Diselenide Covalent Allosteric Inhibitors of Glutaminase with Strong Anticancer Activity.

Allosteric glutaminase inhibitors demonstrate inhibition of glutamine-dependent cancer cells with low general drug toxicity, but have issues with efficacy . Here, we designed a series of diselenide compounds with 6 atoms in the middle, aiming to target the allosteric site of kidney type glutaminase (KGA) with a covalent linkage to strengthen the interaction. Proteomic analysis demonstrated that the diselenide compounds cross-linked with the Lys320 residue at the KGA allosteric site; this was confirmed by the KGA K320A mutant which showed essentially no binding to the diselenide.

Novel 1,3,4-Selenadiazole-Containing Kidney-Type Glutaminase Inhibitors Showed Improved Cellular Uptake and Antitumor Activity.

Kidney-type glutaminase [KGA/isoenzyme glutaminase C (GAC)] is becoming an important tumor metabolism target in cancer chemotherapy. Its allosteric inhibitor, CB839, showed early promise in cancer therapeutics but limited efficacy in in vivo cancer models. To improve the in vivo activity, we explored a bioisostere replacement of the sulfur atom in bis-2-(5-phenylacetamido-1,2,4-thiadiazol)ethyl sulfide and CB839 analogues with selenium using a novel synthesis of the selenadiazole moiety from carboxylic acids or nitriles.

Identification of a diverse synthetic abietane diterpenoid library and insight into the structure-activity relationships for antibacterial activity.

A diverse natural product-like (NPL) synthetic abietane diterpenoid library containing 86 compounds were obtained and the SARs were studied based on their antibacterial potential. Further in vitro cytotoxic and in silico drug-like properties evaluation showed that the potent antibacterial compound 84 had good drug-like properties and displayed low cytotoxicity toward noncancerous mammalian cells, indicating the study of AA and DHAA might be a good starting point for the search of novel antimicrobial molecules. Future work should be focused on the optimization of their potency and selectivity.

Ebselen: Mechanisms of Glutamate Dehydrogenase and Glutaminase Enzyme Inhibition.

Ebselen modulates target proteins through redox reactions with selenocysteine/cysteine residues, or through binding to the zinc finger domains. However, a recent contradiction in ebselen inhibition of kidney type glutaminase (KGA) stimulated our interest in investigating its inhibition mechanism with glutamate dehydrogenase (GDH), KGA, thioredoxin reductase (TrxR), and glutathione S-transferase. Fluorescein- or biotin-labeled ebselen derivatives were synthesized for mechanistic analyses.

Click chemistry-based synthesis and anticancer activity evaluation of novel C-14 1,2,3-triazole dehydroabietic acid hybrids.

A concise and efficient synthetic approach has been established to readily access a series of novel C-14 1,2,3-triazole-tethered dehydroabietic acid derivatives in moderate to high yields. In vitro antiproliferative activity evaluation indicated that most of the hybrids exhibited potent inhibitory activities in a variety of cancer cell lines with low micromolar to submicromolar IC values. Further studies demonstrated that some of these analogues such as 20, 21, and 24 were also effective against adriamycin-resistant MCF-7 clone at low concentrations in a dose-dependent manner.