1,3-Dipolar cycloaddition reactions can be considered a powerful synthetic tool in the building of heterocyclic rings, with applications in different fields. In this review we focus on the synthesis of biologically active compounds possessing the 1,2,3-triazole core through 1,3-dipolar cycloaddition reactions. The 1,2,3-triazole skeleton can be present as a single disubstituted ring, as a linker between two molecules, or embedded in a polyheterocycle. The cycloaddition reactions are usually catalysed by copper or ruthenium. Domino reactions can be achieved through dipolarophile anion formation, generally followed by cyclisation. The variety of attainable heterocyclic structures gives an illustration of the importance of the 1,2,3-triazole core in medicinal chemistry
Dihydrofolate reductase inhibitors are an important class of drugs, as evidenced by their use as antibacterial, antimalarial, antifungal, and anticancer agents. Progress in understanding the biochemical basis of mechanisms responsible for enzyme selectivity and antiproliferative effects has renewed the interest in antifolates for cancer chemotherapy and prompted the medicinal chemistry community to develop novel and selective human DHFR inhibitors, thus leading to a new generation of DHFR inhibitors. This work summarizes the mechanism of action, chemical, and anticancer profile of the DHFR inhibitors discovered in the last six years. New strategies in DHFR drug discovery are also provided, in order to thoroughly delineate the current landscape for medicinal chemists interested in furthering this study in the anticancer field.
The presence in the mRNA of premature
stop codons (PTCs) results
in protein truncation responsible for several inherited (genetic)
diseases. A well-known example of these diseases is cystic fibrosis
(CF), where approximately 10% (worldwide) of patients have nonsense
mutations in the CF transmembrane regulator (CFTR) gene. PTC124 (3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)-benzoic
acid), also known as Ataluren, is a small molecule that has been suggested
to allow PTC readthrough even though its target has yet to be identified.
In the lack of a general consensus about its mechanism of action,
we experimentally tested the ability of PTC124 to promote the readthrough
of premature termination codons by using a new reporter. The reporter
vector was based on a plasmid harboring the H2B histone coding sequence
fused in frame with the green fluorescent protein (GFP) cDNA, and
a TGA stop codon was introduced in the H2B-GFP gene by site-directed
mutagenesis. Additionally, an unprecedented computational study on
the putative supramolecular interaction between PTC124 and an 11-codon
(33-nucleotides) sequence corresponding to a CFTR mRNA fragment containing
a central UGA nonsense mutation showed a specific interaction between
PTC124 and the UGA codon. Altogether, the H2B-GFP-opal based assay
and the molecular dynamics (MD) simulation support the hypothesis
that PTC124 is able to promote the specific readthrough of internal
TGA premature stop codons.
Subnanometric samples, containing exclusively Ag2 and Ag3 clusters, were synthesized for the first time by kinetic control using an electrochemical technique without the use of surfactants or capping agents. By combination of thermodynamic and kinetic measurements and theoretical calculations, we show herein that Ag3 clusters interact with DNA through intercalation, inducing significant structural distortion to the DNA. The lifetime of Ag3 clusters in the intercalated position is two to three orders of magnitude longer than for classical organic intercalators, such as ethidium bromide or proflavine.
The emergence in
late 2019 of the coronavirus SARS-CoV-2 has resulted
in the breakthrough of the COVID-19 pandemic that is presently affecting
a growing number of countries. The development of the pandemic has
also prompted an unprecedented effort of the scientific community
to understand the molecular bases of the virus infection and to propose
rational drug design strategies able to alleviate the serious COVID-19
morbidity. In this context, a strong synergy between the structural
biophysics and molecular modeling and simulation communities has emerged,
resolving at the atomistic level the crucial protein apparatus of
the virus and revealing the dynamic aspects of key viral processes.
In this Review, we focus on how
in silico
studies
have contributed to the understanding of the SARS-CoV-2 infection
mechanism and the proposal of novel and original agents to inhibit
the viral key functioning. This Review deals with the SARS-CoV-2 spike
protein, including the mode of action that this structural protein
uses to entry human cells, as well as with nonstructural viral proteins,
focusing the attention on the most studied proteases and also proposing
alternative mechanisms involving some of its domains, such as the
SARS unique domain. We demonstrate that molecular modeling and simulation
represent an effective approach to gather information on key biological
processes and thus guide rational molecular design strategies.
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