Urea-Modified Self-Assembling Peptide Amphiphiles That Form Well-Defined Nanostructures and Hydrogels for Biomedical Applications.

Hydrogen bonding plays a critical role in the self-assembly of peptide amphiphiles (PAs). Herein, we studied the effect of replacing the amide linkage between the peptide and lipid portions of the PA with a urea group, which possesses an additional hydrogen bond donor. We prepared three PAs with the peptide sequence Phe-Phe-Glu-Glu (FFEE): two are amide-linked with hydrophobic tails of different lengths and the other possesses an alkylated urea group.

Structure activity relationship (SAR) study identifies a quinoxaline urea analog that modulates IKKβ phosphorylation for pancreatic cancer therapy.

Genetic models validated Inhibitor of nuclear factor (NF) kappa B kinase beta (IKKβ) as a therapeutic target for KRAS mutation associated pancreatic cancer. Phosphorylation of the activation loop serine residues (S, S) in IKKβ is a key event that drives tumor necrosis factor (TNF) α induced NF-κB mediated gene expression. Here we conducted structure activity relationship (SAR) study to improve potency and oral bioavailability of a quinoxaline analog 13-197 that was previously reported as a NFκB inhibitor for pancreatic cancer therapy.

Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax.

Cyclin-dependent kinase 9 (CDK9) is a member of the cyclin-dependent kinase (CDK) family which is involved in transcriptional regulation of several genes, including the oncogene Myc, and is a validated target for pancreatic cancer. Here we report the development of an aminopyrazole based proteolysis targeting chimera (PROTAC 2) that selectively degrades CDK9 (DC = 158 ± 6 nM). Mass spectrometry-based kinome profiling shows PROTAC 2 selectively degrades CDK9 in MiaPaCa2 cells and sensitizes them to Venetoclax mediated growth inhibition.

Tricyclic Imidazolidin-4-ones by Witkop Oxidation of Tetrahydro-β-carbolines.

1-Substituted and 1,1-disubstituted tetrahydro-β-carbolines undergo sodium periodate oxidative ring expansion in the presence of formaldehyde and other aldehydes to form 5,6-dihydro-7-1,4-methanobenzo[][1,4]diazonine-2,7(3)-diones in 30-81% yield. In most cases, the reaction to form this new 6/8/5-tricyclic ring system proceeds with high diastereoselectivity. These benzannulated medium-ring keto imidazolidin-4-ones expand the menu of tetrahydro-β-carboline oxidation products.

Synthesis of 2-Azaadamantan-6-one: A Missing Isomer.

2-Azaadamantan-6-one and its Boc and ethylene ketal derivatives were synthesized from 9-oxo -bicyclo[3.3.1]non-6-ene-3-carboxylic acid.