Nuclear magnetic resonance (NMR)
spectroscopy is a widely used
analytical technique for molecular structure determination, and is
highly valued in the fields of chemistry, biochemistry, and medicinal
chemistry. The importance of NMR methods in the European (PhEur) and
United States Pharmacopeia (USP) is steadily growing. However, undergraduates
often have problems becoming familiar with handling the complex data.
We have developed a simple experiment in which undergraduates, who
are learning 1H NMR spectroscopy for the first time, investigate
natural amino acids, and determine their structure and identity using
low-field 1H NMR measurements and simple COSY experiments.
These students see and learn the connection between the chemical shift
of the αC-proton and the isoelectric point of the amino acid.
They engage with the spectroscopic topic by acquiring their own spectra,
and processing and interpreting the data. Understanding important
natural amino acids and their physicochemical character is highly
relevant to all students studying life sciences.
The histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationships of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of
Marketed pain relief drugs with one
to three biologically active
components, as well as mixtures of these ingredients, were qualitatively
and quantitatively analyzed in an undergraduate student lab using
a compact, low-field 1H NMR spectrometer. The students
successfully analyzed more than 50 self-made sample mixtures with
two or three components as well as the two marketed tablet formulations
containing acetylsalicylic acid/l-ascorbic acid, or acetylsalicylic
acid/paracetamol (acetaminophen)/caffeine. The NMR-based quantification
is an attractive application of the technique, as well as a helpful
introduction to NMR spectroscopic applications in life sciences. Problem-based
learning on NMR techniques on commonly known drugs provided students
the opportunity to develop and improve their skills in solving 1H NMR problems.
Acanthamoeba is
a ubiquitous and free-living protozoan
pathogen responsible for causing Acanthamoeba keratitis
(AK), a severe corneal infection inflicting immense pain that can
result in permanent blindness. A drug-based treatment of AK has remained
arduous because Acanthamoeba trophozoites undergo
encystment to become highly drug-resistant cysts upon exposure to
harsh environmental conditions such as amoebicidal agents (e.g., polyhexanide,
chloroquine, and chlorohexidine). As such, drugs that block the Acanthamoeba encystation process could result in a successful
AK treatment. Histone deacetylase inhibitors (HDACi) have recently
emerged as novel therapeutic options for treating various protozoan
and parasitic diseases. Here, we investigated whether novel HDACi
suppress the proliferation and encystation of Acanthamoeba. Synthetic class II HDACi FFK29 (IIa selective) and MPK576 (IIb
selective) dose-dependently decreased the viability of Acanthamoeba trophozoites. While these HDACi demonstrated a negligible effect
on the viability of mature cysts, Acanthamoeba encystation
was significantly inhibited by these HDACi. Apoptosis was slightly
increased in trophozoites after a treatment with these HDACi, whereas
cysts were unaffected by the HDACi exposure. The viability of human
corneal cells was not affected by HDACi concentrations up to 10 μmol/L.
In conclusion, these synthetic HDACi demonstrated potent amoebicidal
effects and inhibited the growth and encystation of Acanthamoeba, thus highlighting their enormous potential for further development.
The treatment of leukemias, especially acute myeloid leukemia (AML), is still a challenge as can be seen by poor 5-year survival of AML. Therefore, new therapeutic approaches are needed to increase the treatment success. Epigenetic aberrations play a role in pathogenesis and resistance of leukemia. Histone deacetylase (HDAC) inhibitors (HDACIs) can normalize epigenetic disbalance by affecting gene expression. In order to decrease side effects of so far mainly used pan-HDACIs, this paper introduces the novel highly selective class IIa HDACI YAK540. A synergistic cytotoxic effect was observed between YAK540 and the proteasome inhibitor bortezomib (BTZ) as analyzed by the Chou-Talalay method. The combination of YAK540 and BTZ showed generally increased proapoptotic gene expression, increased p21 expression, and synergistic, caspase 3/7-mediated apoptosis. Notably, the cytotoxicity of YAK540 is much lower than that of pan-HDACIs. Further, combinations of YAK540 and BTZ are clearly less toxic in non-cancer HEK293 compared to HL-60 leukemia cells. Thus, the synergistic combination of class IIa selective HDACIs such as YAK540 and proteasome inhibitors represents a promising approach against leukemias to increase the anticancer effect and to reduce the general toxicity of HDACIs.
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