No abstract

The ganglioside GM1 has neuroprotective effects but is not of therapeutic value because of its lack of bioavailability. Thus, molecules that mimic GM1 represent a novel approach to neuroprotection. We have synthesized 19 small GM1-like analogues whose simplified structure includes a hydrophobic saturated or unsaturated moiety linked to a hydrophilic moiety. We report their neuroprotective effects in two distinct models of nerve cell death using hippocampus-derived HT22 cells. We found that several analogues protected the HT22 cells from death at concentrations ranging from 2 to 5 microM. Additional neuroprotective assays using cortical slices injured by glutamate confirmed these results. Since members of the MAP kinase family are known to be key players in nerve cell survival and death, we characterized the role of these kinases in the neuroprotective mechanisms of the GM1-like analogues. Interestingly, the results indicate that the compounds provide neuroprotection through distinct mechanisms of action.

magnified imageThe synthesis of a series of bis‐8‐hydroxyquinoline‐ and bis‐8‐hydroxyquinaldine‐substituted N‐benzyl or thiophenyl amines and their corresponding bis‐8‐hydroxyquinoline is reported. In vitro growth inhibitory effects of both series have been evaluated. It has been observed that analogs from the bis‐8‐hydroxyquinoline series exert nanomolar range activity, whereas the antiproliferative activity of the corresponding analogs from the bis‐8‐hydroxyquinaldine series was found to be drastically lower. Molecular docking and chemical–physical properties account for these observed growth inhibitory differences between the two series of analogs, which differ only by the presence of a methyl group at the 2 position of the heterocyclic ring. J. Heterocyclic Chem., (2010).

Gliomas account for 5% to 7% of all solid cancers in adults and up to 30% of solid cancers in children; glioblastomas are the most malignant type of glioma and often have dismal prognoses. The alkylating agent temozolomide provides the greatest chemotherapeutic benefits currently available; however, glioblastoma patients cannot be cured. Novel drugs that efficiently combat glioblastomas are therefore of great interest. We report here that JLK1486, an 8-hydroxyquinoline-substituted benzylamine, could represent a novel chemical scaffold to reach this goal. Indeed, JLK1486 mediated anticancer activity in vivo (through intravenous as well as oral routes of administrations) in an orthotopic xenograft model and displayed efficiency similar to that of temozolomide. The therapeutic benefits of JLK1486 seem to relate to its ability to activate various transcription factors (including Myt1, STAT1, and peroxisome proliferator-activated receptor γ) in glioma cells. These transcription factors are implicated in the control of glioma cell proliferation, and the resultant global effect of their activation by JLK1486 was cytostatic, not cytotoxic. Thus, the current study opens the door for the development of novel compounds to combat glioblastoma using 8-hydroxyquinoline benzylamine analogs.