Modified dinucleoside tetraphosphonates, new potential inhibitors of HIV reverse transcriptase

New gamma-substituted analogues of dNTP were synthesized and their enzymatic stability and antiviral properties were evaluated.     

Identification of structural DNA variations in human cell cultures after long-term passage

Random amplified polymorphic DNA (RAPD) analysis was adapted for genomic identification of cell cultures and evaluation of DNA stability in cells of different origin at different culture passages. DNA stability was observed in cultures after no more than 5 passages. Adipose-derived stromal cells demonstrated increased DNA instability. RAPD fragments from different cell lines after different number of passages were cloned and sequenced. The chromosomal localization of these fragments was identified and single-nucleotide variations in RAPD fragments isolated from cell lines after 8–12 passages were revealed. Some of them had permanent localization, while most variations demonstrated random distribution and can be considered as de novo mutations.     

Situation of mycotoxins in milk, dairy products and human milk in Egypt

Abstact  Milk and dairy products purchased at Egyptian markets and breast milk from lactating mothers in Cairo and Giza governorates were analyzed for some mycotoxins. Three of 15 cows’ milk samples were found positive for Afl. M₁ with mean value 6.3 ppb. Only one sample of dried milk was positive (5 ppb). Two of 10 hard cheese samples contained detectable levels of Afl. M₁ (3and 6 ppb), whereas one sample containing Afl. B₁ and G₁ (10 and 4 ppb resp.). For soft cheese one sample of 10 was positive for Afl. M₁ (0.5 ppb). Blue veined cheeses were free of Afl. M₁ and PR-toxins. For breast milk two of 10 samples were positive for Afl. M₁ (20%) with mean value 2.75 ppb, while 3 of 10 samples were positive for Ochratoxin A (30 %).     

Synthesis,Anti-HIV Activity and Stability Studies of 3′-Azido-2′,3′-dideoxythymidine-5′-fluorophosphate

Abstract

The synthesis, in vitro anti-HIV activity, and stability studies of AZT 5′-fluorophosphate (F-AZTMP) are reported. The present results demonstrate that such compound is a bioprecursor of its parent 5′-mononucleotide (AZTMP) but its biotransformation does not allow its selective intracellular delivery. Moreover, several attempts were carried out in order to improve the biological activity of this compound by the use of a SATE prodrug strategy.     

Possibility for the Existence of a General Conformational Motif in the Active Sites of Enzymes Which are Involved in Nucleic Acids Metabolism

Abstract

Many different modified nucleosides and nucleotides with conformationally restricted partly flattened sugar residues are analyzed as substrates or inhibitors of several groups of enzymes of nucleic acid metabolism. A detailed examination of the sugar moiety of large group of modified nucleosides showed that there is a striking conformational similarity, i.e., they are flattened. We propose herein a hypothesis which can represent a general conformational elements in the structure of the active sites of several different groups of enzymes. This proposal envisions that during the enzymatic process natural substrates should reflect these flattened conformations. This hypothesis allows computation of conformational analyses of the enzyme actives centers as well as the design of new actively metabolized modified nucleosides.     

Reasons and Limits of Substrate Activity of Modified L-dNTP in DNA Biosynthesis

Abstract

Theoretical and experimental analysis of interaction of modified D- and L- dNTP as substrates for template-dependent and template-independent DNA polymerases was performed. It is shown that if the modified nucleoside 5′-triphosphates do not contain a substituent in position 3′ DNA chains can be extended by both strereoisomeric series with the same kinetic parameters. But the presence of even a 3′- hydroxy group in L-dNTP prevents their incorporation into the DNA chain.     

Phosphate-Modified Nucleotides: Conversions in Human Serum

Abstract

Mechanisms and rates of hydrolytic dephosphorylation of 5′-hydrogenphosphonates, 5′-phosphorofluoridates, and 5′-phosphates of natural and 3′-substituted thymidines in human serum were studied. The stability of 5′-phosphonates of 2′-deoxy- and 2′,3′-dideoxyadenosines in calf and human sera was found.     

2′-Deoxynucleoside 5′-Triphosphates with Reporter Groups Modified at α-, β,γ- or γ-Phosphates as Substrates for DNA Polymerases

Abstract

The presence of reporter or ligand groups in 2′-deoxynucleoside 5′-triphosphates (dNTP) makes it possible to monitor the diffusion of these compounds into cell and to observe their incorporation into DNA. Here we present the synthesis of new dNTPs modified at α-, β,γ- or γ-phosphates of types I-IV, and containing reporter or ligand groups at the C5 position of dUTP.     

Differential effects of pre and post-payment on neurologists' response rates to a postal survey

Background  

Monetary incentives are an effective way of increasing response rates to surveys, though they are generally less effective in physicians, and are more effective when the incentive is paid up-front rather than when made conditional on completion.