Photochemical Behavior of 2-Azidopurine Tri-O-Acetylribonucleoside in Aqueous Solution: Unprecedented Transformation into 1-(5′-O-Acetyl-β-D-Ribofuranosyl)-5-[(2-Oxo-1,3,5-Oxadiazocan-4-Ylidene)Amino]-1H-Imidazole-4-Carbaldehyde

The photochemical behavior of 2-azidopurine 2′,3′,5′-tri-O-acetylribonucleoside has been investigated in aqueous solution under aerobic and anaerobic conditions. The two major processes under anaerobic irradiation of 2-azidopurine 2′,3′,5′-tri-O-acetylribonucleoside involve unprecedented transformation into 1-(5′-O-acetyl-β-D-ribofuranosyl)-5-[(2-oxo-1,3,5-oxadiazocan-4-ylidene)amino]-1H-imidazole-4-carbaldehyde and photoreduction to respective 2-aminopurine derivative, whereas under aerobic conditions these two processes occur to a much lesser extent and photooxidation to respective 2-nitropurine derivative dominates. The structures of photoproducts formed were confirmed by NMR and high-resolution electrospray ionization mass spectral data.     

Synthesis of Deoxycytidine (dC) Building Blocks for Amide-Linked Dimers or Oligomers: Example of a Deoxycytidine-amide-thymidine Dimer

Abstract

5′-Azido-3′-carbomethoxymethyl-4-N-benzoyl-2′,3′,5′-trideoxy-cytidine 17 and 5′-O-t-butyldimethylsilyl-3′-carboxymethyl-4-N-benzoyl-2′,3′-dideocytidine 22 were efficiently synthesized from 2′-deoxyuridine via a new method which transformed the uracil heterocycle to 4-N-benzoylcytosine (four steps, 60 % overall yield). The amide-linked deoxycytidine-thymidine dimer analog was synthesized.     

Roles of β-d-ribofuranose ring and the functional groups of the d-ribose moiety of adenosylcobalamin in the diol dehydratase reaction

Four analogs of adenosylcobalamin (AdoCbl) modified in the d-ribose moiety of the Coβ ligand were synthesized, and their coenzyme properties were studied with diol dehydratase of Klebsiella pneumoniae ATCC 8724. 2′-Deoxyadenosylcobalamin (2′-dAdoCbl) and 3′-deoxyadenosylcobalamin (3′-dAdoCbl) were active as coenzyme. 2′,3′-Secoadenosylcobalamin (2′,3′-secoAdoCbl), an analog bearing the same functional groups as AdoCbl but nicked between the 2′ and 3′ in the ribose moiety, and its 2′,3′-dialdehyde derivative (2′,3′-secoAdoCbl dialdehyde) were totally inactive analogs of the coenzyme. It is therefore evident that the β-d-ribofuranose ring itself, possibly its rigid structure, is essential and much more important than the functional groups of the ribose moiety for coenzyme function (relative importance; β-d-ribofuranose ring ⪢ 3′-OH ⪢ 2′-OH ⪢ ether group). With 2′-dAloCbl and 3′-dAdoCbl as enzymes. an absorption peak at 478 nm appeared during enzymatic reaction, suggesting homolysis of the CCo bound to form cob(II)alamin as intermediate. In the absence of substrate, the complexes of the enzyme with these active analogs underwent rapid inactivation by oxygen. This suggests that their CCo bond is activated even in the absence of substrate by binding to the apoprotein. No significant spectral changes were observed with 2′,3′-secoAdoCbl upon binding to the apoenzyme. In contrast, spectroscopic observation indicates that 2′,3′-secoAdoCbl dialdehyde, another inactive analog, underwent gradual and irreversible cleavage of the CCo bond by interaction with the apodiol dehydratase, forming the enzyme-bound cob(II)alamin without intermediates.     

Photochemical Synthesis of 6-Aryluridines1)

Abstract

Synthesis of 6-aryluridines was effected by photochemical arylation of 6-iodo-2′,3′-O-isopropylidene-5′-O-methoxymethyluridine.     

The Photochemical Reaction of Pentachlorophenol

A herbicide, sodium pentachlorophenoxide (Na-PCP), used in Japan, is easily decomposed with sunlight after its application in the rice field. The photochemical reaction of Na-PCP in an aqueous solution on exposure to sunlight afforded numerous products which were mainly accompanied with chloranilic acid and a yellow compound (I). The chemical structure of the yellow compound I was established as being 3, 4, 5-trichloro-6-(2′-hydroxy-3′, 4′, 5′, 6′-tetrachlorophenoxy)-o-benzoquinone by chemical and spectroscopic evidences.

Minor decomposition products of sodium pentachlorophenoxide (Na-PCP) in an aqueous solution by sunlight have been isolated. Chemical structures of them are described, and infrared and ultraviolet spectra are presented in support of these stractures. These illustrate a new type of oxidative reaction of phenols.     

Impact of UV‐Visible Light on the Morphological and Photochemical Behavior of a Low‐Bandgap Poly(2,7‐Carbazole) Derivative for Use in High‐Performance Solar Cells

This paper reports on the photochemical behavior upon exposure to UV‐visible light of a poly(2,7‐carbazole) derivative for use in high‐performance solar cells. Poly[N‐9′‐hepta‐decanyl‐2,7‐carbazole‐alt‐5,5‐(4′,7′‐di‐2‐thienyl‐2′,1′,3′‐benzothiadiazole)] (PCDTBT) is one of a relatively large class of push‐pull carbazole‐based copolymers that have been synthesized to better harvest the solar spectrum. The 2,7‐carbazole building block of PCDTBT is also used with different electron‐accepting units in a large variety of low‐band‐gap polymers. The photochemical and morphological behavior of PCDTBT thin films is investigated from the molecular scale to the nanomechanical properties. The photo‐oxidation mechanism is shown to be governed by chain‐scission and cross‐linking reactions. It results in dramatic evolution of the morphology, roughness and stiffness of thin PCDTBT films. Based on the identification of several photoproducts formed along the macromolecular chains or released into the gas phase, the main pathways of PCDTBT photochemical evolution are discussed. These processes first involve the scission of the C–N bond between the carbazole group and the tertiary carbon atom bearing the alkyl side‐chain. Modifications of the chemical structure of PCDTBT, the evolution of its UV‐visible absorbance, and its nanomechanical properties initiated by light irradiation are shown to be closely related.     

S-Adenosyl-L-homocysteine dialdehyde: An affinity labeling reagent for histamine-N-methyltransferase

S-Adenosyl-L-homocysteine (SAH) was converted to 2′-O-[(R)-formyl(adenin-9-yl)methyl]-3′-S-homocysteinyl-3′-deoxy-(R)-glyceraldehyde (SAH dialdehyde) by periodic acid oxidation. SAH dialdehyde was then reduced with sodium borohydride to the corresponding diol, 2′,3′-acyclic SAH. SAH dialdehyde, but not 2′,3′-acyclic SAH, was found to inhibit histamine-N-methyltransferase (HMT). Neither analog showed significant inhibitory activity toward other methyltransferases. The inhibition of HMT by SAH dialdehyde was irreversible with the inactivation following first-order kinetics. A kinetic analysis suggests the formation of a dissociable enzyme-inhibitor complex prior to inactivation. The enzyme could be protected from inactivation by inclusion of S-adenosyl-L-methionine in the preincubation mixture.     

Hepatic uptake and metabolism of galactose can be quantified in vivo by 2-[18F]fluoro-2-deoxygalactose positron emission tomography

Metabolism of galactose is a specialized liver function. The purpose of this PET study was to use the galactose analog 2-[(18)F]fluoro-2-deoxygalactose (FDGal) to investigate hepatic uptake and metabolism of galactose in vivo. FDGal kinetics was studied in 10 anesthetized pigs at blood concentrations of nonradioactive galactose yielding approximately first-order kinetics (tracer only; n = 4), intermediate kinetics (0.5-0.6 mmol galactose/l blood; n = 2), and near-saturation kinetics (>3 mmol galactose/l blood; n = 4). All animals underwent liver C15O PET (blood volume) and FDGal PET (galactose kinetics) with arterial and portal venous blood sampling. Flow rates in the hepatic artery and the portal vein were measured by ultrasound transit-time flowmeters. The hepatic uptake and net metabolic clearance of FDGal were quantified by nonlinear and linear regression analyses. The initial extraction fraction of FDGal from blood-to-hepatocyte was unity in all pigs. Hepatic net metabolic clearance of FDGal, K(FDGal), was 332-481 ml blood.min(-1).l(-1) tissue in experiments with approximately first-order kinetics and 15.2-21.8 ml blood.min(-1).l(-1) tissue in experiments with near-saturation kinetics. Maximal hepatic removal rates of galactose were on average 600 micromol.min(-1).l(-1) tissue (range 412-702), which was in agreement with other studies. There was no significant difference between K(FDGal) calculated with use of the dual tracer input (Kdual(FDGal)) or the single arterial input (Karterial(FDGal)). In conclusion, hepatic galactose kinetics can be quantified with the galactose analog FDGal. At near-saturated kinetics, the maximal hepatic removal rate of galactose can be calculated from the net metabolic clearance of FDGal and the blood concentration of galactose.     

Role of phosphodiesterase 2 in growth and invasion of human malignant melanoma cells

Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations and effects of adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP). The role of PDEs in malignant tumor cells is still uncertain. The role of PDEs, especially PDE2, in human malignant melanoma PMP cell line was examined in this study. In PMP cells, 8-bromo-cAMP, a cAMP analog, inhibited cell growth and invasion. However, 8-bromo-cGMP, a cGMP analog, had little or no effect. PDE2 and PDE4, but not PDE3, were expressed in PMP cells. Growth and invasion of PMP cells were inhibited by erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), a specific PDE2 inhibitor, but not by rolipram, a specific PDE4 inhibitor. Moreover, cell growth and invasion were inhibited by transfection of small interfering RNAs (siRNAs) specific for PDE2A and a catalytically-dead mutant of PDE2A. After treating cells with EHNA or rolipram, intracellular cAMP concentrations were increased. Growth and invasion were stimulated by PKA14-22, a PKA inhibitor, and inhibited by N⁶-benzoyl-c AMP, a PKA specific cAMP analog, whereas 8-(4-chlorophenylthio)-2′-O-methyl-cAMP, an Epac specific cAMP analog, did not. Invasion, but not growth, was stimulated by A-kinase anchor protein (AKAP) St-Ht31 inhibitory peptide. Based on these results, PDE2 appears to play an important role in growth and invasion of the human malignant melanoma PMP cell line. Selectively suppressing PDE2 might possibly inhibit growth and invasion of other malignant tumor cell lines.     

Carbovir: A Carbocyclic Nucleoside with Potent and Selective Activity Against Human Immunodeficiency Virus (HIV) in Vitro

Abstract

Carbocyclic 2′, 3′-didehydro-2′,3′-dideoxyquanosine (carbovir), a novel nucleoside analog, emerged as a potent and selective anti-HIV agent from a primary screen of a large number of carbocyclic nucleosides.¹ Carbovir inhibited the infectivity and replication of HIV in T-cells at concentrations 200 to 400-fold below toxicity to host cells. Carbovir was also evaluated for its Inhibitory effects on the expression of viral antigen in HIV-infected CEM cells. Production of p 24 core antigen at optimal inhibitory concentrations of the antiviral agents indicated comparable results for AZT, ddA and carbovir.     

Effect of tracer infusion site on measurement of bicarbonate-carbon dioxide metabolism in dogs

Ten dogs were given a primed infusion of H13CO3- for 220 min while under general anesthesia. Isotopic steady state was reached within 60 min in exhaled CO2, femoral arterial blood HCO3-, and femoral venous blood HCO3-. Halfway through each infusion study, the site of tracer infusion was changed either from the central aorta to a peripheral vein, or vice versa. The mean HCO3(-)-CO2 flux measured from blood HCO3- enrichments was 15.7 +/- 2.1 (SD) mmol X kg-1 X h-1. The mean fraction of tracer recovered in exhaled CO2 was 79 +/- 7% (SD) of the infused dose. No significant difference in either HCO3- flux or recovery of tracer was found between the venous and arterial infusions of tracer. These results indicate that when venous administration of HCO3- tracer is compared with central arterial infusion, the initial loss of tracer into expired CO2 is an unimportant consideration in experiments measuring HCO3- kinetics.     

A selective effect of Mg2+ on the photochemistry at one type of reaction center in photosystem II of chloroplasts

The area growth over the seemingly exponential fluorescence rise curve of 3-(3′,4′-dichlorophenyl)-1,1-dimethylurea-poisoned, envelope-free chloroplasts suspended in media devoid of Mg²⁺ is biphasic. Its kinetics can be described as the sum of two independently occurring first order processes which are attributed to two different types of photochemical centers in unicentral photosystem II units. An addition of Mg²⁺ changes the kinetic pattern of the photochemistry at one type of centers to nonfirst order, but does not affect the kinetics at the other type. This differential effect of Mg²⁺ suggests that certain photochemical centers and their light harvesting pigments may become integrated in larger, multicentral units under the influence of Mg²⁺, or become more tightly coupled to adjacent light harvesting pigment beds.     

Studies Towards the Synthesis of the Saturated and Unsaturated Carbocyclic Methylene Phosphonate Analogs of Dideoxyadenosine

Abstract

The synthesis of the saturated carbocyclic methylene phosphonate analog of ddAMP is described by two different methods (epoxyde opening and “purinoselenylation”). Studies towards the formation of 2′,3′ unsaturated analogs by selenoxyde or mesylate elimination are also reported.     

Two-component laser velocimeter measurements downstream of heart valve prostheses in pulsatile flow

Elevated turbulent shear stresses resulting from disturbed blood flow through prosthetic heart valves can cause damage to red blood cells and platelets. The purpose of this study was to measure the turbulent shear stresses occurring downstream of aortic prosthetic valves during in-vitro pulsatile flow. By matching the indices of refraction of the blood analog fluid and model aorta, correlated, simultaneous two-component laser velocimeter measurements of the axial and radial velocity components were made immediately downstream of two aortic prosthetic valves. Velocity data were ensemble averaged over 200 or more cycles for a 15-ms window opened at peak systolic flow. The systolic duration for cardiac flows of 8.4 L/min was 200 ms. Ensemble-averaged total shear stress levels of 2820 dynes/cm2 and 2070 dynes/cm2 were found downstream of a trileaflet valve and a tilting disk valve, respectively. These shear stress levels decreased with axial distance downstream much faster for the tilting disk valve than for the trileaflet valve.     

How Photoinduced Crosslinking Under Operating Conditions Can Reduce PCDTBT‐Based Solar Cell Efficiency and then Stabilize It

Bulk heterojunction (BHJ) photovoltaic devices made of PCDTBT (poly[N‐9′‐hepta‐decanyl‐2,7‐carbazole‐alt‐5,5‐(4′,7′‐di‐2‐thienyl‐2′,1′,3′‐benzothiadiazole)]) and PC₇₀BM ([6,6]‐phenyl‐C₇₀‐butyric acid methyl ester) are among the most efficient and stable devices studied so far. However, during a short regime called “burn‐in”, a significant decrease of power conversion efficiency was observed. A study of the photochemical mechanisms involved in the PCDTBT:PCBM active layer exposed to light in encapsulated systems is presented. It is found that the photochemical reactions resulting from the absorption of light by PCDTBT involve crosslinking between the 2,7 carbazole unit of PCDTBT and the fullerene unit of PCBM. Those reactions stabilize the BHJ by avoiding the formation of microsized PCBM crystals known to cause failure of BHJ solar cells. Using classical electron paramagnetic resonance spectroscopy (EPR) (without illumination), paramagnetic defects along the polymer chains have been detected. The kinetics of defects intensity show a burn‐in trend. The evolution of their relaxation times upon aging is in good agreement with a structural change (crosslinking) of the BHJ observed from the nanomechanical properties. Finally, light‐induced electron paramagnetic resonance (LEPR) measurements performed on aged samples revealed that electron transfer is not significantly affected upon aging, confirming thus the stabilization of the BHJ in solar cell operating conditions.     

The influence of the non-Newtonian properties of blood on the flow in large arteries: steady flow in a carotid bifurcation model.

Laser Doppler anemometry experiments and finite element simulations of steady flow in a three dimensional model of the carotid bifurcation were performed to investigate the influence of non-Newtonian properties of blood on the velocity distribution. The axial velocity distribution was measured for two fluids: a non-Newtonian blood analog fluid and a Newtonian reference fluid. Striking differences between the measured flow fields were found. The axial velocity field of the non-Newtonian fluid was flattened, had lower velocity gradients at the divider wall, and higher velocity gradients at the non-divider wall. The flow separation, as found with the Newtonian fluid, was absent. In the computations, the shear thinning behavior of the analog blood fluid was incorporated through the Carreau-Yasuda model. The viscoelastic properties of the fluid were not included. A comparison between the experimental and numerical results showed good agreement, both for the Newtonian and the non-Newtonian fluid. Since only shear thinning was included, this seems to be the dominant non-Newtonian property of the blood analog fluid under steady flow conditions.     

Cellular Phosphorylation of 2′, 3′-Dideoxyadenosine-5′-monophosphate,a Key Intermediate in The Activation of the Antiviral Agent DDI,in Human Peripheral Blood Mononuclear Cells

Abstract

2′,3′-dideoxyadenosine 5-monophosphate (ddAMP), is a key intermediate in the metabolism of the antiviral agent 2′,3′-dideoxyinosine (ddI) to its active triphosphate derivative, 2′,3′-dideoxyadenosine-5′-triphosphate (ddATP). The potential role of adenylate kinase in the phosphorylation of ddAMP was studied in human peripheral blood mononuclear cells (PBMC) and a human T cell line, CEMss. Subcellular distribution, sulfhydryl inhibitor, and substrate specificity studies support the hypothesis that the mitochondrial adenylate kinase (AK2) is a major route of cellular activation of these compounds in human lymphocytes.     

Synthesis of Pyrazolo[3, 4-d]Pyrimidine Ribonucleoside 3′, 5′-Cyclic Phosphates Related to cAMP,cIMP and cGMP1

Abstract

The synthesis of pyrazolo[3,4-d]pyrimidine ribonucleoside 3′, 5′-cyclic phosphates related to cAMP, cIMP and cGMP has been achieved for the first time. Phosphorylation of 4-amino-6-methylthio-1-β-D-ribo-furanosylpyrazolo[3,4-d]pyrimidine (1) with POCl₃ in trimethyl phosphate gave the corresponding 5′-phosphate (2a). DCC mediated intramolecular cyclization of 2a gave the corresponding 3′, 5′-cyclic phosphate (3a), which on subsequent dethiation provided the cAMP analog 4-amino-1-β-D-ribofuranosylpyrazolo[3, 4-d]pyrimidine 3′, 5′-cyclic phosphate (3b). A similar phosphorylation of 6-methylthio-1-β-D-ribofuranosylpyrazolo[3, 4-d]pyrimidin-4(5H)-one (5), followed by cyclization with DCC gave the 3′, 5′-cyclic phosphate of 5 (9a). Dethiation of 9a with Raney nickel gave the cIMP analog 1-β-D-ribofuranosylpyrazolo[3, 4-d]pyrimidin-4(5H)-one 3′, 5′-cyclic phosphate (9b). Oxidation of 9a with m-chloroperoxy benzoic acid, followed by ammonolysis provided the cGMP analog 6-amino-1-β-D-ribofuranosylpyrazolo [3, 4-d] pyrimidin-4(5H)-one 3′, 5′-cyclic phosphate (7). The structural assignment of these cyclic nucleotides was made by UV and H NMR spectroscopic studies.