Antitumor effect of steroidal tetraoxanes on malignantly transformed human cell lines

Uvod: Pronalaženje agenasa sa potencijalnim antitumorskim dejstvom je imperativ u modernoj onkologiji. Pri tome se sve više zapaža da određene hemijske strukture imaju specifičnije toksično dejstvo na maligne ćelije. Otkriće artemizinina je označilo početak istraživanja peroksida kao potencijalne zamene za tradicionalne antimalarijske lekove, a iz ovih istraživanja nastala je i strukturno jednostavna klasa peroksida - 1,2,4,5-tetraoksani, za koje je ubrzo pokazano da pored antimalarijskog pokazuju i snažan antiproliferativni efekat. Maligne ćelije imaju poremećaje u regulatornim mehanizmima koji upravljaju ćelijskom proliferacijom i homeostazom. Sposobnost tumorskih ćelijskih populacija da povećaju broj ćelija je određena ne samo intenzitetom ćelijske proliferacije, već i brzinom uklanjanja ćelija. Programirana ćelijska smrt - apoptoza, predstavlja glavni izvor ovog uklanjanja. Cilj rada je bio da se odredi nivo citotoksičnog dejstva grupe mešovitih tetraoksana prema različitim humanim malignim ćelijama, kao i da se odredi koeficijenat selektivnosti u njihovom dejstvu u odnosu na zdrave imunokompetentne ćelije. U cilju dobijanja uvida u mehanizam dejstva ispitivanih jedinjenja odrediće se tip ćelijske smrti koju indukuju ispitivani tetraoksani, kao i produkcija reaktivnih kiseoničnih vrsta u Hela ćelijama. Cilj 3D QSAR studije o antiproliferativoj aktivnosti trideset tri 1,2,4,5-tetraoksanska derivata prema Hela i Fem-x tumorskim ćelijskim linijama, je bio da se utvrdi koje su najvažnije farmakofore steroidnih tetraoksana koje utiču na potenciju ispitivanih jedinjenja prema HeLa i Fem-x tumorskim ćelijskim linijama. Materijal i metode: Citotoksično dejstvo tetraoksana DO-122 - DO-124 i DO-126 - DO-128, prema pet tumorskih ćelijskih linija je ispitivano standardnim MTT testom. U cilju određivanja tipa ćelijske smrti indukovane tretmanom ispitivanim tetraoksanima načinjena je morfološka analiza HeLa ćelija obojenih smešom akridin oranža i etidijum bromida. Analiza određivanja distribucije faza ćelijskog ciklusa HeLa ćelija obojenih propidijum jodidom, urađena je na protočnom citometru. Produkcija intraćelijskih reaktivnih vrsta kiseonika (ROS) je merena fluorometrijski pomoću fluorescentne boje 2’,7’-dihlorodihidrofluorescein diacetata. Zavisnost strukture i funkcije trideset tri 1,2,4,5-tetraoksanskih derivata prema HeLa i Fem-x ćelijskim linijama pokazana je 3D QSAR studijom..

Self-Heating Flower-like Nanoconstructs with Limited Incorporation of Yttrium in Maghemite: Effect of Chemical Composition on Heating Efficiency, Cytotoxicity and Genotoxicity

Partial cation substitution can significantly change the physical properties of parent compounds. By controlling the chemical composition and knowing the mutual relationship between composition and physical properties, it is possible to tailor the properties of materials to those that are superior for desired technological application. Using the polyol synthesis procedure, a series of yttrium-substituted iron oxide nanoconstructs, γ-Fe2−xYxO3 (YIONs), was prepared. It was found that Y3+ could substitute Fe3+ in the crystal structures of maghemite (γ-Fe2O3) up to a limited concentration of ~1.5% (γ-Fe1.969Y0.031O3). Analysis of TEM micrographs showed that crystallites or particles were aggregated in flower-like structures with diameters from 53.7 ± 6.2 nm to 97.3 ± 37.0 nm, depending on yttrium concentration. To be investigated for potential applications as magnetic hyperthermia agents, YIONs were tested twice: their heating efficiency was tested and their toxicity was investigated. The Specific Absorption Rate (SAR) values were in the range of 32.6 W/g to 513 W/g and significantly decreased with increased yttrium concentration in the samples. Intrinsic loss power (ILP) for γ-Fe2O3 and γ-Fe1.995Y0.005O3 were ~8–9 nH·m2/Kg, which pointed to their excellent heating efficiency. IC50 values of investigated samples against cancer (HeLa) and normal (MRC-5) cells decreased with increased yttrium concentration and were higher than ~300 μg/mL. The samples of γ-Fe2−xYxO3 did not show a genotoxic effect. The results of toxicity studies show that YIONs are suitable for further in vitro/in vivo studies toward to their potential medical applications, while results of heat generation point to their potential use in magnetic hyperthermia cancer treatment or use as self-heating systems for other technological applications such as catalysis

Antiproliferative and antibacterial activity of some glutarimide derivatives

Antiproliferative and antibacterial activities of nine glutarimide derivatives (1–9) were reported. Cytotoxicity of compounds was tested toward three human cancer cell lines, HeLa, K562 and MDA-MB-453 by MTT assay. Compound 7 (2-benzyl-2-azaspiro[5.11]heptadecane-1,3,7-trione), containing 12-membered ketone ring, was found to be the most potent toward all tested cell lines (IC50 = 9–27 μM). Preliminary screening of antibacterial activity by a disk diffusion method showed that Gram-positive bacteria were more susceptible to the tested compounds than Gram-negative bacteria. Minimum inhibitory concentration (MIC) determined by a broth microdilution method confirmed that compounds 1, 2, 4, 6–8 and 9 inhibited the growth of all tested Gram-positive and some of the Gram-negative bacteria. The best antibacterial potential was achieved with compound 9 (ethyl 4-(1-benzyl-2,6-dioxopiperidin-3-yl)butanoate) against Bacillus cereus (MIC 0.625 mg/mL; 1.97 × 10−3 mol/L). Distinction between more and less active/inactive compounds was assessed from the pharmacophoric patterns obtained by molecular interaction fields

Prunus spinosa L. leaf extracts: polyphenol profile and bioactivities

Prunus spinosa leaf extracts in solvents of different polarity (water, ethanol and acetone), their phenol, flavonoid and anthocyanin contents and biological properties were the object of this study. The richest in phenols as well as in flavonoids was acetone extract with 181.19 mg GAE and 80.10 mg QE per gram of dry extract, respectively. Moreover, the quantity of anthocyanins obtained by HPLC analysis was also the highest in acetone sample. Examined samples possessed antioxidant properties evaluated through four in vitro assays (DPPH, ABTS, FRAP and TRC). The acetone extract was proved to be the best antioxidant among tested samples, which could be ascribed to polyphenols, especially anthocyanins. The aqueous and the ethanol extract exhibited antibacterial effects, being particularly active against B. cereus and E. cloacae. T. viride, P. funiculosum, P. ochrochloron, P. verrucosum var. cyclopium were the most susceptible among fungal microorganisms examined. Both, the aqueous and the ethanol extract expressed inhibitory activity towards enzymes linked to diabetes mellitus type II. Additionally, the ethanol extract showed significantly higher potential in inhibiting α-glucosidase than the drug used as the positive control. Furthermore, the aqueous sample revealed antitumor effects on following malignant cell lines: HeLa, K562 and MDA-MB-453. The results presented herein suggest that P. spinosa leaves should be considered as a natural source of bioactive compounds with potential application in phytopharmacy and food industry

Tetraoxanes induced ROS production and activation of caspase 3 in HeLa cells

It was demonstrated that mixed steroidal tetraoxanes inhibit cancer cell proliferation at micromolar level through an apoptotic mechanism. It will be interesting to see if these compounds may possibly induce oxidative stress, which could lead to induction of apoptosis in tumour cells. As tumour cells contain more iron than other normal tissues it is reasonable to suggest that tetraoxanes could react with iron, generating alkoxy radicals or even highly reactive hydroxyl radicals in a Fenton-like reaction. To gain further insight into the mechanism of cell death induced by tetraoxane endoperoxides, we tested production of reactive oxygen species (ROS) and level of activation of caspase 3 in tumour cells treated with several newly synthesized tetraoxanes

Examination of the polyphenol content and bioactivities of Prunus spinosa L. fruit extracts

We investigated the total phenolic and flavonoid contents and the anthocyanin profiles in aqueous, ethanol and acetone extracts of Prunus spinosa (Rosaceae) fruit, and their antioxidant, antibacterial, antifungal, antidiabetic and antitumor properties. The contribution of polyphenol contents to the bioactivity of the extracts was calculated and observed through Pearson’s coefficient of correlation. The acetone extract was the richest in phenols and anthocyanins and the ethanol extract in flavonoids. Cyanidin was the most abundant anthocyanin compound in all examined extracts. The ethanol extract showed the most promising antioxidant activity in DPPH, ABTS and FRAP assays. Tested bacteria were more affected by the ethanol than by the aqueous extract. Both the ethanol and aqueous extracts exhibited potential antidiabetic effects, observed as inhibition of α-amylase and α-glucosidase, enzymes linked with diabetes mellitus type II. The ethanol extract was a potent α-glucosidase-inhibitor with a significantly lower IC50 value than the positive control, glucobay, used to treat diabetes mellitus type II. Neither the ethanol nor the aqueous extracts had any effects on tested human malignant cell lines. Our results indicate that the ethanol extract showed the most pronounced in vitro antioxidant and antimicrobial effects, and a potential antidiabetic activity, which can be ascribed to its high flavonoid content. Our results indicate that research of compounds, particularly of flavonoids present in the ethanol extract and their anti-diabetic properties should be examined further

Electronic Supplementary Information associated with the paper: Ristovski (Trifunović), J., Žižak, Ž., Marković, S., Janković, N., Ignjatović, N., 2020. Chitosan nanobeads loaded with Biginelli hybrids as cell-selective toxicity systems with a homogeneous distribution of the cell cycle in cancer treatment. RSC Adv. 10, 41542–41550. https://doi.org/10.1039/D0RA08085C

Related to the article: [https://hdl.handle.net/21.15107/rcub_dais_9814]Supplementary data for: [https://doi.org/10.1039/D0RA08085C

Iron salt-promoted oxidation of steroidal phenols by m -chloroperbenzoic acid: a route to possible antitumor agents

Iron salt-promoted reaction of estrone and its derivatives with meta -chloroperoxybenzoic acid was developed and epoxyquinols were further transformed. Most compounds showed in vitro antiproliferative activity. , A new oxidant, containing m -chloroperoxybenzoic acid (MCPBA) and an iron salt, was developed and used for oxidation of steroidal phenols to a quinol/epoxyquinol mixture. Reaction was optimized for estrone, by varying initiators (Fe-salts), reaction temperature, time and mode of MCPBA application. A series of five more substrates (17β-estradiol and its hydrophobized derivatives) was subjected to the optimized oxidation, providing corresponding p -quinols and 4β,5β-epoxyquinols in good to moderate yields. The obtained epoxyquinols were additionally transformed by oxidation, as well as the acid-catalyzed oxirane opening. In a preliminary study of the antiproliferative activity against human cancer cell lines, all newly synthesized compounds expressed moderate to high activity

Synthesis and anticancer potential of 4-azolylcoumarins

Kumarini su heterociklična jedinjenja veoma rasprostranjen u prirodi. Kao privilegovana struktura, ovaj molekul se nalazi i u velikom broju sintetskih derivata sa značajnom biološkom aktivnošću. Posebno su interesantni hibridi koji sadrže dve farmakofore, od kojih je jedna kumarin. Cilj ovog istraživanja bio je sinteza serije jednostavnih novih 4-azolil kumarina i evaluacija njihove in vitro citotoksičnosti prema humanim kancerskim ćelijskim linijama HeLa, K562, MCF-7 i MDA-MB- 453.Coumarins are heterocyclic compounds widely distributed in nature. As a privileged structure, coumarin is also found in a large number of synthetic molecules with important biological activity. Particularly interesting compounds are coumarin-containing hybrids, compounds with two or more pharmacophores. The aim of this work was preparation of simple novel azolyl-coumarin hybrids and evaluation of their cytotoxic effect on human cancer cells, HeLa, K562, MDA-MB-453 and MCF-7