11 research outputs found
Isoquinoline-1,3-diones as Selective Inhibitors of Tyrosyl DNA Phosphodiesterase II (TDP2)
Tyrosyl DNA phosphodiesterase II
(TDP2) is a recently discovered
enzyme that specifically repairs DNA damages induced by topoisomerase
II (Top2) poisons and causes resistance to these drugs. Inhibiting
TDP2 is expected to enhance the efficacy of clinically important Top2-targeting
anticancer drugs. However, TDP2 as a therapeutic target remains poorly
understood. We report herein the discovery of isoquinoline-1,3-dione
as a viable chemotype for selectively inhibiting TDP2. The initial
hit compound <b>43</b> was identified by screening our in-house
collection of synthetic compounds. Further structure–activity
relationship (SAR) studies identified numerous analogues inhibiting
TDP2 in low micromolar range without appreciable inhibition against
the homologous TDP1 at the highest testing concentration (111 μM).
The best compound <b>64</b> inhibited recombinant TDP2 with
an IC<sub>50</sub> of 1.9 μM. The discovery of this chemotype
may provide a platform toward understanding TDP2 as a drug target
Synthesis and Biological Evaluation of Nitrated 7‑, 8‑, 9‑, and 10-Hydroxyindenoisoquinolines as Potential Dual Topoisomerase I (Top1)–Tyrosyl-DNA Phosphodiesterase I (TDP1) Inhibitors
The
structure–activity relationships and hit-to-lead optimization
of dual Top1–TDP1 inhibitors in the indenoisoquinoline drug
class were investigated. A series of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines
were synthesized and evaluated. Several compounds displayed potent
dual Top1–TDP1 inhibition. The 9-hydroxy series exhibited potencies
and cytotoxicities vs Top1 that surpassed those of camptothecin (CPT),
the natural alkaloid that is being used as a standard in the Top1-mediated
DNA cleavage assay. One member of this series was a more potent Top1
inhibitor at a concentration of 5 nM and produced a more stable ternary
drug–DNA–Top1 cleavage complex than CPT
Discovery of Potent Indenoisoquinoline Topoisomerase I Poisons Lacking the 3‑Nitro Toxicophore
3-Nitroindenoisoquinoline
human topoisomerase IB (Top1) poisons
have potent antiproliferative effects on cancer cells. The undesirable
nitro toxicophore could hypothetically be replaced by other functional
groups that would retain the desired biological activities and minimize
potential safety risks. Eleven series of indenoisoquinolines bearing
3-nitro bioisosteres were synthesized. The molecules were evaluated
in the Top1-mediated DNA cleavage assay and in the National Cancer
Institute’s 60 cell line cytotoxicity assay. The data reveal
that fluorine and chlorine may substitute for the 3-nitro group with
minimal loss of Top1 poisoning activity. The new information gained
from these efforts can be used to design novel indenoisoquinolines
with improved safety
Investigation of the Structure–Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons
Several indenoisoquinolines
have shown promise as anticancer agents
in clinical trials. Incorporation of a nitrogen atom into the indenoisoquinoline
scaffold offers the possibility of favorably modulating ligand-binding
site interactions, physicochemical properties, and biological activities.
Four series of aza-A-ring indenoisoquinolines were synthesized in
which the nitrogen atom was systematically rotated through positions
1, 2, 3, and 4. The resulting compounds were tested to establish the
optimal nitrogen position for topoisomerase IB (Top1) enzyme poisoning
activity and cytotoxicity to human cancer cells. The 4-aza compounds
were the most likely to yield derivatives with high Top1 inhibitory
activity. However, the relationship between structure and cytotoxicity
was more complicated since the potency was influenced strongly by
the side chains on the lactam nitrogen. The most cytotoxic azaindenoisoquinolines <b>45</b> and <b>46</b> had nitrogen in the 2- or 3-positions
and a 3′-dimethylaminopropyl side chain, and they had MGM GI<sub>50</sub> values that were slightly better than the corresponding
indenoisoquinoline <b>64</b>
Investigation of the Structure–Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons
Several indenoisoquinolines
have shown promise as anticancer agents
in clinical trials. Incorporation of a nitrogen atom into the indenoisoquinoline
scaffold offers the possibility of favorably modulating ligand-binding
site interactions, physicochemical properties, and biological activities.
Four series of aza-A-ring indenoisoquinolines were synthesized in
which the nitrogen atom was systematically rotated through positions
1, 2, 3, and 4. The resulting compounds were tested to establish the
optimal nitrogen position for topoisomerase IB (Top1) enzyme poisoning
activity and cytotoxicity to human cancer cells. The 4-aza compounds
were the most likely to yield derivatives with high Top1 inhibitory
activity. However, the relationship between structure and cytotoxicity
was more complicated since the potency was influenced strongly by
the side chains on the lactam nitrogen. The most cytotoxic azaindenoisoquinolines <b>45</b> and <b>46</b> had nitrogen in the 2- or 3-positions
and a 3′-dimethylaminopropyl side chain, and they had MGM GI<sub>50</sub> values that were slightly better than the corresponding
indenoisoquinoline <b>64</b>
Advanced Monitoring Is Associated with Fewer Alarm Events During Planned Moderate Procedure-Related Sedation
BackgroundDiagnostic and interventional procedures are often facilitated by moderate procedure-related sedation. Many studies support the overall safety of this sedation; however, adverse cardiovascular and respiratory events are reported in up to 70% of these procedures, more frequently in very young, very old, or sicker patients. Monitoring with pulse oximetry may underreport hypoventilation during sedation, particularly if supplemental oxygen is provided. Capnometry may result in false alarms during sedation when patients mouth breathe or displace sampling devices. Advanced monitor use during sedation may allow event detection before complications develop. This 2-part pilot study used advanced monitors during planned moderate sedation to (1) determine incidences of desaturation, low respiratory rate, and deeper than intended sedation alarm events; and (2) determine whether advanced monitor use is associated with fewer alarm events.MethodsAdult patients undergoing scheduled gastroenterology or interventional radiology procedures with planned moderate sedation given by dedicated sedation nurses under the direction of procedural physicians (procedural sedation team) were monitored per standard protocols (electrocardiography blood pressure, pulse oximetry, and capnometry) and advanced monitors (acoustic respiratory monitoring and processed electroencephalograpy). Data were collected to computers for analysis. Advanced monitor parameters were not visible to teams in part 1 (standard) but were visible to teams in part 2 (advanced). Alarm events were defined as desaturation-SpO2 ≤92%; respiratory depression, acoustic respiratory rate ≤8 breaths per minute, and deeper than intended sedation, indicated by processed electroencephalograpy. The number of alarm events was compared.ResultsOf 100 patients enrolled, 10 were excluded for data collection computer malfunction or consent withdrawal. Data were analyzed from 90 patients (44 standard and 46 advanced). Advanced had fewer total alarms than standard (Wilcoxon-Mann-Whitney = 2.073, P = 0.038; Wilcoxon-Mann-Whitney odds, 1.67; 95% confidence interval [CI], 1.04-2.88). Similar numbers of standard and advanced had ≥1 alarm event (Wald difference, -10.2%; 95% CI, -26.4% to 7.0%; P = 0.237). Fewer advanced patients had ≥1 respiratory depression event (Wald difference, -22.1%; 95% CI, -40.9% to -2.4%; P = 0.036) or ≥1 desaturation event (Wald difference, -24.2%; 95% CI, -42.8% to -3.6%; P = 0.021); but there was no significant difference in deeper than intended sedation events (Wald difference, -1.38%; 95% CI, -20.21% to 17.49%; P = 0.887).ConclusionsUse of advanced monitoring parameters during planned moderate sedation was associated with fewer alarm events, patients experiencing desaturation, and patients experiencing respiratory depression alarm events. This pilot study suggests that further study into the safety and outcome impacts of advanced monitoring during procedure-related sedation is warranted