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This study presents comparison of our recently formulated two compartmental model with General fractional derivative (GFD) and Korsmeyer–Peppas, Makoid–Banakar and Kopcha diffusion models. We have used our GFD model to study the release of gentamicin in poly (vinyl alcohol)/chitosan/gentamicin (PVA/CHI/Gent) hydrogel aimed for wound dressing in medical treatment of deep chronical wounds. The PVA/CHI/Gent hydrogel was prepared by physical cross linking of poly(vinyl alcohol)/chitosan dispersion using freezing-thawing method, and then was swollen for 48 h in gentamicin soluteion, at 37ºC. Different physicochemical (FTIR, SEM), mechanical and biological (cytotoxicity, antibacterial activity) properties have been determined. The concentration of released gentamicin was determined using a high-performance liquid chromatography (HPLC) coupled with mass spectrometry (MS). The ratio between concentration of released gentamicin and initial concentration of gentamicin in the hydrogel was monitored for the prolonged time period in order to obtain gentamicin release profile. It was proven that our novel diffusion GFD model better fitted to experimental data then other models, and enabled the determination of diffusion coefficient precisely for the entire time period.

Four novel conformationally restricted (–)-muricatacin analogues, bearing a methoxy group at the C-5 position and with an alkoxymethyl group аs the C-7 side chain, have been synthesised and their in vitro antiproliferative activity was evaluated against a panel of seven human tumour cell lines, as well as a single normal cell line. All analogues (9–12) showed diverse antiproliferative effects against all tested human malignant cell lines, but were devoid of any significant cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). A structure–activity relationship study reveals that the introduction of tetrahydrofuran ring, the replacement of C-8 methylene group in the side chain of muricatacin analogues with the O-8 ether functionality, as well as the length of side chain may be beneficial for the antiproliferative effects of these lactones. All novel analogues were more potent than lead compound, (–)-muricatacin, against HL-60 cell line.

New thiazole hybrids were synthesized and evaluated for their in vitro cytotoxicity against a panel of human malignant cell lines. The key steps in the synthesis of hybrids 3–7 involved the initial condensation of appropriate aldononitriles with cysteine ethyl ester hydrochloride, followed by subsequent treatment of resulting thiazolines with diazabicycloundecene to form the thiazole ring. Bioisosteres 8 and 14 have been prepared after the stereoselective addition of 2-(trimethylsilyl)thiazole to the hemiacetals obtained by periodate cleavage of terminal diol functionality in the suitably protected d-glucose derivatives. The obtained analogues showed various antiproliferative activities in the cultures of several tumour cell lines. Hybrid 6 was the most potent in HeLa cells, exhibiting more than 10 and 4 times stronger activity than both leads 1 and 2, respectively. The most active compound in Raji cells was hybrid 12, which was nearly 2-fold more potent than the clinical antitumour drug doxorubicin. All analogues were more potent in A549 cells with respect to lead 1, while compounds 6 and 7 were slightly more active than doxorubicin. Preliminary structure–activity relationship analysis revealed that the presence of a cinnamate group at the C-3 position in analogues of type 7 increases the activity of resulting molecular hybrids.

α-Tricalcium phosphate/fluorapatite (α-TCP/FAp) mixed powders were prepared in order to obtain dental root canal filling cements. Different liquids for cement pastes have been investigated and the most suitable one for obtaining rheologically optimal pastes was chosen for further analysis. Morphological changes in the cement materials as a consequence of the formation of hydroxyapatite (HAp) after the immersion in a simulated body fluid (SBF), an influence on the cell viability, and final success of the filling were investigated by field emission scanning electron microscopy. Treatment of the α-TCP/FAp mixtures in SBF at 37°C resulted in a complete transformation of α-TCP into HAp after 10 days, while the exposure of MRC-5 human and L929 animal fibroblast cells to the cement showed complete absence of cytotoxicity. The root canal of an extracted tooth was filled with the α-TCP/FAp cement containing 5 wt.% of FAp and relatively strong adhesion between the cement and dentine was observed after 48h. The same cement material was immersed during 10 days in SBF and after that both human and animal fibroblast cells during in vitro MTT tests showed higher cell viability compared to the control sample. These findings lead to a conclusion that the α-TCP/FAp based cement demonstrates potential for further development towards dental cement application.

Steroids are good candidates for drug development, thanks to their low general toxicity and possibility for structure modifications connected with change of their activity. Several 16,17-secoandrost-4-ene-16,17a-dinitrile compounds were synthesized and screened for anticancer effect previously, including 6-oxo and 6-hydroxyimino compounds. This research is continued with the attempts for different synthetic strategy and evaluation of anticancer effect mechanism. Synthesis of 3-hydroxyimino compounds was successful, but inseparable mix of isomers was excluded from biological tests. Tested secodinitriles expressed cytotoxic effect on HeLa cervix cancer cells as a model system, with submicromolar to molar IC50 values, where 6-substituted derivatives were more effective. After 72 h treatment with equitoxic concentrations equal IC50 values of test compounds the mechanism of this effect was studied using flow cytometry and specific fluorescent dyes. Modest change in both G0/G1 and G2/M resting phases and change in mitochondrial membrane potential were noticed, while the most pronounced effect was apoptosis induction. Total apoptosis was in range 50.72–58.31 % in all cell samples treated with secodinitriles, compared to 7.44 % in control samples. Total percent of dead cells, including both apoptotic and necrotic, ranged from 55.24 to 65.34 %, compared to 10.68 % in control. Selectivity towards cancer cells is very important feature of these compounds indicating their potential use as lead compounds in the drug development for the treatment of cancers of steroid hormone-dependent tissues.

A dicarboxylato-diamide-type compound 2,2'-[(1,2-dioxoethane-1,2- -diyl)diimino]dibenzoic acid (H4obbz) (1) was synthesized and characterized. The crystal structure of K2H2obbz·2H2O (2) was determined by X-ray diffracttion analysis. The cytotoxic activities of the compounds were tested against four different cancer cell lines MCF-7, A549, HT-29, HeLa and a human normal cell line MRC-5. The results indicate reasonable dose-dependent cytotoxicity of the ligands that show selectivity against the tested carcinoma and healthy cell lines. Flow cytometric analysis and fluorescence microscopy showed that the most active compound, H4obbz, induced apoptosis and G0/G1 cell cycle arrest, indicating blockage of DNA synthesis as a possible mechanism that triggers apoptosis. Docking and molecular dynamics simulations gave similar responses regarding interactions (binding) between their ligands and chaperon Grp78. The MMGBSA determined ΔG binding energies were in the range from –104 to –140 kJ mol-1.

Several (+)-goniofufurone analogues with simplified structures were designed, synthesized and evaluated for their in vitro antitumour activity, against a panel of human tumour cell lines. Dephenylated compounds 2 and 3 demonstrated remarkable antitumour activities, in the cultures of K562 and Raji cells with IC50 values in the range of 3.0–9.3 nM. Each of goniofufurone analogues lacking the tetrahydrofuran ring (4, 5 and 6) strongly inhibited the growth of at least one malignant cell line, with IC50 values in the range of 11-30 nM. Brief structure–activity relationship (SAR) analysis showed that the simplified goniofufurone analogues, designed by removing the phenyl group from C-7, or by opening the THF ring, could show stronger antiproliferative effects compared to control molecules. It is noticeable that analogues 2–8 are completely inactive with respect to the normal MRC-5 cell line. These findings, together with their potent antitumour activities, provide a suitable basis for the development of new and selective antitumour drugs.

Ionic liquids (ILs) are well known for their physicochemical properties that recommend them for many purposes. However, many ILs are not environmentally friendly. Bearing these facts in mind, a series of imidazoliumand salicylate-based ILs with low general toxicity were designed and their pharmacological potential studied. Herein, their antiproliferative effect against human cancer cell lines and antimicrobial activity on selected Gram-positive and Gram-negative bacteria and Candida strains are presented. ILs with 1-butyl- -3-methylimidazolium or imidazolium cation (IL 1 and compound 5), with the lowest dipole moments and highest lipophilicity, exerted highest cytotoxicity against colon and/or lung cancer cells, manifesting high selectivity to the normal cells. The most non-polar IL with the 1-butyl-3-methylimidazolium cation expressed the strongest anticancer potential, but it was also toxic against normal cells, although its cytotoxicity was less than the cytotoxic effect of commercially used chemotherapeutic agents. The same compounds, IL 1 and compound 5, expressed modest effect on the bacterial strain that causes serious lung diseases and pulmonary infections (Staphylococcus aureus) or which are included in colon cancer formation (Esherichia coli and Enterococcus faecalis). Salicylate itself was toxic against lung cancer cell line A549 and affected some Candida strains. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172012 and Grant no. 172058]

Background/Aim. There is limited published evidence on the cytotoxicity of 3D printed polymer materials for dentistry applications, despite that they are now being widely used in medicine. Stereolithography (SLA) is one of the foremost 3D processes used in 3D printing, yet there are only a small number of resin materials reported to be suitable for medical applications. The aim of this study was to investigate, in vitro, the cytotoxic effect of the 3D printed resin in order to establish the suitability for its usage in dentistry and related medical applications such as surgical dental guides, occlusal splits and orthodontic devices. Methods. To examine the cytotoxicity of the 3D printed polymer-based epoxy resin, Accura® ClearVue™ (3D-Systems, USA), two cell cultures were used: mouse fibroblasts L929 and human lung fibroblasts MRC-5. Cell viability was determined by Mosmann's colorimetric (MTT) test and the agar diffusion test (ADT). Results. Direct contact of the tested material with ADT test showed nontoxic effects of tested material in any cell culture. The tested material showed no cytotoxic effect after 3 days of extraction of the eluate by MTT test, but mild cytotoxic effect after 5, 7 and 21 days on both cell lines. The cytotoxicity increased with increasing the time of the eluate extraction. Conclusion. 3D printed polymer-based epoxy resin, Accura® ClearVue™ (3D-Systems, USA) is considered appropriate for making surgical dental implant guides according to the cytotoxic behavior. According to the mild level of cytotoxicity after the longer extraction periods, there is a need for further evaluation of biocompatibility for its application for occlusal splints and orthodontic devices. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. TR 35020: Research and development of modeling methods and approaches in manufacturing of dental recoveries with the application of modern technologies and computer aided systems]

Divergent syntheses of novel (–)-goniofufurone mimics with an alkoxymethyl group as the side chain have been accomplished from D-glucose in nine synthetic steps and in overall yields 6.7–8.7 %. Their in vitro antiproliferative activity was evaluated against eight human tumour cell lines as well as a single normal cell line. All analogues demonstrated powerful to good antiproliferative effects toward all malignant cell lines under evaluation. Against the HL-60 cell line, all mimics showed increased activities being 27- to 1604-fold more potent than the lead compound, (–)-goniofufurone. Remarkably, the majority of synthesized analogues displayed higher or similar activity to the commercial antitumour agent doxorubicin (DOX) against A549 cell line. The most potent compound exhibited 196-fold stronger cytotoxicity than DOX in the culture of this cell line.

A simple synthesis of mono- and bis-salicylic acid derivatives 1-10 by the transesterification of methyl salicylate (methyl 2-hydroxybenzoate) with 3-oxapentane-1,5-diol, 3,6- dioxaoctane-1,8-diol, 3,6,9-trioxaundecane-1,11-diol, propane-1,2-diol or 1-aminopropan- 2-ol in alkaline conditions is reported. All compounds were tested in vitro on three malignant cell lines (MCF-7, MDA-MB-231, PC-3) and one non-tumor cell line (MRC- 5). Strong cytotoxicity against prostate PC-3 cancer cells expressed compounds 3, 4, 6, 9 and 10, all with the IC50 less than 10 μmol/L, which were 11-27 times higher than the cytotoxicity of antitumor drug doxorubicin. All tested compounds were not toxic against the non-tumor MRC-5 cell line. Antioxidant activity of the synthesized derivatives was also evaluated. Compounds 2, 5 and 8 were better OH radical scavengers than commercial antioxidants BHT and BHA. The synthesized compounds showed satisfactory scavenger activity, which was studied by QSAR modeling. A good correlation between the experimental variables IC50 DPPH and IC50 OH and MTI (molecular topological indices) molecular descriptors and CAA (accessible Connolly solvent surface area) for the new compounds 1, 3, and 5 was observed.

Proton NMR spectroscopy and cyclic voltammetry have been applied to study the stability of three gold(III) complexes with L-histidine-containing peptides, [Au(Gly-L-His-N,N’,N’’)Cl]NO3.1.25H2O (Au1), [Au(L-Ala-L-His-N,N’,N’’)Cl]NO3.2.5H2O (Au2) and [Au(Gly-Gly-L-His-N,N’,N’’,N’’’)]Cl.H2O (Au3) under physiologically relevant conditions. It was found that tridentate coordination of Gly-L-His and L-Ala-L-His dipeptides, as well as tetradentate coordination of Gly-Gly-L-His tripeptide in Au1, Au2 and Au3 complexes, respectively, stabilized +3 oxidation state of gold and prevented its reduction to Au(I) and Au(0). No release of the coordinated peptides from Au(III) was observed under these experimental conditions. Considering remarkable stability of Au1, Au2 and Au3 complexes, their cytotoxic activity was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay toward five human tumor cell lines, MCF-7 (human breast adenocarcinoma), HT-29 (human colon adenocarcinoma), HeLa (human cervix carcinoma), HL-60 (human promyelocytic leukemia), Raji (human Burkitt’s lymphoma) and one human normal cell line MRC-5 (human fetal lung fibroblasts). While the cytotoxic activity of Au1, Au2 and Au3 against investigated human malignant cell lines was strongly cell line dependent, none of these complexes was cytotoxic against normal MRC-5 cell line. This study can contribute to the future development of gold(III)-peptide complexes as potential antitumor agents.

In order to obtain multifunctional materials with good biocompatibility and antimicrobial effect, hydroxyapatite (HAp) doped with Zn2+ was synthesized by hydrothermal method. Powders with different content of zinc ions were synthesized and compared with undoped HAp to investigation of Zn2+ ion influence on the antimicrobial activity of HAp. Analyses of undoped and Zn2+-doped powders before and after thermal treatment at 1200ºC were performed by SEM and XRD. Antimicrobial effects of powders were examined in relation to Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans in liquid medium. The results showed that the obtained powders have good antimicrobial activity, but higher antimicrobial activities of powders doped with Zn2+ were observed after annealing at 1200°C. For powders annealed at 1200°C in vitro biocompatibility tests MTT and DET with MRC-5 fibroblast cells in liquid medium were carried out. Based on MTT and DET tests it was shown that powders do not have a significant cytotoxic effect, which was confirmed by SEM analysis of MRC-5 fibroblast cells after theirs in vitro contact with powders. [Projekat Ministarstva nauke Republike Srbije, br. III 45019 and FP7-REGPOT-2009-1 NANOTECH FTM]

The new conjugates of selected bile acids (hyocholic (2), deoxycholic (3), hyodeoxycholic (4) and 12-ketocholic (5) acids) with ethyl 11-aminoundecanoate 7, 8, 11, and 13 were synthesized. The conjugation reaction was carried out in ethyl acetate in the presence of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) and triethylamine. Under the same experimental conditions, the conjugation reaction involving ethyl 6-aminohexanoate resulted in formation of a conjugate 9 only in the case of deoxycholic acid (3) in addition to the unexpected ethyl ester 10. In the case of the other bile acids (cholic (1), hyodeoxycholic (4) and 12-ketocholic (5) acids) only an unexpected ester formation took place giving esters 6, 12, and 14. Cytotoxic activity against four tumor cell lines (human breast adenocarcinoma ER-, MDA-MB-231; breast adenocarcinoma ER+, MCF-7; cervix epiteloid carcinoma, HeLa S-3; and prostate cancer, PC-3) was evaluated. Conjugate 8 showed strong activity against HeLa S-3 and conjugate 11 for PC-3. Ethyl ester of 12-ketocholic acid 14 showed very strong antiproliferative activity against MCF-7 and HeLa S-3.

New functionally substituted 5-arylidene-2,4-dioxotetrahydro 1,3-thiazole- 3-carboxylic acid cholesteryl esters were synthesized from 2,4-dioxotetrahydro- 1,3-thiazole and evaluated for their in vitro cytotoxicity against several human tumor cell lines and one normal lung fibroblast cell line.

Background: Single-walled carbon nanotubes (SWCNTs) have been reported to induce cytotoxicity in different cell lines. Although the mechanisms underlying cytotoxicity are not fully understood, accumulation of reactive oxygen species (ROS) and oxidative damage is considered to be a likely contributing factor. Methods: Human lung carcinoma cells, A549, and human fetal lung fibroblasts, MRC-5 were used to assess the cytotoxicity of SWCNT in the presence and absence of a redox status regulator, N-acetylcysteine (NAC), via the MTT assay. Results: SWCNT induced a nearly three-fold greater loss of viability in A594 vs. MRC-5 cells at ≤250 μg/ml. SWCNT cytotoxicity at higher concentrations was similar for both cell lines, while NAC alone was non-toxic. The cytotoxicity of SWCNT (250 μg/ml) in combination with NAC to A549 cells was significantly decreased at the lowest NAC concentration (1.5 µg/ml), and was similar to NAC treatment alone at that concentration. Higher concentrations of NAC in combination with SWCNT (250 μg/ml) resulted in increased cytotoxicity in both A549 and MRC-5 cells. Conclusion: A549 malignant lung cells are more susceptible to low concentrations of SWCNT vs. normal lung cells, and low concentrations of N-acetylcysteine appear to be cytoprotective, possibly due to its antioxidant properties. [Projekat Ministarstva nauke Republike Srbije, br. 173014: Molecular mechanisms of redoxsignaling in homeostasis: Adaptation and pathology]

In order to obtain compounds with better biological activity and lower toxicity, numerous modifications have been made to the cisplatin and carboplatin molecules. The aim of the study was to examine the in vitro antiproliferative activity of two new carboplatin analogues and their effect on both the cell cycle and the induction of apoptosis. Carboplatin and analogues were tested on four human cell lines: myelogenous leukemia K562, colon adenocarcinoma HT-29, breast adenocarcinoma MCF-7 and lung fibroblasts MRC-5. Cell lines were exposed to commercial and synthesized carboplatin and two carboplatin analogues. Their growth inhibition was measured by the MTT test after 24 h incubation. The cell cycle modulation and induction of apoptosis were analyzed by flow cytometry on MCF-7 cell line. After 24 h exposure, both carboplatin analogs induced dose-dependent cytotoxicity in all tested cell lines. The most sensitive was MCF-7 cell line. Tested substances showed moderate cytotoxicity against healthy MRC-5 cells. Flow cytometry analysis showed that both analogues modulated the cell cycle, increasing cell population in sub-G1 phase. The same response in the form of the apoptosis induction was also obtained with the Annexin-V test. Apoptosis induction was confirmed with double-fluorescence staining method. Two new carboplatin analogues strongly inhibit the growth of MCF-7 breast cancer cells, inducing apoptosis and changes in cell cycle distribution. [ABSTRACT FROM AUTHOR]