8 research outputs found
Synthesis of a Nucleobase-Modified ProTide Library
A new
method for the construction of (aryloxy)phosphoramidate nucleoside
prodrugs is presented. An (aryloxy)phosphoramidate ribose derivative
as key building block was used for coupling with a number of nucleobases
under Vorbrüggen reaction conditions yielding the protected
ProTides in excellent yields. Selective hydrolysis of the acetoxy
groups on the sugar moiety afforded a series of the desired ProTides.
The advantage of this approach, when compared to classical procedures,
is the greater flexibility for achieving structural variety of the
nucleobase moiety
Synthesis of a C‑Nucleoside Phosphonate by Base-Promoted Epimerization
The efficient synthesis
of a [2′S] C-nucleoside phosphonate
and its corresponding prodrug has been realized. A phosphonomethoxy
group was stereoselectively introduced at the anomeric 5′-carbon
atom through glycosylation of a benzoyl protected [5′R]-acetoxy-[2′R]-9-deazaadenine.
An unexpected epimerization at the 2′-position of the sugar
moiety occurred upon removal of the protecting groups, but this was
further exploited as a key reaction for improved synthesis of the
target compound
Amidate Prodrugs of Cyclic 9‑(<i>S</i>)‑[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine with Potent Anti-Herpesvirus Activity
A series
of amidate prodrugs of cyclic 9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine
(cHPMPA) featuring different amino acid motifs were synthesized. All
phosphonamidates derived from (<i>S</i>)-cHPMPA displayed
a broad spectrum activity against herpesviruses with EC<sub>50</sub> values in the low nanomolar range. A phosphonobisamidate prodrug
of (<i>S</i>)-HPMPA also exhibited a remarkably potent antiviral
activity. In addition, the leucine ester prodrug of (<i>S</i>)-cHPMPA and phosphonobisamidate valine ester prodrug of (<i>S</i>)-HPMPA proved stable in human plasma. These data warrant
further development of cHPMPA prodrugs, especially against human cytomegalovirus
(HCMV), for which there is a high need for treatment in transplant
recipients
Amidate Prodrugs of Deoxythreosyl Nucleoside Phosphonates as Dual Inhibitors of HIV and HBV Replication
The
synthesis of four l-2′-deoxy-threose nucleoside
phosphonates with the natural nucleobases adenine, thymine, cytosine,
and guanosine has been performed. Especially the adenine containing
analogue (PMDTA) was endowed with potent antiviral activity displaying
an EC<sub>50</sub> of 4.69 μM against HIV-1 and an EC<sub>50</sub> value of 0.5 μM against HBV, whereas completely lacking cytotoxicity.
The synthesis of a number of phosphonomonoamidate and phosphonobisamidate
prodrugs of PMDTA led to a boost in antiviral potency. The most potent
congeners were a l-aspartic acid diisoamyl ester phenoxy
prodrug and a l-phenylalanine propyl ester phosphonobisamidate
prodrug that both display anti-HIV and anti-HBV activities in the
low nanomolar range and selectivity indexes of more than 300
Imidazopyridine- and Purine-Thioacetamide Derivatives: Potent Inhibitors of Nucleotide Pyrophosphatase/Phosphodiesterase 1 (NPP1)
Nucleotide
pyrophosphatase/phosphodiesterase 1 (NPP1) belongs to
the family of ecto-nucleotidases, which control extracellular nucleotide,
nucleoside, and (di)phosphate levels. To study the (patho)physiological
roles of NPP1 potent and selective inhibitors with drug-like properties
are required. Therefore, a compound library was screened for NPP1
inhibitors using a colorimetric assay with <i>p</i>-nitrophenyl
5′-thymidine monophosphate (<i>p</i>-Nph-5′-TMP)
as an artificial substrate. This led to the discovery of 2-(3<i>H</i>-imidazo[4,5-<i>b</i>]pyridin-2-ylthio)-<i>N</i>-(3,4-dimethoxyphenyl)acetamide (<b>5a</b>) as a
hit compound with a <i>K</i><sub>i</sub> value of 217 nM.
Subsequent structure–activity relationship studies led to the
development of purine and imidazo[4,5-<i>b</i>]pyridine
analogues with high inhibitory potency (<i>K</i><sub>i</sub> values of 5.00 nM and 29.6 nM, respectively) when assayed with <i>p</i>-Nph-5′-TMP as a substrate. Surprisingly, the compounds
were significantly less potent when tested versus ATP as a substrate,
with <i>K</i><sub>i</sub> values in the low micromolar range.
A prototypic inhibitor was investigated for its mechanism of inhibition
and found to be competitive versus both substrates
Amidate Prodrugs of Deoxythreosyl Nucleoside Phosphonates as Dual Inhibitors of HIV and HBV Replication
The
synthesis of four l-2′-deoxy-threose nucleoside
phosphonates with the natural nucleobases adenine, thymine, cytosine,
and guanosine has been performed. Especially the adenine containing
analogue (PMDTA) was endowed with potent antiviral activity displaying
an EC<sub>50</sub> of 4.69 μM against HIV-1 and an EC<sub>50</sub> value of 0.5 μM against HBV, whereas completely lacking cytotoxicity.
The synthesis of a number of phosphonomonoamidate and phosphonobisamidate
prodrugs of PMDTA led to a boost in antiviral potency. The most potent
congeners were a l-aspartic acid diisoamyl ester phenoxy
prodrug and a l-phenylalanine propyl ester phosphonobisamidate
prodrug that both display anti-HIV and anti-HBV activities in the
low nanomolar range and selectivity indexes of more than 300
Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents
Cyclin
G associated kinase (GAK) emerged as a promising drug target
for the treatment of viral infections. However, no potent and selective
GAK inhibitors have been reported in the literature to date. This
paper describes the discovery of isothiazolo[5,4-<i>b</i>]pyridines as selective GAK inhibitors, with the most potent congeners
displaying low nanomolar binding affinity for GAK. Cocrystallization
experiments revealed that these compounds behaved as classic type
I ATP-competitive kinase inhibitors. In addition, we have demonstrated
that these compounds exhibit a potent activity against hepatitis C
virus (HCV) by inhibiting two temporally distinct steps in the HCV
life cycle (i.e., viral entry and assembly). Hence, these GAK inhibitors
represent chemical probes to study GAK function in different disease
areas where GAK has been implicated (including viral infection, cancer,
and Parkinson’s disease)
Optimization of Isothiazolo[4,3‑<i>b</i>]pyridine-Based Inhibitors of Cyclin G Associated Kinase (GAK) with Broad-Spectrum Antiviral Activity
There is an urgent need for strategies
to combat dengue and other
emerging viral infections. We reported that cyclin G-associated kinase
(GAK), a cellular regulator of the clathrin-associated host adaptor
proteins AP-1 and AP-2, regulates intracellular trafficking of multiple
unrelated RNA viruses during early and late stages of the viral lifecycle.
We also reported the discovery of potent, selective GAK inhibitors
based on an isothiazolo[4,3-<i>b</i>]pyridine scaffold,
albeit with moderate antiviral activity. Here, we describe our efforts
leading to the discovery of novel isothiazolo[4,3-<i>b</i>]pyridines that maintain high GAK affinity and selectivity.
These compounds demonstrate improved in vitro activity
against dengue virus, including in human primary dendritic cells,
and efficacy against the unrelated Ebola and chikungunya viruses.
Moreover, inhibition of GAK activity was validated as an important
mechanism of antiviral action of these compounds. These findings demonstrate
the potential utility of a GAK-targeted broad-spectrum approach for
combating currently untreatable emerging viral infections