Seliciclib

Cerebral edema is one of the deadliest complications of ischemic stroke for which there is currently no pharmaceutical treatment. Aquaporin‐4 (AQP4), a water‐channel polarized at the astrocyte endfoot, is known to be highly implicated in cerebral edema. We previously showed in randomized studies that (S)‐roscovitine, a cyclin‐dependent kinase inhibitor, reduced cerebral edema 48 h after induction of focal transient ischemia, but its mechanisms of action were unclear. In our recent blind randomized study, we confirmed that (S)‐roscovitine was able to reduce cerebral edema by 65% at 24 h post‐stroke (t test, p = .006). Immunofluorescence analysis of AQP4 distribution in astrocytes revealed that (S)‐roscovitine decreased the non‐perivascular pool of AQP4 by 53% and drastically increased AQP4 clusters in astrocyte perivascular end‐feet (671%, t test p = .005) compared to vehicle. Non‐perivascular and clustered AQP4 compartments were negatively correlated (R = −0.78; p < .0001), suggesting a communicating vessels effect between the two compartments. α1‐syntrophin, AQP4 anchoring protein, was colocalized with AQP4 in astrocyte endfeet, and this colocalization was maintained in ischemic area as observed on confocal microscopy. Moreover, (S)‐roscovitine increased AQP4/α1‐syntrophin interaction (40%, MW p = .0083) as quantified by proximity ligation assay. The quantified interaction was negatively correlated with brain edema in both treated and placebo groups (R = −.57; p = .0074). We showed for the first time, that a kinase inhibitor modulated AQP4/α1‐syntrophin interaction, and was implicated in the reduction of cerebral edema. These findings suggest that (S)‐roscovitine may hold promise as a potential treatment for cerebral edema in ischemic stroke and as modulator of AQP4 function in other neurological diseases.

A hypoxic environment occurs predominantly in tumors. During the growth phase of a tumor, it grows until it exceeds its blood supply, leaving regions of the tumor in which the oxygen pressure is dramatically low. They are virtually absent in normal tissues, thus creating perfect conditions for selective bioreductive therapy of tumors. To this aim, a novel series of cytotoxic radiosensitizer agents were synthesized by linking the nitroimidazole scaffold with oxadiazole or triazole rings. The majority of the compounds exhibited moderate to excellent antiproliferative activities toward HCT116 cell line under normoxic and hypoxic conditions. The structure–activity relationship study revealed that compounds containing the free thiol group either in the oxadiazoles 11a,b or the triazoles 21a,b–23a,b demonstrated the strongest antiproliferative activity, which proves that the free thiol group plays a crucial role in the antiproliferative activity of our compounds under both normoxic (half‐maximal inhibitory concentration [IC50] = 12.50–24.39 µM) and hypoxic conditions (IC50 = 4.69–11.56 µM). Radiosensitizing assay of the four most active cytotoxic compounds 11b and 21–23b assured the capability of the compounds to enhance the sensitivity of the tumor cells to the DNA damaging activity of γ‐radiation (IC50 = 2.23–5.18 µM). To further investigate if the cytotoxicity of our most active compounds was due to a specific signaling pathway, the online software SwissTargetPrediction was exploited and a molecular docking study was done that proposed cyclin‐dependent kinase 2 (CDK2) enzyme to be the most promising target. The CDK2 inhibitory assay assured this assumption as five out of six compounds demonstrated a comparable inhibitory activity with roscovitine, among which compound 21b showed threefold more potent inhibitory activity in comparison with the reference compound. A further biological evaluation proved compound 21b to have an apoptotic activity and cell cycle arrest activity at the G1 and S phases. During the AutoQSAR analysis, the model demonstrated excellent regression between the predicted and experimental activity with r2 = 0.86. Subsequently, we used the model to predict the activity of the test set compounds that came with r2 = 0.95.