Medicinal chemistry approaches to target the MNK-eIF4E axis in cancer.

Aberrant translation of proteins that promote cell proliferation is an essential factor that defines oncogenic processes and cancer. The process for ribosomal translation of proteins from mRNA requires an essential initiation step which is controlled by the protein eIF4E, which binds the RNA 5'-cap and forms the eIF4F complex that subsequently translates protein. Typically, eIF4E is activated by phosphorylation on Ser209 by MNK1 and MNK2 kinases.

Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer.

Chemoenzymatic route to stereodefined 2-(azidophenyl)oxazolines for click chemistry.

Aryl-substituted esters of a racemic diprotected 2-azido-1-alkanol were submitted to the Staudinger/aza-Wittig reaction in order to assess scope and establish conditions for their cyclization to the corresponding 2,4,5-trisubstituted oxazolines. Following the cyclization study, the (2,3)-antipode of the azidoalkanol was obtained in high ee by incubation of the corresponding racemic azidoacetate with pig liver esterase (PLE). The -nitrobenzoate of the enantioenriched 2-azido-1-alcohol was cyclized by the Staudinger/aza-Wittig to give the corresponding (4,5)-disubstituted-2-(4-nitrophenyl) oxazoline.

Applicability of aluminum amalgam to the reduction of arylnitro groups.

An array of arylnitro compounds with various functionality were treated with freshly-prepared aluminum amalgam in THF/water solution and resulted in the corresponding arylamines. The Al(Hg)-mediated reductions are relatively rapid with consumption of the amalgam and disappearance of starting material occurring over 20-30 minutes. The workup of the reductions involves only removal of the insoluble by-products by filtration followed by concentration.

Antiangiogenic Activity and Chemical Derivatization of the Neurotoxic Acetogenin Annonacin Isolated from Asimina triloba.

Annonacin (1) was isolated from the North American pawpaw ( Asimina triloba), as reported earlier from these laboratories. Natural 1 was submitted to the rat aortic ring bioassay for evaluation of antiangiogenic activity and was found to inhibit microvessel growth (IC value of 3 μM). 4,10,15,20-Tetraazido derivatives of 1 were prepared by permesylation followed by azide displacement or by iodination followed by azide displacement.