Study of the anticancer properties of optically active titanocene oximato compounds

New water soluble and optically active cyclopentadienyl titanium derivatives [(¿5-C5H5)2Ti{(1R, 4S)-¿ON, (R)NH}Cl] (R = Bn (Benzyl) 1a’, 2-pic (2-picolylamine) 1b’) have been synthesized. The novel compounds along with those previously described [(¿5-C5H5)2Ti{(1S, 4R)-¿ON, (R)NH}Cl] (R = Bn 1a, 2-pic 1b) were evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of 1b was determined by single crystal X-ray crystallography and showed a unique terminal monohapto Ti–O disposition of the oximato ligand. All enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3 and DU-145, lung A-549, pancreas MiaPaca-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. In addition, 1a, 1b and 1b’ were tested against non-tumorigenic prostate RWPE-1 cell line. After 24 h of incubation, 1b and 1b’ were moderately active against Jurkat and A-549 cells. The anti-proliferative effect of titanium compounds on prostate PC-3, DU-145 and RWPE-1 cell lines was also assessed after 72 h of drug exposure. The cytotoxic profile of the enantiomers was similar, exception made for the PC-3 cells, with S, R-isomers exhibiting cytotoxicities 2 to 3 times higher than R, S-compounds. Under these conditions, derivative 1b showed calculated IC50 values better than those of Tacke''s Titanocene-Y (bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride) on both the prostate PC-3 and DU-145 cells. 1a and 1b cytotoxic behaviour shows certain selectiveness, with activities 2–4 times lower on normal prostate RWPE-1 than on cancer PC-3 cells. Furthermore, 1b produces higher cytotoxicity on prostate PC-3, DU-145 and RWPE-1 cells than the additive dose of titanocene dichloride and pro-ligand b·HCl. Additionally, compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, which suggest that these metal complexes and/or their hydrolysis products bind DNA either in the minor groove or externally

Persistencia: Nuestro primer cortometraje

Universidad de Sevilla. Grado en Comunicación Audiovisua

Biological evaluation of water soluble arene Ru(II) enantiomers with amino-oxime ligands

New water soluble, enantiopure arene ruthenium compound SRuSN-(1R, 4S)-[(¿6-p-cymene)Ru{¿NH(Bn), ¿NOH}Cl]Cl (Bn = benzyl, 1a') has been synthesized. The novel compound along with that previously described RRuRN-(1S, 4R)-[(¿6-p-cymene)Ru{¿NH(Bn), ¿NOH}Cl]Cl (1a) was evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of novel ruthenium derivative 1a' was determined by single crystal X-ray crystallography. Both enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3, lung A-549, pancreas MIA PaCa-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. Both enantiomers are active and versatile cytotoxic agents, showing IC50 values from 2 to 12 times lower than those found for cisplatin in the different cell lines evaluated. The mechanism of cell death induced by the metal compounds was analyzed in A-549 and Jurkat cell lines. Derivatives 1a and 1a' induced apoptotic cell death of A-549 cells while dose-dependent cell death mechanisms have been found in the Jurkat cell line. Compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, revealing moderate binding affinity of 1a and 1a' towards duplex DNA. Finally, the efficacy of 1a in a preliminary in vivo assay of PC-3 xenografts in nude mice has been evaluated, resulting in a promising inhibition of tumor growth by 45%. Analysis of tumor tissue also showed a significant decrease of levels of crucial molecules in the invasive phenotype of PC-3 cells

Study of the anticancer properties of optically active titanocene oximato compounds

New water soluble and optically active cyclopentadienyl titanium derivatives [(η5-C5H5)2Ti{(1R,4S)-ĸON,(R)NH}Cl] (R = Bn (Benzyl) 1a’, 2-pic (2-picolylamine) 1b’) have been synthesized. The novel compounds along with those previously described [(η5-C5H5)2Ti{(1S,4R)-ĸON,(R)NH}Cl] (R = Bn 1a, 2-pic 1b) were evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of 1b was determined by single crystal X-ray crystallography and showed a unique terminal monohapto Tisingle bondO disposition of the oximato ligand. All enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3 and DU-145, lung A-549, pancreas MiaPaca-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. In addition, 1a, 1b and 1b’ were tested against non-tumorigenic prostate RWPE-1 cell line. After 24 h of incubation, 1b and 1b’ were moderately active against Jurkat and A-549 cells. The anti-proliferative effect of titanium compounds on prostate PC-3, DU-145 and RWPE-1 cell lines was also assessed after 72 h of drug exposure. The cytotoxic profile of the enantiomers was similar, exception made for the PC-3 cells, with S,R-isomers exhibiting cytotoxicities 2 to 3 times higher than R,S-compounds. Under these conditions, derivative 1b showed calculated IC50 values better than those of Tacke's Titanocene-Y (bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride) on both the prostate PC-3 and DU-145 cells. 1a and 1b cytotoxic behaviour shows certain selectiveness, with activities 2–4 times lower on normal prostate RWPE-1 than on cancer PC-3 cells. Furthermore, 1b produces higher cytotoxicity on prostate PC-3, DU-145 and RWPE-1 cells than the additive dose of titanocene dichloride and pro-ligand b·HCl. Additionally, compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, which suggest that these metal complexes and/or their hydrolysis products bind DNA either in the minor groove or externally.Ministerio de Economía y CompetitividadComunidad Autónoma de MadridUniversidad de Alcal

Inulin extraction from common inulin-containing plant sources

Currently there is a growing interest from the food industry in obtaining inulin for its possible use in the elaboration of functional foods. A set of optimum extraction conditions was developed for the recovery of inulin plus fructo-oligosaccharides (FOS) from several common inulin-containing plant sources, like chicory roots (Cichorium intybus L.) and Jerusalem artichoke tubers (Helianthus tuberosus L.), as well as from novel sources like globe artichoke inflorescence (Cynara cardunculus L.) and its by-product. Optimal conditions for temperature (60−80 °C), time (20−60 min) and solvent to solid ratio (10−40 mL/g) were estimated in order to maximize inulin plus FOS extraction by using response surface methodology (RSM) with a Box-Behnken design. Inulin plus FOS were estimated colorimetrically by difference between total carbohydrate and reducing sugar contents for the optimization. Moreover, the profile of inulin and low molecular weight carbohydrates was studied in optimized plant extracts by HPLC. Inulin in raw samples and optimal extracts were further characterized by Fourier Transformed Infrared spectroscopy. According to response surface methodology model, optimal conditions for inulin plus FOS extraction depended on plant source and were achieved at a solvent to solid ratio of 27.8–37.4 mL/g, from 62−80 °C and a variable time of 22−60 min. The highest inulin plus FOS contents were achieved in chicory root (70.5 g/100 g dry weight) and Jerusalem artichoke tuber (81.1 g/100 g dry weight), and the lowest ones were attained in globe artichoke by-product (4.2 g/100 g). Nevertheless, its high availability and low cost would support this novel globe artichoke by-product as an alternative and valuable source of inulin and FOS for the food industry. At the same time their reuse as potential prebiotic ingredients would contribute to the circular economy

Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells

New palladium compounds [Pd{(1S,4R)-NOHNH(R)}Cl-2] (R = Ph 1a or Bn 1b), [Pd{(1S,4R)-NOHNH(R)}{(1S,4R)-NONH(R)}][Cl] (R = Ph 2a or Bn 2b) and corresponding [Pd{(1R,4S)-NOHNH(R)}Cl-2] (R = Ph 1a' or Bn 1b') and [Pd{(1R,4S)-NOHNH(R)}{(1R,4S)-NONH(R)}][Cl] (R = Ph 2a' or Bn 2b') have been synthesized. Novel compounds 1a, 1b, and 2b (and 1a', 1b', and 2b') were obtained in solution as a mixture of diastereomers whose relative ratios depend on the solvent and the nature of the amino substituent. In contrast, the synthetic reactions of derivatives 2a and 2a' were stereospecific, and afforded single enantiomers of absolute configuration (S-N,1S(C),4R(C))-(R-N,1S(C),4R(C)) and (R-N,1R(C),4S(C))-(S-N,1R(C),4S(C)), respectively. All compounds have been fully characterized by NMR and IR spectroscopy, time-dependent UV-spectroscopy, ESI-HR-MS in water, and CHN elemental analysis. Absolute configurations of the major epimers of 1a and 1a', both epimers of 1b and enantiomer 2a', were determined by single crystal X-ray crystallography, and confirmed by 2D NOESY NMR experiments in solution. Additionally, the pH-dependent stability of 2b in water was assessed by H-1-NMR spectroscopy. Metal derivatives have been tested in vitro against three human cancer (prostate PC-3, cervical HeLa, and breast MCF-7) cell lines. The highest anticancer activities were shown by palladium compound 2a' in all cancer cells, with IC50 values up to 80 times lower than those found for cisplatin. The cytotoxicity of 2a and 2a '' is stereo-dependent, with IC50 values that differ significantly for each enantiomer in all the cell lines tested. The cytotoxic activity of 2a and 2a' was further evaluated against the non-tumorigenic human prostate RWPE-1 cell line, revealing a selectivity index (SI) of ca. 30 for derivative 2a'. DNA interactions have been investigated by equilibrium dialysis, fluorescence resonance energy transfer (FRET) DNA melting assays, and viscometric titrations, pointing to groove and/or external binding. Cell cycle assay on PC-3 cells after treatment with 2a or 2a' shows cell cycle arrest in the S and G2/M phases, especially when the cells are treated with compound 2a'.Ministerio de Ciencia e InnovaciónMinisterio de Economía, Industria y CompetitividadUniversidad de AlcaláComunidad de Madri

Biological evaluation of water soluble arene Ru(II) enantiomers with amino-oxime ligands

New water soluble, enantiopure arene ruthenium compound SRuSN-(1R,4S)-[(η6-p-cymene)Ru{ĸNH(Bn),ĸNOH}Cl]Cl (Bn = benzyl, 1a′) has been synthesized. The novel compound along with that previously described RRuRN-(1S,4R)-[(η6-p-cymene)Ru{ĸNH(Bn),ĸNOH}Cl]Cl (1a) was evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of novel ruthenium derivative 1a′ was determined by single crystal X-ray crystallography. Both enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3, lung A-549, pancreas MIA PaCa-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. Both enantiomers are active and versatile cytotoxic agents, showing IC50 values from 2 to 12 times lower than those found for cisplatin in the different cell lines evaluated. The mechanism of cell death induced by the metal compounds was analyzed in A-549 and Jurkat cell lines. Derivatives 1a and 1a′ induced apoptotic cell death of A-549 cells while dose-dependent cell death mechanisms have been found in the Jurkat cell line. Compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, revealing moderate binding affinity of 1a and 1a′ towards duplex DNA. Finally, the efficacy of 1a in a preliminary in vivo assay of PC-3 xenografts in nude mice has been evaluated, resulting in a promising inhibition of tumor growth by 45%. Analysis of tumor tissue also showed a significant decrease of levels of crucial molecules in the invasive phenotype of PC-3 cells.Ministerio de Economía y CompetitividadComunidad Autónoma de MadridUniversidad de Alcal

Influence of high‐pressure processing on nutritional composition and bioactive compounds of Phaseolus coccineus L

The influence of high-pressure processing (HPP) prior to cooking on nutritional composition and bioactive compounds content of four varieties of Phaseolus coccineus L. was studied. Cooking and HPP+C increased the protein content. However, minerals, total carbohydrates, ciceritol and α-galactosides were reduced. Fat was not affected by cooking but decreased after HPP+C. For dietary fiber, the behavior observed was different depending on the sample and the treatment applied. HPP+C could be considered a good processing technology to retain the advantageous lower myo-inositol phosphates isoforms and supply prebiotic oligosaccharides. The trypsin inhibitors activity was lower in the cooked and HPP+C samples; however, there were no significant differences between both thermal treatments. Thus, HPP+C reduced cooking time and preserving or improving the nutritional composition of the beans and their bioactive compounds content