Design, synthesis and antiproliferative activity evaluation of new 3,7-disubstituted pyrrolo[2,3-c]pyridines

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.

Antiproliferative and apoptotic activities of sequence-specific histone acetyltransferase inhibitors

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.

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 pyrazolone compounds with different substitution patterns have been synthesized using microwave-assisted methods and evaluated their in vitro antiproliferative activity against human lung adenocarcinoma cell lines (A549 and NCI-H522). Among the tested compounds, the pyrazolone P7 exhibited high antiproliferative activity against both A549 and NCIH522 cancer cell lines while being 10 times less cytotoxic to non-cancerous cells. Moreover, our compounds P7 and P11 exhibited higher antiproliferative activity and selectivity against A549 and NCIH522 cells compared with the clinically approved drugs Afatinib and Gefitinib. The cell cycle analysis showed that the compound P7 and P11 arrests the cell cycle at G0/G1 phase, whereas the compounds P13 and P14 involved in G2/M phase arrest. The results from antiproliferative activity screening, cell cycle analysis, and kinase profiling indicate that the suitably substituted 1,3-diarylpyrazolones exhibit high antiproliferative activity against non-small cell lung cancer cells.

Polyamine toxins (PATs) are conjugates of polyamines (PAs) with lipophilic carboxylic acids, which have been recently shown to present antiproliferative activity. Ten analogs of the spider PATs Agel 416, HO-416b, and JSTX-3 and the wasp PAT PhTX-433 were synthesized with changes in the lipophilic head group and/or the PA chain, and their antiproliferative activity was evaluated on MCF-7 and MDA-MB-231 breast cancer cells, using Agel 416 and HO-416b as reference compounds. All five analogs of PhTX-433 were of very low activity on both cell lines, whereas the two analogs of JSTX-3 were highly active only on the MCF-7 cell line with IC50 values of 2.63–2.81 μΜ. Of the remaining three Agel 416 or HO-416b analogs, only the one with the spermidine chain was highly active on both cells with IC50 values of 3.15–12.6 μM. The two most potent compounds in this series, Agel 416 and HO-416b, with IC50 values of 0.09–3.98 μΜ for both cell lines, were found to have a very weak cytotoxic effect on the MCF-12A normal breast cells. The present study points out that the structure of both the head group and the PA chain determine the strength of the antiproliferative activity of PATs and their selectivity towards different cells.

Colon adenocarcinoma is the most common form of gastro intestinal tract cancer, predominantly in ageing population. Chemotherapy with 5-Fluorouracil and oxaliplatin is an indispensable treatment regimen, nevertheless having limitation of systemic toxicity and lower therapeutic index. The present study is based on evaluation of anti-proliferative potential, pharmacokinetics parameters, safety profile, biodistribution and efficacy of 5-FU/oxaliplatin loaded lactoferrin nanoparticles in cell lines and wistar rats in order to overcome the above limitation. Nanoparticles were prepared by Water-in-oil process. The anti-proliferative efficacy and mode of cellular entry was evaluated in COLO-205 cells. The pharmacokinetics and biodistribution analysis were performed in healthy rats while efficacy and safety assay were performed in ACF induced rats. 5-FU and oxaliplatin loaded nanoparticles shows enhanced antiproliferative activity as compare to free drugs in COLO-205 cells. Lactoferrin nanoparticles also improve the pharmacokinetics profile, safety parameters and efficacy of 5-FU and Oxaliplatin. Lactoferrin nanoparticles demonstrated an attractive drug delivery module to manage the colon adenocarcinoma as it has improved the antiproliferative activity of 5-FU and Oxaliplatin against colon adenocarcinoma cells. Moreover, it also improves the pharmacokinetic profile and safety parameters of the same drug in wistar rat.

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

The purpose of this study was to ascertain the phytochemical composition and antiproliferative properties of methanolic extract made from the roots, branches, leaves, and flowers of Echinophora chrysantha (EC). Phytochemical content was determined using RP-HPLC. Sixteen metabolites were identified as a result of RP-HPLC examination of EC extracts. Using the XTT technique, antiproliferative activity tests were examined on HT29 and A549 cell lines. All extracts strongly inhibited the examined cell lines. In particular, the branch extract shown outstanding antiproliferative activity against A549 (IC50:7.40 μg/mL) and HT-29 (IC50:1.70 μg/mL). Echinophora chrysantha's traditional use and therapeutic usefulness are further reinforced by the identification of its metabolites and assessment of its bioactivity.

The antiproliferative activities on tumoral cells, namely, human breast cancer (MCF-7 and MDA-MB-231), hepatoma (HepG2) and myeloid leukemia (HL-60), of ethanolic extracts from two species of Ganoderma, G. lucidum and G. sinense, were investigated. Though both extracts had certain antiproliferative activities, their chemical characteristics, including nucleosides, triterpenoids and sterols, were significantly different. Their effects on MDA-MB-231 cells were further studied using apoptotic detection and cell cycle analyses. As a result, both had apoptosis induction through the alternation of mitochondrial transmembrane depolarization, though no triterpenoids were detected in ethanolic extract of G. sinense. Furthermore, the two extracts from G. lucidum and G. sinense could arrest cell cycle at different phases. This study showed that ethanol extracts of both G. lucidum and G. sinense have antitumoral proliferation effect through both apoptosis pathway and cell cycle arrest effect, and some other compounds such as sterols and/or nucleosides may contribute to their activity besides triterpenoids.

In view of the various and promising biological activities of gallic acid, we designed and prepared a series of poly-phenolic compounds carrying multi-gallic acids residues. These dimer and tetramer of gallic acids were facilely synthesized by convergent approach. Subsequently, antioxidant activity evaluation was carried out using DPPH assay, and the resulting polyphenol exerted enhanced activity to gallic acid monomer. Antiproliferative activity evaluation was performed using MTT assay with three human cancer cell lines (Hela, A549 and MCF-7) and two human normal cell lines (HEK293 and HUVEC). The cytotoxicity of the dimer and tetramer of gallic acid were higher than that of the monomer against both cancer and normal cell lines, however the cytotoxicity of the dimer and tetramer against cancer cells was much fiercer than normal cells, which resulted in better selectivity. Consequently, vanlency effects embodied in both antioxidant and antiproliferative activities of the obtained multi-gallic acid derivatives. Keywords: Gallic acid, Polyphenol, Antioxidant activity, Antiproliferative activity, Vanlency effects, Convergent synthesis.

An important role has been considered forthe vascular endothelial growth factor receptor 2 (VEGFR-2) in the angiogenesis process, so that its inhibition is an important scientific way for cancer treatment. In this work, new thienopyrimidine derivatives were synthesized and evaluated. Compared with sorafenib, the majority of the target compounds had antiproliferative activity against the PC3, HepG2, MCF7, SW480, and HUVEC cell lines, especially 9h with IC50 values of 4.5-15.1 μM, confirming the noticeable cytotoxic effects on the listed cell lines (PC3, HepG2, SW480, and HUVEC). Analyses by flow cytometry on SW480 and HUVEC cells revealed that 9n, 9k, 9h, and 9q led to apoptotic cell death. The result of the chick chorioallantoic membrane assay showed that 9h effectively reduced the number of corresponding blood vessels. Finally, the inhibitory effect on VEGFR-2 phosphorylation was considered as the outcome of Western blot analysis of compound 9h.

The current study was performed to screen the extracts of Artemisia nilagirica (C.B. Clarke) Pamp. for antiproliferative and antiinflammatory properties. Antiproliferative activity was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Antiinflammatory activity was evaluated in terms of lipoxygenase and xanthine oxidase inhibitory activities. Results indicated that out of the 3 extracts tested, methanol extract was found to inhibit Y79 (human retinoblastoma) and MCF-7 (human breast adenocarcinoma) cell lines. The same extract was also found to inhibit lipoxygenase and xanthine oxidase enzymes in a concentration-dependent manner with an IC50 of 128.20±3.39 and 144.23±2.04 μg/ml for lipoxygenase and xanthine oxidase, respectively. The present study highlighted the antiproliferative potential of the plant against cancer cell lines. The extracts inhibited lipoxygenase and xanthine oxidase enzymes. Therefore, this plant could be a valuable source for anticancer and antiinflammatory molecules.

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

Colorectal cancer (CRC) is a disease with high incidence and mortality, constituting the fourth most common cause of death from cancer worldwide. Naphthoquinones are attractive compounds due to their biological and structural properties. In this work, 36 naphthoquinone derivatives were synthesized and their activity evaluated against HT-29 cells. Overall, high to moderate anti-proliferative activity was observed in most members of the series, with 15 compounds classified as active (1.73 < IC50 < 18.11 μM). The naphtho[2,3-b]thiophene-4,9-dione analogs showed potent cytotoxicity, 8-hydroxy-2-(thiophen-2-ylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione being the compound with the highest potency and selectivity. Our results suggest that the toxicity is improved in molecules with tricyclic naphtho[2,3-b]furan-4,9-dione and naphtho[2,3-b]thiophene-4,9-dione systems 2-substituted with an electron-withdrawing group. A 3D-QSAR study of comparative molecular field analysis (CoMFA) was carried out, resulting in the generation of a reliable model (r2 = 0.99 and q2 = 0.625). This model allowed proposing five new compounds with two-fold higher theoretical anti-proliferative activity, which would be worthwhile to synthesize and evaluate. Further investigations will be needed to determine the mechanism involved in the effect of most active compounds which are potential candidates for new anticancer agents.