Preparation of guanine and diaminopurine from biuret. Part III.

Because of their potential prebiotic origin and relative chemical stability, urea, biuret, formic acid, and glycine amide might have played a role in the assembly process of purine bases. In this paper, we describe a short reaction path to purine nucleobases from these acyclic precursors. The formation of different purines was verified by UV and NMR spectroscopy, as well as by mass spectrometry.

Some novel aminopropyl nucleoside phosphonates.

The aminopropyl nucleoside phosphonates 1-3 have an amino function within either the acyclic chain (series 2 and 3) or as substituent (series 1) of HPMPC (Cidofovir). Both purine and pyrimidine nucleoside anologs have been synthesized. In contrast to HPMPC, only a weak antiherpes virus activity could be demonstrated for 2b and 2c.

Pyrimidine as constituent of natural biologically active compounds.

This review describes the various manifestations of the pyrimidine system (alkylated, glycosylated, benzo-annelated.). These comprise pyrimidine nucleosides as well as alkaloids and antibiotics--some of them have been discovered and isolated from natural sources already long time ago, others have been reported very recently. A short overview on pyrimidine syntheses (prebiotic synthesis, biosynthesis, and metabolism) is given. The biological activities of most of the pyrimidine analogs are briefly described, and, in some cases, syntheses are formulated.

A potential prebiotic route to adenine from hypoxanthine.

A possible reaction mechanism for the dehydration of glycinamide (3) and N,N'-diformylurea (4) yielding hypoxanthine (2) has been investigated. Furthermore, a potential prebiotic route converting hypoxanthine (2) into adenine (1) via phosphate activation followed by substitution reaction with NH3 was studied. This reaction mimics the proposed biochemical mechanism for the conversion of IMP to AMP.

N-aminoimidazole derivatives inhibiting retroviral replication via a yet unidentified mode of action.

The synthesis of a series of N-aminoimidazoles (NAIMs) with an uncommon spectrum of antiretroviral activity is described. From a group of 60 closely related molecules, we were able to subdivide the molecules in different groups based on their anti-HIV and anti-SIV activity in vitro: (i) molecules acting on a new, immediate postintegration step, (ii) molecules acting on both postintegration and HIV-1 reverse transcriptase (RT) as NNRTI, and (iii) molecules that mainly act at the HIV-1 RT according to an NNRTI-type mode of action.

One-step synthesis of hypoxanthine from glycinamide and diformylurea.

Because of their easy availability and their relative chemical stability, urea, formic acid, and glycine might have played a role in the assembly process of nucleobases. In this paper, a short reaction path is described to prepare hypoxanthine starting from the above mentioned precursors. The formation of hypoxanthine has been verified by high-resolution mass spectrometry with the 15N-labelled urea as starting material, and HPLC analysis. The yield of this condensation reaction has been determined spectrophotometrically.

Anti-influenza virus agents: synthesis and mode of action.

Annual epidemics of influenza virus infection are responsible for considerable morbidity and mortality, and pandemics are much more devastating. Considerable knowledge of viral infectivity and replication has been acquired, but many details still have to be elucidated and the virus remains a challenging target for drug design and development. This review provides an overview of the antiviral drugs targeting the influenza viral replicative cycle. Included are a brief description of their chemical syntheses and biological activities. For other reviews, see References1-9.

Use of RNA in drug design.

This is a review of RNA as a target for small molecules (ribosomes, riboswitches, regulatory RNAs) and RNA-derived oligonucleotides as tools (antisense/small interfering RNA, ribozymes, aptamers/decoy RNA and microRNA). This review highlights the present state of research using RNA as a drug target or as a potential drug candidate and explains at which stage and to what extent rational design could eventually be involved. Special attention has been paid to the recent potential clinical applications of RNA either as drugs or drug targets. The review deals mainly with mechanistic approaches rather than with physicochemical or computational aspects of RNA-based drug design.

Synthesis of ribonucleosides by condensation using trimethylsilyl triflate.

This unit describes, in detail, the optimized condition for the synthesis of nucleosides making use of the trimethysilyl triflate-mediated silyl-Hilbert-Johnson synthesis. This unit focuses on the mechanistic understanding of this universal and conveniently applicable method.

Inhibition of human immunodeficiency virus type 1 transcription by N-aminoimidazole derivatives.

This study describes the mechanism of antiviral action of the N-aminoimidazole derivatives which exclusively inhibit retroviruses such as HIV-1, HIV-2, SIV and MSV. These antiretroviral compounds, with lead prototype NR-818, were found to inhibit HIV-1 replication at the transcriptional level. Analysis of each individual step of viral transcription, including transcriptional activation mediated by NF-kappaB, the chromatin remodeling process at the viral promoter and viral mRNA transcription mediated by RNAPII, showed that NR-818 was able to prolong the binding of NF-kappaB to its consensus sequence. The compound also increased the acetylation of histones H3 and H4 within the nucleosome nuc-1 at the transcription initiation site and inhibited the recruitment of viral Tat and the phosphorylation of the RNA polymerase II C-terminal domain (RNAPII CTD) at the viral promoter upon stimulation of latently HIV-1-infected cell lines. As a result, viral mRNA expression and subsequent viral p24 production in stimulated latently HIV-1-infected cell lines was suppressed by NR-818. These data suggest that the N-aminoimidazole derivatives effectively inhibit the reactivation of HIV-1 and may contribute to the control of the latent HIV-1 reservoir.

Synthesis and properties of aminopropyl nucleic acids.

Oligonucleotides that contain up to three aminopropyl nucleoside analogues have been synthesized. Dimers of aminopropyl adenine and thymidine were prepared and used as building blocks by applying phosphoramidite chemistry. Both R and S isomers of the aminopropyl nucleosides were used. This incorporation led to a reduction of thermal stability of double-stranded DNA. Furthermore, the (R)-adenine analogue, which yielded (S)-APNA, can be considered as a candidate for universal base pairing.

Synthesis of 1,5-anhydrohexitol building blocks for oligonucleotide synthesis.

This unit describes in detail, the optimized preparations of 1,5-anhydrohexitol and the 1,5-anhydrohexitol building blocks for oligonucleotide synthesis (hG, hA, hC, hT).

A short path synthesis of [13C/15N] multilabeled pyrimidine nucleosides starting from glucopyranose nucleosides.

The synthesis of fully [13C/15N] labeled pyrimidine nucleosides has been achieved from 13C-glucose and labeled nucleobases. The reaction scheme leads directly to the protected nucleosides without the need for the inversion of configuration of C-3 of 13C-glucose. This was achieved by an oxitative ring-opening reaction removing the carbon with the wrong configuration.