Irene M. Lagoja

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 References. 1–9

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.

1,2,4-triazole derivatives inhibiting the human immunodeficiency virus type 1 (HIV-1) in vitro

A novel series of selective 1,2,4-triazole nonnucleoside reverse transcriptase inhibitors (NNRTIs) is described. In MT-4 cells compound, 4f inhibited human immunodeficiency virus type 1 (HIV-1) induced cytopathology at an IC50 of 9.98 μM with a selectivity index of 18.6. The hypothetical docking model of RT/4f derived from X-ray crystallographic structure of capravirine complex with HIV-1 RT links the activity profile to the H-bonding network.

α-Homo-DNA and RNA Form a Parallel Oriented Non-A, Non-B-Type Double Helical Structure

Cross-talking between nucleic acids is a prerequisite for information transfer. The absence of observed base pairing interactions between pyranose and furanose nucleic acids has excluded considering the former type as a (potential) direct precursor of contemporary RNA and DNA. We observed that alpha-pyranose oligonucleotides (alpha-homo-DNA) are able to hybridize with RNA and that both nucleic acid strands are parallel oriented. Hybrids between alpha-homo-DNA and DNA are less stable. During the synthesis of alpha-homo-DNA we observed extensive conversion of N6-benzoyl-5-methylcytosine into thymine under the usual deprotection conditions of oligonucleotide synthesis. Alpha-homo-DNA:RNA represents the first hybridization system between pyranose and furanose nucleic acids. The duplex formed between alpha-homo-DNA and RNA was investigated using CD, NMR spectroscopy, and molecular modeling. The general rule that orthogonal orientation of base pairs prevents hybridization is infringed. NMR experiments demonstrate that the base moieties of alpha-homo-DNA in its complex with RNA, are equatorially oriented and that the base moieties of the parallel RNA strand are pseudoaxially oriented. Modeling experiments demonstrate that the duplex formed is different from the classical A- or B-type double stranded DNA. We observed 15 base pairs in a full helical turn. The average interphosphate distance in the RNA strand is 6.2 A and in the alpha-homo-DNA strand is 6.9 A. The interstrand P-P distance is much larger than found in the typical A- and B-DNA. Most helical parameters are different from those of natural duplexes.

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).

Substituted 2-aminothiazoles are exceptional inhibitors of neuronal degeneration in tau-driven models of Alzheimer’s disease

A novel series of 2-aminothiazoles with strong protection in an Alzheimers disease (AD) model comprising tau-induced neuronal toxicity is disclosed. These derivatives can be synthesized in one-pot and a small SAR of the substitution within these series afforded several compounds that counteracted tau-induced cell toxicity at nanomolar concentrations. These congeners therefore have strong potential as possible treatment for Alzheimers disease and other related tauopathies.

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.

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.