DNA-binding site of hTopoI and hTopoII as possible anticancer targets and purine nucleoside phosphorylase as possible anti-toxoplasmosis target. Our UV–Vis spectroscopic results indicate also that diaminotriazine-thiazoles tends to interact with DNA by intercalation. Additionally, the structure and the interaction and binding energies of a model complex formed by compound 4a and two thymine molecules are investigated using quantum mechanical methods.

Cashew apple extract (CAE) is a product with intense yellow color obtained from residual fibers of juice processing. Although CAE is known to be rich in carotenoids and anacardic acids, the biological activities of this potential natural food colorant remain unexplored. The present study is the first to investigate the toxicity, antiproliferative and antimicrobial activities of the lyophilized CAE (L-CAE) and its encapsulated products, using maltodextrin (M-CAE) or cashew gum (CG-CAE) as carriers. In addition to their high carotenoid content, the phenolic contents in all materials was determined using UPLC-QTOF-MSE. The acute toxicity was performed using adult zebrafish (Danio rerio); antiproliferative activity was assessed using seven different human tumor cell lines [U-251 (glioblastoma), MCF-7 (breast, adenocarcinoma), NCI-ADR/RES (multidrug-resistant ovarian adenocarcinoma), NCI-H-460 (lung, large cell carcinoma), PC-3 (prostate, adenocarcinoma), OVCAR-3 (ovarian adenocarcinoma), and HT-29 (colon, adenocarcinoma)] and an immortalized human keratinocyte (HaCaT) while the antimicrobioal activity was evaluated on Staphylococcus aureus ATCC 25923, Listeria monocytogenes ATCC 19115, Escherichia coli ATCC 25922 and Salmonella Typhimurium ATCC 51812 microorganisms. Both lyophilized and encapsulated CAE samples did not exert acute toxicity against zebrafish neither antiproliferative effect against human tumor and non-tumor cell lines. Further, L-CAE showed potential antimicrobial activity against Listeria monocytogenes, which was confirmed using electron microscopy. The current findings demonstrated that CAE is a potential source of bioactive compounds to use as an additive in the food industry.

Thiosemicarbazones and 4-thiazolidinones indole-based derivatives: Synthesis, evaluation of antiproliferative activity, cell death mechanisms and topoisomerase inhibition assay

Novel derivatives of deoxycholic acid bearing aliphatic or cyclic diamine moieties at the C-3 position: Synthesis and evaluation of anti-proliferative activity

In this work, we evaluated the antiproliferative and anti-inflammatory activities of two diosgenin prodrugs. The prodrugs were obtained by esterification of diosgenin at position 3 with 4-oxo-4-(prop-2-yn-1-yloxy)butanoic acid followed by click reaction on terminal alkyne with 3-azidopropan-1-ol N-alkylated dendrons, resulting in a prodrug with methyl ester end-groups and a derivative with tert-butyl ester end-groups, hydrolysis of tert-butyl ester derivative afforded a prodrug with carboxylic acid terminals. All compounds were fully characterized by 1H and 13C NMR, ATR-FTIR and HR-ESI TOF. Studies of the anti-inflammatory effects on mouse ear edema of prodrugs methyl ester and carboxylic acid, ended, using diosgenin and dexamethasone as positive controls, showed the superiority of methyl ester ended prodrug with an ED50 four times lower than that of dexamethasone. Further, carboxylic acid ended prodrug was found to be more active than diosgenin as an antiproliferative agent, according to crystal violet assay. Diosgenin was transformed to ester and acid prodrugs through succinic ester and a 1,2,3-triazole linkers. The prodrug with methyl ester terminals was four times more active than dexamethasone as anti-inflammatory compound, while prodrug with carboxylic acid terminals improved antiproliferative activity over MCF-7 cells.

Phytochemical study of the bark of Guatteria blepharophylla (Mart.) Mart. afforded twelve compounds, namely two sesquiterpenes, caryophyllene oxide (1) and spathulenol (3), one xanthone, lichexanthone (2), a mixture of steroids, β-sitosterol (4), and stigmasterol (5), and seven isoquinoline alkaloids, O-methylmoschatoline (6), lysicamine (7), nornuciferine (8), liriodenine (9), isocoreximine (10), subsessiline (11), and isomoschatoline (12). Their structures were established on the basis of spectroscopic methods. Compounds 1-6, 11 and 12 were reported for the first time in this species. The 13C NMR (nuclear magnetic resonance) data for the compounds 11 and 12 are described for the first time in the literature. The antiproliferative activity against human tumour cell lines and antimicrobial activities were investigated for the major compounds. Compound 9 showed significant activity against cell lines of breast (MCF-7, Michigan Cancer Foundation-7), superior to the positive control doxorubicin. Compound 12 presented antifungal activity similar to the positive control nystatin against Candida albicans.

Lung cancer is the most commonly diagnosed and the main cause of cancer death, usually related to cigarette smoking. Furthermore, the microbiota of people exposed to cigarette smoke can be modified, making it difficult to eliminate opportunistic microorganisms. The leaves of Eugenia pyriformis are a by-product of fruit production and, to date, there have been no studies addressing the antiproliferative, anti-inflammatory, and antimicrobial activities. Investigate the antimicrobial, Nitric Oxide (NO)-production inhibition, and antiproliferative activities of the essential oil from E. pyriformis leaves and its possible effect on the treatment and prevention of damage caused by tobacco. The essential oil (EO) was obtained by hydrodistillation (3h). Its chemical composition was investigated by GC-MS. It was proposed to investigate antiproliferative activity against human tumor cell lines, namely, breast adenocarcinoma (MCF-7), lung (NCI-H460), cervical (HeLa), and hepatocellular (HepG2) carcinomas. A non-tumor primary culture from pig liver (PLP2) was also tested. The EO capacity to inhibit nitric oxide (NO) production was evaluated by a lipopolysaccharide stimulated murine macrophage cell line. Antibacterial and antifungal activities against opportunistic pathogens were investigated against seven strains of bacteria and eight fungi. The results indicated the presence of 23 compounds in the essential oil, the majority were spathulenol (45.63%) and β-caryophyllene oxide (12.72%). Leaf EO provided 50% inhibition of nitric oxide production at a concentration of 92.04µgmL-1. The EO also demonstrated antiproliferative activity against all human tumor cell lines studied, with GI50 values comprised between 270.86 and 337.25µgmL-1. The essential oil showed antimicrobial potential against the bacteria Listeria monocytogenes (Murray et al.) Pirie (NCTC 7973) and Salmonella Typhimurium ATCC 13311 (MIC 1870µgmL-1) and fungi Aspergillus versicolor ATCC 11730, Aspergillus ochraceus ATCC 12066, Penicillium ochrochloron ATCC 90288, Penicillium verrucosum var. cyclopium (Westling) Samson, Stolk & Hadlok (food isolate) (MIC 1870µgmL-1) and Trichoderma viride Pers. IAM 5061 (1,400µg mL-1). The demonstrated anti-inflammatory, antiproliferative, and antimicrobial activities in the leaves of E. pyriformis can add value to the production chain of this plant, being a possible option for preventing and combating cancer, including lung cancer.

Synthesis and characterization of new monothiooxalamides containing pyridine nuclei with promising antiproliferative and antioxidant activity

Antiproliferative and apoptotic activities of sequence-specific histone acetyltransferase inhibitors

In this study, phthalonitriles 6 , 7 and their corresponding bromo derivatives 8 , 9 were synthesized from 8-hydroxyquinoline to investigate antiproliferative and cytotoxic activities on C6 (rat brain tumor), HeLa (human cervix carcinoma) and HT29 (human colon carcinoma) cancer cell lines of these molecules. The antiproliferative and apoptotic effects of 7-bromo- and 5,7-dibromo-8-hydroxyquinoline derivatives ( 2 and 3 ) and phthalonitrile 6 , 7 and their brominated derivatives 8 , 9 were compared in terms of Structure Activity Relationship (SAR). Although bromohydroxyquinoline derivatives 2 and 3 exhibited high antiproliferative activity according to literature, it has been determined that phthalonitrile compounds 6 , 7 and their brominated 8 , 9 derivatives are significantly reduced in antiproliferative activity. The SAR of the quinoline core at C-8 revealed that OH group lead to antiproliferative and apoptotic activity. In addition, biological activity was decreased when alkyl or substituted cyclic groups bounded to OH of quinoline, and the bromination of these derivatives did not increase the antiproliferative activity.

Isopentenyladenosine (iPA), a member of the cytokinin family of plant hormones, exerts a marked antiproliferative activity on some leukemic and epithelial cancer cell lines. To characterize the molecular moieties required for the in vitro antitumor activity of the molecule and to obtain cytostatic iPA derivatives potentially useful as chemotherapeutic agents, N9-acyclic analogues have been synthesized using regioselective Mitsunobu reaction and characterized by elemental analyses, 1H and 13C NMR. These compounds were analyzed for their activity on human bladder cancer cell lines. In this study, we report that iPA inhibited the proliferation but not the migration of human bladder cancer cells, while the newly synthesized analogues revealed no significant cytostatic activity apart from the compound with a saturated double bond of the isopentenyl chain. These results indicate that the integrity of the ribose ring is required for the cytostatic activity of iPA.

Some novel 1-(inden-3-ylidene)-2-(thiazol-2-ylidene)hydrazine derivatives 3–9 were synthesized by the Hantzsch reaction of thiosemicarbazone derivatives 2a–2c with halo ketones and halo esters. Thiosemicarbazone derivatives reacted with hydrozonyl chlorides to give diazenyl-4-methylthiazole derivatives 11a–11d. Structures of the products were elucidated from IR, 1H, and 13C NMR, and Mass spectra elucidate. The synthesized compounds were screened for their cytotoxicity against three human tumor cell lines. Twenty compounds showed high (≥60 %) antiproliferative activity over breast cancer (MCF-7). Compounds 2b, 3c, 4a, 4b, 6b, 6c, 7b, 8a, and 11b possessed higher cytotoxic activity over breast tumor cell line than Doxorubicin.

BackgroundWithout doubt, natural products have been, and still are, the cornerstone of the health care armamentarium. Of all natural sources, the marine environment is clearly the last great frontier for pharmaceutical and medical research.MethodsThis work progresses in the direction of identifying component(s) from the Mediterranean sponge, Spongia officinalis with pharmacological activities. In the present study we investigated the efficacy of methanol extract and its semi-purified fractions (F2, F3) from Spongia officinalis for their in vivo anti-inflammatory activity using the carrageenan-induced paw edema in rats and their in vitro antiproliferative effects by their potential cytotoxic activity using the MTT colorimetric method and clonogenic inhibition against three human cancer cell lines (A549, lung cell carcinoma, HCT15, colon cell carcinoma and MCF7, breast adenocarcinoma).ResultsThe fractions F2 and F3 showed interesting anti-inflammatory and antiproliferative activities in a dose dependent manner.ConclusionsThe present study indicates that the methanolic extrac and its fractions from Spongia officinalis are a significant source of compounds with the antiproliferative and anti-inflammatory activities, and this may be useful for developing potential chemopreventive substances.

A series of (Z)-N-(adamantan-1-yl)-3,4-diarylthiazol-2(3H)-imines (5a-r) was synthesized via condensation of 1-(adamantan-1-yl)-3-arylthioureas (3a-c) with various aryl bromomethyl ketones (4a-f). The structures of the synthesized compounds were characterized by 1H NMR, 13C NMR and by X-ray crystallography. The in vitro inhibitory activities of the synthesized compounds were assessed against a panel of Gram-positive and Gram-negative bacteria, and pathogenic fungi. Compounds 5c, 5g, 5l, 5m, and 5q displayed potent broad-spectrum antibacterial activity, while compounds 5a and 5o showed activity against the tested Gram-positive bacteria. Compounds 5b, 5l and 5q displayed potent antifungal activity against Candida albicans. In addition, the synthesized compounds were evaluated for anti-proliferative activity towards five human tumor cell lines. The optimal anti-proliferative activity was attained by compounds 5e and 5k which showed potent inhibitory activity against all the tested cell lines. Molecular docking analysis reveals that compounds 5e and 5k can occupy the positions of NAD cofactor and the histone deacetylase inhibitor EX527 at the active site of SIRT1 enzyme.