2 research outputs found
Microwave-Based Reaction Screening: Tandem Retro-Diels–Alder/Diels–Alder Cycloadditions of <i>o</i>-Quinol Dimers
We have accomplished a parallel screen of cycloaddition
partners
for <i>o</i>-quinols utilizing a plate-based microwave system.
Microwave irradiation improves the efficiency of retro-Diels–Alder/Diels–Alder
cascades of <i>o-</i>quinol dimers which generally proceed
in a diastereoselective fashion. Computational studies indicate that
asynchronous transition states are favored in Diels–Alder cycloadditions
of <i>o</i>-quinols. Subsequent biological evaluation of
a collection of cycloadducts has identified an inhibitor of activator
protein-1 (AP-1), an oncogenic transcription factor
Exploiting Drug-Resistant Enzymes as Tools To Identify Thienopyrimidinone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H
The
thienopyrimidinone 5,6-dimethyl-2-(4-nitrophenyl)ÂthienoÂ[2,3-<i>d</i>]Âpyrimidin-4Â(3<i>H</i>)-one (DNTP) occupies the
interface between the p66 ribonuclease H (RNase H) domain and p51
thumb of human immunodeficiency virus reverse transcriptase (HIV RT),
thereby inducing a conformational change incompatible with catalysis.
Here, we combined biochemical characterization of 39 DNTP derivatives
with antiviral testing of selected compounds. In addition to wild-type
HIV-1 RT, derivatives were evaluated with rationally designed, p66/p51
heterodimers exhibiting high-level DNTP sensitivity or resistance.
This strategy identified 3′,4′-dihydroxyphenyl (catechol)
substituted thienopyrimidinones with submicromolar in vitro activity
against both wild type HIV-1 RT and drug-resistant variants. Thermal
shift analysis indicates that, in contrast to active site RNase H
inhibitors, these thienopyrimidinones <i>destabilize</i> the enzyme, in some instances reducing the <i>T</i><sub>m</sub> by 5 °C. Importantly, catechol-containing thienopyrimidinones
also inhibit HIV-1 replication in cells. Our data strengthen the case
for allosteric inhibition of HIV RNase H activity, providing a platform
for designing improved antagonists for use in combination antiviral
therapy