Synthesis and detailed biological testing of thiazole C-nucleozides

U radu je ostvarena totalna sinteza novih acikličnih tiazolnih C-nukleozide sa dvostrukom  vezom i 2′,3′-dideoksi funkcijom u šećernoj komponenti. Ostvarena višefazna sinteza  pomenutih acikličnih analoga tiazofurina zasnovana je na D-arabinozi kao hiralnom prekursoru. Ispitana je in vitro citotoksična aktivnost novosintetizovanih nukleozida prema ćelijskim linijama K562, HL-60, HT-29, MCF-7, MDA-MB-231, HeLa, Raji, PC3, Jurkat, Hs 294T i MRC-5, kao i provera ćelijskih mehanizama koji su u osnovi  uočenog citotoksičnog potencijala novosintetisanih analoga u odnosu na tiazofurin kao referentno jedinjenje.A total synthesis of new acyclic thiazole C-nucleozides bearing a double bond or 2′,3′-dideoxy functionality in the sugar moiety was achieved in this work. The multi-step synthesis of the mentioned thiazofurin analogues is based on  D-arabinose as a chiral precursor. In vitro cytotoxic activity of newly synthesized compounds was evaluated against the following cell lines: K562, HL-60, HT-29, MCF-7, MDA-MB-231, HeLa, Raji, PC3, Jurkat, Hs 294T and MRC-5. A study of cell mechanisms underlaying the significant cytotoxic potential of these molecules was caried out and the results were compared to thiazofurin that servad as a referent compound in all biological testings

In vitro procena citotoksičnosti 3D štampanog polimera na bazi epoksi smole namenjenog za upotrebu u stomatologiji

Background/Aim. There is limited published evidence on the cytotoxicity of 3D printed polymer materials for dentistry applications, despite that they are now 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. The cell viability was determined by the Mosmann's colorimetric (MTT) test and the agar diffusion test (ADT). Results. Direct contact of the tested material with the 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 the MTT, 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. The 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 the occlusal splints and orthodontic devices.Uvod/Cilj. Malo je objavljenih dokaza o citotoksičnosti 3D štampanih polimernih materijala za upotrebu u stomatologiji, bez obzira na njihovu sve širu primenu u medicini. Stereolitografija (SLA) jedan je od najvažnijih 3D procesa koji se primenjuje za 3D štampu, ali postoji samo Mali broj materijala na bazi smola za koje je dokazano da su pogodni za medicinsku primenu. Cilj ove studije je bio da se ispita, in vitro, citotoksični efekat 3D štampanog polimera kako bi se utvrdila mogućnost za njegovu upotrebu u stomatologiji i srodnim medicinskim oblastima, kao što su hirurške dentalne vođice, okluzalni splintovi i ortodontski aparati. Metode. Da bi se ispitala citotoksičnost 3D štampanog polimera na bazi epoksi smole, Accura® ClearVue ™ (3D-Sistems, USA), korišc'ene su dve c'elijske kulture: fibroblasti miša L929 i humani fibroplasti pluc'a MRC-5. Vijabilnost c'elija utvrđena je Mosmannovim kolorimetrijskim testom (MTT) i testom difuzije agara (ADT). Rezultati. Direktan kontakt testiranog materijala ispitan pomoću ADT pokazao je da materijal nije imao citotoksičan efekat ni na jednu ćelijsku kulturu. Testitrani materijal je imao blag citotoksični efekat posle 5, 7 i 21 dana ekstrakcije eluata primenom MTT na obe ćelijske linije. Citotoksičnost je rasla sa produženjem vremena ekstrakcije eluata. Zaključak. 3D štampani polimer na bazi epoksi smole, Accura® ClearVue ™ (3D-Sistems, USA) se može smatrati pogodnim za izradu hirurških dentalnih implantnih vođica sa tačke gledišta njegovog citotoksičnog uticaja. Zbog pokazanih blagih citotoksičnih efekata nakon dužih ekstrakcionih perioda eluata potrebna su dalja istraživanja u oblasti biokompatibilnosti materijala da bi se taj polimer mogao koristiti za izradu okluzalnih splintova i ortodontskih aparata

Cell-selective toxicity of hydroxyapatite-chitosan oligosaccharide lactate particles loaded with a steroid cancer inhibitor

The applicative potential of synthetic calcium phosphates, especially hydroxyapatite (HAp), has become intensely broadened in the past 10 years, from bone tissue engineering to multiple other fields of biomedicine. Hybrid systems based on nano hydroxyapatites (HAp) are the subject of numerous studies in preventive and regenerative medicine. HAp nanoparticles coated with bioresorbable polymers have been successfully used as fillers, carriers of antibiotics, vitamins and stem cells in bone tissue engineering, etc. In this study we utilize an emulsification process and freeze drying to load the hybrid system made of nano HAp particles coated with chitosan oligosaccharide lactate (ChOSL) with two different but similar steroid derivatives: 3β-hydroxy- 16-hydroxymino-androst-5-ene-17-one (A), C19H27NO3 and 3β, 17β-dihydroxy-16-hydroxyminoandrost- 5-ene (B), C19H29NO3. The cell-selective toxicity of HAp particles coated with of A- or B-loaded ChOSL was examined simultaneously on the following cell lines: human breast carcinoma (MCF-7, MDA-MB-231), human lung carcinoma (A549) and human lung fibroblasts (MRC-5), using dye exclusion (DET) and MTT assays. 1H NMR, 13C NMR and high-resolution time-of-flight mass spectrometry (MS) techniques confirmed the intact structure of the derivatives A or B. FT-IR, XRD, DTA, TGA and DSC techniques confirmed the drug loading process of steroide (A or B) in core–shell particles based on nano hydroxyapatite. Atomic force microscopy and particle size analyses were used to confirm that the particles were spherical with sizes between 80 and 240 nm. The measured values of electrokinetic parameters (zeta potential, electrophoretic mobility and conductivity) were significantly different for the steroid free carrier (HAp/ChOLS) and A- or B-loaded ChOSL. The value of the topological molecular polar surface area (TPSA, the sum of the surfaces of polar atoms and groups in the molecule), were also different for drug free carrier and A- or BHAp/ ChOLS. Highly selective anticancer activity was noted towards breast cancer cells (MDAMB- 231) by B-loaded HAp/ChOLS. DET testing after 48 hours (after incubation and recovery) of the treatment with A-HAp/ChOSL and B-HAp/ChOSL particles showed a high viability of healthy cells (over 80%). The lowest viability was found in MDA-MB-231 cancer cells treated with B-HAp/ChOSL (28%). The obtained results of the DET and MTT tests showed that the particles of A-HAp/ChOLS exhibited nearly four-fold greater cytotoxicity towards breast cancer cells (MDA-MB-231) than towards healthy cells (MRC-5). B-HAp/ChOSL particles exhibited nearly six times greater cytotoxicity to all breast cancer cells than to healthy ones

Stictic acid inhibits cell growth of human colon adenocarcinoma HT-29 cells

The growth inhibition of stictic acid, a secondary metabolite isolated from the lichen Lobaria pulmonaria (L.) Hoffm. (Lobariaceae), was evaluated in vitro on three human cell lines for the first time. The cell lines HT-29 and MCF-7 were utilized for measuring the activity of stictic acid against cancer cells, while the cell line MRC-5 was selected for estimation of its effect on normal cells. The results suggest a moderate anticancer activity (IC50 value for the cell line HT-29 was 29.29 mu g/ml) and a low growth inhibition on nonmalignant cells (IC50 value for the cell line MRC-5 was 2478.40 mu g/ml) of stictic acid. This natural product can be considered as a promising lead compound for the design of novel human colon adenocarcinoma drugs. (C) 2013 Production and hosting by Elsevier B.V

Highly selective anticancer activity of core shell particles based on hydroxyapatite, chitosan lactate and different androstane derivatives

Hybrid systems based on nano hydroxyapatites (HAp) are the subject of numerous studies in preventive and regenerative medicine. Special interests are directed towards the creation of a system based on HAp for use in a nano-oncology. The main objective of this research is directed towards the creation of a system with cytotoxic properties towards the cancer cells with the same time, minimum side effects. Carriers base on core shell of HAp/chitosan-poly(D,L)-lactide-coglycolide (PLGA) loaded with androstane-based cancer inhibitor could be seen as promising drug delivery platforms for selective cancer therapies. In this study we utilize an emulsification process and freeze drying to load the composite particles based on HAp nanocarrier, chitosane (Ch), PLGA and chitosan oligosaccharide lactate (ChOL) with 17β-hydroxy-17α-picolyl-androst-5-en-3β-acetate (A) and 3β,17β-dihydroxy-16-hydroxymino-androst-5-en (B), a chemotherapeutic derivatives of androstane. The picolyl androstane derivatives showed high potency in the cell inhibitors of hormone-dependent cancers (lung, prostate and colon cancer; adeno and cervix carcinoma; etc.). 1H NMR, 13C NMR and high-resolution time-of-flight mass spectrometry (MS) techniques confirmed the intact structure of the derivatives A and B. The thermogravimetric and differential thermal analysis (TGA, DTA) coupled with mass spectrometry was used to qualitatively confirm the drug loading process. FT-IR, XRD, AFM and DSC techniques have confirmed the success of androstane (A and B) loading process in core shell particles base on nano hydroxyapatite. All the synthesized particles were found to be spherical in shape with a uniform size distribution from d50=167 to d50=231 nm. Highly selective anticancer activity was noted towards the human lung carcinoma (A549) by A loaded HAp/Ch-PLGA and towards the human breast adenocarcinoma (MDA-MB-231) by B loaded HAp/ChOL. The obtained results of the DET and MTT tests were in agreement

Tumor-selective hybrid system based on hydroxyapatite nanocarrier, chitosan, poly(lactic-co-glycolic acid) and androstan derivate

The applicative potential of synthetic calcium phosphates, especially hydroxyapatite (HAp), has become intensely broadened in the past 10 years, from bone tissue engineering to multiple other fields of biomedicine. Previously we have shown that hydroxyapatite nanoparticles coated with chitosan-poly(D,L)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous administration into mice. For this purpose radioactive 125-Iodine (125I), a low energy gamma emitter, was used to develop a novel in situ method for radiolabeling of particles and investigation of their biodistribution. In this study we utilize an emulsification process and freeze drying to load the composite particles based on hydroxyapatite nanocarrier, chitosane and poly(lactic-co-glycolic acid) with 17β- hydroxy-17α-picolyl-androst-5-en-3β-acetate (A), a chemotherapeutic derivative of androstane. The picolyl androstane derivatives showed high potency in the cell inhibitors of hormonedependent cancers (adenocarcinoma, prostate cancer, cervix carcinoma, colon cancer, etc.). 1H NMR, 13C NMR and high-resolution time-of-flight mass spectrometry (MS) techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The synthesized particles of A-loaded HAp/Ch-PLGA were found to be spherical in shape with a uniform size distribution of d50=168 nm. The release of A from HAp/Ch-PLGA was sustained, with no burst release or plateauing after three weeks. The obtained results of the DET and MTT tests show that the particles of A-loaded HAp/Ch-PLGA exhibit almost three times higher cytotoxicity towards lung adenocarcinoma cells (A549) than towards healthy cells (MRC5), while at the same time allowing twice as fast recovery of healthy cells. We have also analyzed the period of recovery of healthy, as well as cancer cells, following the treatment with A-loaded HAp/Ch-PLGA. After treatment with A-loaded HAp/Ch-PLGA, healthy cells recover twice as fast as the malignant ones. Immunofluorescent staining of primary fibroblasts interacting with HAp/Ch-PLGA and A-HAp/Ch-PLGA particles demonstrates no negative morphological or proliferative effects on cells

Tumor-selective hybrid system based on hydroxyapatite nanocarrier, chitosan, poly(lactic-co-glycolic acid) and androstan derivate

The applicative potential of synthetic calcium phosphates, especially hydroxyapatite (HAp), has become intensely broadened in the past 10 years, from bone tissue engineering to multiple other fields of biomedicine. Previously we have shown that hydroxyapatite nanoparticles coated with chitosan-poly(D,L)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous administration into mice. For this purpose radioactive 125-Iodine (125I), a low energy gamma emitter, was used to develop a novel in situ method for radiolabeling of particles and investigation of their biodistribution. In this study we utilize an emulsification process and freeze drying to load the composite particles based on hydroxyapatite nanocarrier, chitosane and poly(lactic-co-glycolic acid) with 17β- hydroxy-17α-picolyl-androst-5-en-3β-acetate (A), a chemotherapeutic derivative of androstane. The picolyl androstane derivatives showed high potency in the cell inhibitors of hormonedependent cancers (adenocarcinoma, prostate cancer, cervix carcinoma, colon cancer, etc.). 1H NMR, 13C NMR and high-resolution time-of-flight mass spectrometry (MS) techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The synthesized particles of A-loaded HAp/Ch-PLGA were found to be spherical in shape with a uniform size distribution of d50=168 nm. The release of A from HAp/Ch-PLGA was sustained, with no burst release or plateauing after three weeks. The obtained results of the DET and MTT tests show that the particles of A-loaded HAp/Ch-PLGA exhibit almost three times higher cytotoxicity towards lung adenocarcinoma cells (A549) than towards healthy cells (MRC5), while at the same time allowing twice as fast recovery of healthy cells. We have also analyzed the period of recovery of healthy, as well as cancer cells, following the treatment with A-loaded HAp/Ch-PLGA. After treatment with A-loaded HAp/Ch-PLGA, healthy cells recover twice as fast as the malignant ones. Immunofluorescent staining of primary fibroblasts interacting with HAp/Ch-PLGA and A-HAp/Ch-PLGA particles demonstrates no negative morphological or proliferative effects on cells

Growth Effects of Some Platinum(II) Complexes with Sulfur-Containing Carrier Ligands on MCF7 Human Breast Cancer Cell Line upon Simultaneous Administration with Taxol

The platinum (II)complexes, cis-[PtCl2(CH3SCH2CH2SCH3)] (Pt1), cis-[PtCl2(dmso)2] (dmso is dimethylsulfoxide; Pt2) and cis-[PtCl2(NH3)2] (cisplatin), and taxol (T) have been tested at different equimolar concentrations. Cells were exposed to complexes for 2 h and left to recover in fresh medium for 24, 48 or 72 h. Growth inhibition was measured by tetrazolium WST1 assay Analyses of the cell cycle, and apoptosis were performed by flow cytometry, at the same exposure times. The IC50 value of each platinum(II) complex as well as combination index (CI; platinum(II) complex + taxol) for various cytotoxicity levels were determined by median effects analysis

Synthesis and biological activity of new thiazole isosteres of goniofufurone and 7-epi-goniofufurone

Herein we report a total synthesis of two novel (7-epi-)goniofufurone isosteres bearing a 2-thiazolyl-4-carboxylic acid ethyl ester moiety instead of the aromatic ring at C-7