An unusual reaction with Grubbs’ catalyst during the synthesis of bridged epothilones yielded five-membered internal lactones instead of the expected metathesis products. Three of the lactones have comparable activities to epothilone D.
Dynamic histone lysine methylation involves the activities of modifying enzymes (writers), enzymes removing modifications (erasers) and readers of the histone code. One common feature of these activities is the recognition of lysines in methylated and unmethylated states, whether they are substrates, reaction products or binding partners. We applied the concept of adding a lysine mimic to an established inhibitor (BIX-01294) of histone H3 lysine 9 methyltransferases G9a and G9a-like protein (GLP) by including a 5-aminopentyloxy moiety, which is inserted into the target lysine-binding channel and becomes methylated by GLP, albeit slowly. The compound enhanced its potency in vitro and reduced cell toxicity in vivo. We suggest that adding a lysine or methyllysine mimic should be considered in the design of small molecule inhibitors for other methyl-lysine writers, erasers and readers.
Heat shock protein 90 is emerging as an important target in cancer chemotherapy. In a program directed towards identifying novel chemical probes for Hsp90, we found 4-hydroxy-3-(2-hydroxynapthalene-1-yl)phenyl)benzene sulfonamide as an Hsp90 inhibitor with very weak activity. In this report we present a new and general method for the synthesis of variety of analogs around this scaffold and discuss their structure activity relationships.
The molecular chaperone Hsp90 plays important roles in maintaining the malignant phenotypes. Recent studies suggest that Hsp90 exerts high affinity interactions with multiple oncoproteins, which are essential for the growth of tumor cells. As a result, research has been focused on finding Hsp90 probes as potential and selective anticancer agents. In a high-throughput screening exercise, we identified quinoline 7 as a moderate inhibitor of Hsp90. Further hit identification, SAR studies and biological investigation revealed several synthetic analogs in this series with micromolar activities in both fluorescent polarization (FP) assay and a cell-based western-blot (WB) assay. These compounds represent a new class of Hsp90 inhibitors with simple chemical structures.
Paclitaxel (Taxol ®) and docetaxel (Taxotere ®) are very important anti-tumor drugs in clinical use for cancer. However, their clinical utility is limited due to systemic toxicity, low solubility and inactivity against drug resistant tumors. To improve chemotherapeutic levels of these drugs, it would be highly desirable to design strategies which bypass the above limitations. In this respect various prodrug and drug targeting strategies have been envisioned either to improve oral bioavailability or tumor specific delivery of taxoids. Abnormal properties of cancer cells with respect to normal cells have guided in designing of these protocols. This review article records the designed biochemical strategies and their biological efficacies as potential taxoid chemotherapeutics.
Prostaglandin E2 is now widely recognized to play critical roles in brain inflammation and injury, although the responsible prostaglandin receptors have not been fully identified. We developed a potent and selective antagonist for the prostaglandin E2 receptor subtype EP2, TG6-10-1, with a sufficient pharmacokinetic profile to be used in vivo. We found that in the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood–brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. Our results suggest that the prostaglandin receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 receptor antagonism as an adjunctive therapeutic strategy to treat SE.
Activation of the Gαs-coupled EP2 receptor for prostaglandin E2 (PGE2) promotes cell survival in several models of tissue damage. To advance understanding of EP2 functions, we designed experiments to develop allosteric potentiators of this key prostaglandin receptor. Screens of 292,000 compounds identified 93 that at 20 μM (i) potentiated the cAMP response to a low concentration of PGE2 by > 50%; (ii) had no effect on EP4 or β2 adrenergic receptors, the cAMP assay itself, or the parent cell line; and (iii) increased the potency of PGE2 on EP2 receptors at least 3-fold. In aqueous solution, the active compounds are largely present as nanoparticles that appear to serve as active reservoirs for bioactive monomer. From 94 compounds synthesized or purchased, based on the modification of one hit compound, the most active increased the potency of PGE2 on EP2 receptors 4- to 5-fold at 10 to 20 μM and showed substantial neuroprotection in an excitotoxicity model. These small molecules represent previously undescribed allosteric modulators of a PGE2 receptor. Our results strongly reinforce the notion that activation of EP2 receptors by endogenous PGE2 released in a cell-injury setting is neuroprotective.
NADPH oxidases (Nox) are a primary source of reactive oxygen species (ROS), which function in normal physiology and, when overproduced, in pathophysiology. Recent studies using mice deficient in Nox2 identify this isoform as a novel target against Nox2-implicated inflammatory diseases. Nox2 activation depends on the binding of the proline-rich domain of its heterodimeric partner p22phox to p47phox. A high-throughput screen that monitored this interaction via fluorescence polarization identified ebselen and several of its analogs as inhibitors. Medicinal chemistry was performed to explore structure-activity relationships and to optimize potency. Ebselen and analogs potently inhibited Nox1 and Nox2 activity but were less effective against other isoforms. Ebselen also blocked translocation of p47phox to neutrophil membranes. Thus, ebselen and its analogs represent a class of compounds that inhibit ROS generation by interrupting the assembly of Nox2-activating regulatory subunits.