Ultrasound-mediated synthesis of camphoric acid-based chiral salens for the enantioselective trimethylsilylcyanation of aldehydes.

New chiral salen ligands were prepared by the ultrasound-irradiated condensation of optically active (1R, 3S)-1,2,2-trimethyl-1,3-diaminocyclopentane with aromatic 1-hydroxyaldehydes. The ultrasound-mediated process is more convenient due to shorter reaction times, energy economy, and easier isolation of the products. The in situ formed Ti(IV)(salen) complexes, evaluated as catalysts in the enantioselective trimethylsilylcyanation of benzaldehyde, were found to be efficient for this process, originating the corresponding product in high yields (72-99%) and selectivities of up to 79%. The lowest energy transition states were determined by computational studies. These results were in qualitative agreement with the experimentally observed ones.

Molecular analysis of apoptosis pathway after photodynamic therapy in breast cancer: Animal model study.

BACKGROUND: Molecular investigation of breast tumors has permitted better understanding about interaction of genes and pathways involved in tumor progression. OBJECTIVE: The aim of this study was to evaluate the association between genes belonging to the pathway of apoptosis with tumor response to photodynamic therapy. STUDY DESIGN/MATERIALS AND METHODS: The mammary tumors were induced in twenty-four Spraguey-Dawley female rats by oral gavage of 7,12-dimethylbenz(a)anthracene (8mg/Kg body weight). Animals were divided into three groups: G1 (normal tissue), G2 (tumors without treatment), G3 (animals euthanized 48h after treatment). The photosensitizer used was a chlorin, 5,15-bis-(2-bromo-5-hydroxyphenyl) chlorin in the dose of 8mg/kg for each animal. Light source of diode laser at a wavelength of 660nm, fluence rate of 100mW/cm, and light dose of 100J/cm was delivery to lesions for treatment. A sample from each animal was investigated by quantitative real time PCR using Rat Apoptosis RT(2) Profiler™ PCR Array platform. RESULTS: Pro-apoptotic BAK1, CARD6, CASP8, CIDEA, CIDEB, DAPK1, TNF, TNFRSF10B, FASLG, LOC687813, and TP73 genes showed increased expression, and CD40 anti-apoptotic gene showed decreased expression in the group who underwent PDT (G3) in relation to G2. CONCLUSION: The results indicated that these genes are involved more directly with cellular apoptosis induced by PDT using the Chlorin photosensitizer.

Microwave synthesis and in vitro stability of diclofenac-ß-cyclodextrin conjugate for colon delivery.

The aim of this work was to synthesize an ester prodrug of diclofenac and ß-cyclodextrin suitable for colonic delivery. The synthesis of an ester linkage between diclofenac and ß-cyclodextrin was conducted by the nucleophilic substitution of mono-6-tosyl-ß-cyclodextrin under microwaves irradiation. After purification, the conjugate was characterized by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry; infrared (IR) spectroscopy; proton nuclear magnetic resonance ((1)H NMR) spectroscopy; and two-dimensional rotating frame nuclear overhauser effect (ROESY) spectroscopy. The purity was qualified by high pressure liquid chromatography (HPLC). To assess its potential for colonic delivery, the conjugate was evaluated for stability in simulated gastric and small intestinal fluids, and in fecal material from humans processed within a slurry under anaerobic conditions. The conjugate was successfully synthesized with a yield of 20% following purification. The mass spectra showed the parent peak m/z 1434 corresponding to [conjugate+Na] adduct. IR and NMR results confirmed that the carboxyl group of diclofenac is covalently bound to one of the hydroxyl groups of cyclodextrin by an ester linkage. Moreover, ROESY data indicated that the formation of the conjugate is not accompanied by the inclusion of diclofenac within the cyclodextrin. The conjugate was otherwise stable in simulated gastric and small intestinal conditions, but was also readily hydrolyzed liberating diclofenac in less than 2h within the human fecal slurry. This confirmed the potential for this new prodrug as a carrier for colonic delivery.

Synthesis of new 2-galactosylthiazolidine-4-carboxylic acid amides. Antitumor evaluation against melanoma and breast cancer cells.

A set of 2-galactosylthiazolidine-4-carboxylic acid amides was synthesized with different length for the carbon chain amide moiety. The cytotoxicity of the molecules was evaluated against A375 melanoma and MCF7 breast cancer cell lines. For the derivatives tested, the one that contains a C(16) amide carbon chain is the most active with an IC(50) of 17.0 µM for A375 and 5.8 µM for MCF7. This compound also shows cytotoxicity in the triple negative cancer cell line HCC1806. The selectivity of the compounds was assessed by comparing the cytotoxicity in cancer cell line versus in a fibroblast cell line. Flow cytometry studies show the activation of apoptotic pathways and also DNA damages with blockage of the cell cycle in the S-phase and appearance of peaks in G0/G1-phase.

Synthesis of chiral pyrrolo[1,2-c]thiazoles via intramolecular dipolar cycloaddition of münchnones: an interesting rearrangement to pyrrolo[1,2-c]thiazines.

Intramolecular dipolar cycloaddition of bicyclic münchnones, 5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates, derived from cyclodehydration of 2-substituted-N-acylthiazolidine-4-carboxylic acids are reported. A range of new pyrrolo[1,2-c]thiazole derivatives (7, 14, 15, 20, 23, and 26) were obtained as single enantiomers from 2-phenylthiazolidines, 2-benzoylthiazolidines, and 2-methylthiazolidine-4-carboxylates. Pyrrolo[1,2-c][1,4]thiazine derivative 27 was also obtained from pyrrolo[1,2-c]thiazole derivative 26. The structures of methyl (2R,4R)-2-(p-methoxybenzoyl)thiazolidine-4-carboxylate (17a), methyl (2R,4R)-2-(p-methoxybenzoyl)-N-(prop-2-ynyloxyacetyl)thiazolidine- 4-carboxylate (18), and 3-oxo-4-phenyl-3,4,6,8-tetrahydro-1H-furo[3',4':2,3]pyrrolo[1,2-c][1,4]thiazine (27) were determined by X-ray crystallography. Chirooptical studies of the pyrrolo[1,2-c]thiazoles were done by confirming the absolute configuration at the chiral center C-3.