M. Luisa Marin

Organic photocatalysts for the oxidation of pollutants and model compounds

Organic Photocatalysts for the Oxidation of Pollutants and Model Compounds M. Luisa Marin, Lucas Santos-Juanes, Antonio Arques, Ana M. Amat, and Miguel A. Miranda* Instituto Universitario Mixto de Tecnología Química-Departamento de Química (UPV-CSIC), Avda. de los Naranjos s/n, E-46022, Valencia, Spain Departamento de Ingeniería Textil y Papelera, Universidad Polit ecnica de Valencia, Campus de Alcoy, Plaza Ferr andiz y Carbonell s/n, E-03801 Alcoy, Spain

Photoreactivity of the Nonsteroidal Anti-inflammatory 2-Arylpropionic Acids with Photosensitizing Side Effects¶

The photoreactivity of the nonsteroidal anti‐inflammatory 2‐arylpropionic acids benoxaprofen, carprofen, naproxen, ketoprofen, tiaprofenic acid, and suprofen is reviewed with special emphasis on fundamental photophysical and photochemical properties. The absorption and emission properties of the excited states of these drugs as well as their main photodegradation routes are summarized. The photochemical mechanisms are discussed on the basis of product studies and detection of short‐lived intermediates by means of laser flash photolysis. After dealing with the unimolecular processes, attention is focused on the photosensitized reactions of key biomolecules, such as lipids, proteins or nucleic acids. Finally, a short section on the photobiological effects on simple biological models is also included. Although some earlier citations are included, the literature coverage is in general limited to the last decade.

Complexes between Fluorescent Cholic Acid Derivatives and Human Serum Albumin. A Photophysical Approach To Investigate the Binding Behavior

Interaction between bile acids and plasma proteins has attracted considerable attention over past decades. In fact, binding of bile acids to human serum albumin (HSA) determines their level in plasma, a value that can be used as a test for liver function. However, very little is known about the role that bile acids-HSA complexes play in hepatic uptake. In the present paper, we report on the utility of the singlet excited state properties of 4-nitrobenzo-2-oxa-1,3-diazole (NBD) fluorescent derivatives of cholic acid (ChA); namely, 3alpha-NBD-ChA, 3beta-NBD-ChA, 3beta-NBD-ChTau, 7alpha-NBD-ChA, and 7beta-NBD-ChA to clarify key aspects of bile acids-HSA interactions that remain poorly understood. On the basis of either absorption or emission measurements, formation of NBD-ChA@HSA complexes with 1:1 stoichiometry has been proven. Enhancement of the fluorescence emission upon addition of HSA has been used for determination of the binding constants, which are in the range of 10(4) M(-1). Energy transfer from tryptophan to NBD-ChA occurs by a FRET mechanism; the donor-acceptor distances have been determined according to Forsters theory. The estimated values (27-30 A) are compatible with both site I and site II occupancy and do not provide sufficient information for a safe assignment; however, fluorescence titration using warfarin (site I probe) and ibuprofen (site II probe) for displacement clearly indicates that the employed cholic acid derivatives bind to HSA at site I.

Photophysical Probes To Assess the Potential of Cholic Acid Aggregates as Drug Carriers

The two enantiomers of the nonsteroidal antiinflammatory drug naproxen and of its methyl ester have been selected as representative probes with markedly different hydrophobicity to assess the potential of cholic acid aggregates as drug carriers by means of photophysical techniques. The different distribution of the probes between bulk solution and aggregates has been assessed by quenching of their singlet and triplet excited states by iodide and nitrite anions, respectively. This straightforward photophysical methodology can, in principle, be extended to a variety of drugs containing a photoactive chromophore.

Dansyl-labeled cholic acid as a tool to build speciation diagrams for the aggregation of bile acids

Bile acids (BAs) are a family of natural steroids biosynthesized from cholesterol in the liver that tend to form aggregates in solution. A fluorescent derivative of cholic acid, namely 3α-Dns-ChA, was employed as a reporter to establish the speciation diagrams of the most abundant BAs that can be found mainly in three microenvironments, solution, and primary and secondary aggregates. The developed methodology is based on the analysis of the combined steady-state and time-resolved experiments performed on 3α-Dns-ChA whose emission behavior was found to be strongly medium dependent. In particular, speciation diagrams of sodium glycocholate (NaGCh), sodium taurocholate (NaTCh), sodium chenodeoxycholate (NaCDCh), sodium glycochenodeoxycholate (NaGCDCh), sodium deoxycholate (NaDCh), and sodium ursodeoxycholate (NaUDCh) were successfully built up.

Fluorescent benzofurazan-cholic acid conjugates for in vitro assessment of bile acid uptake and its modulation by drugs.

Fluorescent synthetic 7‐nitrobenzo‐2‐oxa‐1,3‐diazole (NBD) conjugates of cholic acid were prepared and characterized. Their photophysical properties make them suitable for monitoring uptake in freshly isolated rat hepatocytes using flow cytometry. This technique makes it possible to screen drug candidates for cholestatic (and thus hepatotoxic) liability.

Spongian pentacyclic diterpenes. Stereoselective synthesis of aplyroseol-1, aplyroseol-2 and deacetylaplyroseol-2

Natural spongian pentacyclic diterpenes aplyroseol-1 19, aplyroseol-2 18 and deacetylaplyroseol-2 17 have been synthesized in enantiomerically pure form from (+)-podacarp-8(14)-en-13-one 3. Key intermediate in these syntheses is a suitably substituted acid-dialdehyde 2, which is prepared from enone 3 by a sequence of transformations involving stereoselective introduction of a C-7 oxygen functionality, photoaddition of acetylene to the C(8)–C(14) double bond to form a cyclobutene ring system, reductive cyanation of the C-13 carbonyl group, hydrolysis of the resulting nitrile group, and ozonolysis of the cyclobutene moiety. An intramolecular participation of the 7α-hydroxy group in the hydrolysis of the 13α-nitrile 8 is set in focus.

Unconjugated bile salts shuttle through hepatocyte peroxisomes for taurine conjugation

Bile acid‐CoA:amino acid N‐acyltransferase (BAAT) conjugates bile salts to glycine or taurine, which is the final step in bile salt biosynthesis. In addition, BAAT is required for reconjugation of bile salts in the enterohepatic circulation. Recently, we showed that BAAT is a peroxisomal protein, implying shuttling of bile salts through peroxisomes for reconjugation. However, the subcellular location of BAAT remains a topic of debate. The aim of this study was to obtain direct proof for reconjugation of bile salts in peroxisomes. Primary rat hepatocytes were incubated with deuterium‐labeled cholic acid (D4CA). Over time, media and cells were collected and the levels of D4CA, D4‐tauro‐CA (D4TCA), and D4‐glyco‐CA (D4GCA) were quantified by liquid chromatography‐tandem mass spectrometry (LC/MS/MS). Subcellular accumulation of D4‐labeled bile salts was analyzed by digitonin permeabilization assays and subcellular fractionation experiments. Within 24 hours, cultured rat hepatocytes efficiently (>90%) converted and secreted 100 μM D4CA to D4TCA and D4GCA. The relative amounts of D4TCA and D4GCA produced were dependent on the presence of glycine or taurine in the medium. Treatment of D4CA‐exposed hepatocytes with 30‐150 μg/mL digitonin led to the complete release of D4CA, D4GCA, and glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) (cytosolic marker). Full release of D4TCA, catalase, and BAAT was only observed at 500 μg/mL digitonin, indicating the presence of D4TCA in membrane‐enclosed organelles. D4TCA was detected in fractions of purified peroxisomes, which did not contain D4CA and D4GCA. Conclusion: We established a novel assay to study conjugation and intra‐ and transcellular transport of bile salts. Using this assay, we show that cholic acid shuttles through peroxisomes for taurine‐conjugation. (HEPATOLOGY 2010)

Podocarpane-to-spongian skeleton conversion. Synthesis of (+)-isoagatholactone and (–)-spongia-13(16),14-diene

A stereoselective synthesis of the spongian diterpenes (+)-isoagatholactone 5 and (–)-spongia-13(16),14-diene 6 is achieved starting from (+)-podocarp-8(14)-en-13-one 3 (R = H)via the common intermediate β-hydroxy ketone 13.

Involvement of triplet excited states in the electron transfer photodegradation of cinnamic acids using pyrylium and thiapyrylium salts as photocatalysts

The mechanistic pathway for degradation of cinnamic acids using 2,4,6-triphenylpyrylium as well as 2,4,6-triphenyl(thia)pyrylium salts (,) as solar photocatalysts has been unambiguously established. Results obtained in steady-state experiments have been correlated with time-resolved photophysical studies. High percentages of photodegradation (60-70%) were achieved when aqueous solutions of caffeic and ferulic acids (,) as model pollutants were submitted to irradiation in the presence of ,. Electron-transfer quenching of both the singlet and triplet excited states of , by , has been proved, and the quenching rate constants (close to diffusion control) have been determined. However, the percentages of singlet quenching by ,, even at relatively high concentrations of the model pollutants, is lower than 5%. In addition to this, growth of the signal corresponding to the pyranyl radical occurs in the microsecond timescale, incompatible with the singlet state as precursor. Thus, photodegradation of , mainly involves the triplet state of the photocatalysts.