In this work, we have developed covalent
and low molecular weight
docetaxel delivery systems based on conjugation with N-acetyl-d-galactosamine and studied their properties related
to hepatocellular carcinoma cells. The resulting glycoconjugates have
an excellent affinity to the asialoglycoprotein receptor (ASGPR) in
the nanomolar range of concentrations and a high cytotoxicity level
comparable to docetaxel. Likewise, we observed the 21–75-fold
increase in water solubility in comparison with parent docetaxel and
prodrug lability to intracellular conditions with half-life values
from 25.5 to 42 h. We also found that the trivalent conjugate possessed
selective toxicity against hepatoma cells vs control cell lines (20–35
times). The absence of such selectivity in the case of monovalent
conjugates indicates the effect of ligand valency. Specific ASGPR-mediated
cellular uptake of conjugates was proved in vitro using fluorescent-labeled
analogues. In addition, we showed an enhanced generation of reactive
oxygen species in the HepG2 cells, which could be inhibited by the
natural ligand of ASGPR. Overall, the obtained results highlight the
potential of ASGPR-directed cytostatic taxane drugs for selective
therapy of hepatocellular carcinoma.
Herein, we describe the design, synthesis,
and biological evaluation
of novel betulin and N-acetyl-d-galactosamine
(GalNAc) glycoconjugates and suggest them as targeted agents against
hepatocellular carcinoma. We prepared six conjugates derived via the
C-3 and C-28 positions of betulin with one or two saccharide ligands.
These molecules demonstrate high affinity to the asialoglycoprotein
receptor (ASGPR) of hepatocytes assessed by in silico modeling and
surface plasmon resonance tests. Cytotoxicity studies in vitro revealed
a bivalent conjugate with moderate activity, selectivity of action,
and cytostatic properties against hepatocellular carcinoma cells HepG2.
An additional investigation confirmed the specific engagement with
HepG2 cells by the enhanced generation of reactive oxygen species.
Stability tests demonstrated its lability to acidic media and to intracellular
enzymes. Therefore, the selected bivalent conjugate represents a new
potential agent targeted against hepatocellular carcinoma. Further
extensive studies of the cellular uptake in vitro and the real-time
microdistribution in the murine liver in vivo for fluorescent dye-labeled
analogue showed its selective internalization into hepatocytes due
to the presence of GalNAc ligand in comparison with reference compounds.
The betulin and GalNAc glycoconjugates can therefore be considered
as a new strategy for developing therapeutic agents based on natural
triterpenoids.
This microperspective
covers the most recent research outcomes
of artificial intelligence (AI) generated molecular structures from
the point of view of the medicinal chemist. The main focus is on studies
that include synthesis and experimental in vitro validation
in biochemical assays of the generated molecular structures, where
we analyze the reported structures’ relevance in modern medicinal
chemistry and their novelty. The authors believe that this review
would be appreciated by medicinal chemistry and AI-driven drug design
(AIDD) communities and can be adopted as a comprehensive approach
for qualifying different research outcomes in AIDD.
Since the asialoglycoprotein receptor (also known as the "Ashwell−Morell receptor" or ASGPR) was discovered as the first cellular mammalian lectin, numerous drug delivery systems have been developed and several gene delivery systems associated with multivalent ligands for liver disease targeting are undergoing clinical trials. The success of these systems has facilitated the further study of new ligands with comparable or higher affinity and less synthetic complexity. Herein, we designed two novel trivalent ligands based on the esterification of tris(hydroxymethyl) aminomethane (TRIS) followed by the azide−alkyne Huisgen cycloaddition with azido N-acetyl-D-galactosamine. The presented triazolyl glycoconjugates exhibited good binding to ASGPR, which was predicted using in silico molecular docking and assessed by a surface plasmon resonance (SPR) technique. Moreover, we demonstrated the low level of in vitro cytotoxicity, as well as the optimal spatial geometry and the required amphiphilic balance, for new, easily accessible ligands. The conjugate of a new ligand with Cy5 dye exhibited selective penetration into HepG2 cells in contrast to the ASGPR-negative PC3 cell line.
The growing resistance of the influenza virus to widely used competitive neuraminidase inhibitors occupying the active site of the enzyme requires the development of bifunctional compounds that can simultaneously interact with other regulatory sites on the protein surface. When developing such an inhibitor and combining structural fragments that could be located in the sialic acid cavity of the active site and the adjacent 430-cavity, it is necessary to select a suitable linker not only for connecting the fragments, but also to ensure effective interactions with the unique arginine triad Arg118-Arg292-Arg371 of neuraminidase. Using molecular modeling, we have demonstrated the usefulness of the sulfonamide group in the linker design and the potential advantage of this functional group over other isosteric analogues.
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