106566-02-3Relevant articles and documents
Synthesis of chiral α-amino-diazoketones on solid support: An access to β-homologated amino acid derivatives
Cantel, Sonia,Martinez, Jean,Fehrentz, Jean-Alain
, p. 2791 - 2793 (2004)
Diazoketone derivatives were obtained on solid support from their corresponding α-amino acids anchored by their N-terminus to the resin. A complete study was performed to optimize the two steps process of this synthesis on solid support: activation of the carboxylic acid function followed by reaction with diazomethane. The obtained diazoketones were then submitted to Wolff rearrangement in the presence of an amine to yield the corresponding homologated amides or in the presence of water to yield the corresponding β-homologated amino acids.
PROTEASOME INHIBITORS
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Paragraph 0207-0208; 0209, (2019/11/19)
The disclosure provides proteasome inhibitors that can be used to halt cell division of rapidly dividing cells by preventing the degradation of cell cycle-regulating proteins, such as cyclins, cyclin-dependent kinase inhibitors, and p53. The proteasome in
Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors
Niroula, Doleshwar,Hallada, Liam P.,Le Chapelain, Camille,Ganegamage, Susantha K.,Dotson, Devon,Rogelj, Snezna,Groll, Michael,Tello-Aburto, Rodolfo
supporting information, p. 962 - 977 (2018/09/04)
The peptidic β-lactone proteasome inhibitors (PIs) cystargolides A and B were used to conduct structure-activity relationship (SAR) studies in order to assess their anticancer potential. A total of 24 different analogs were designed, synthesized and evaluated for proteasome inhibition, for cytotoxicity towards several cancer cell lines, and for their ability to enter intact cells. X-ray crystallographic analysis and subunit selectivity was used to determine the specific subunit binding associated with the structural modification of the β-lactone (P1), peptidic core, (Px and Py), and end-cap (Pz) of our scaffold. The cystargolide derivative 5k, structurally unique at both Py and P1, exhibited the most promising inhibitory activity for the β5 subunit of human proteasomes (IC50 = 3.1 nM) and significant cytotoxicity towards MCF-7 (IC50 = 416 nM), MDA-MB-231 (IC50 = 74 nM) and RPMI 8226 (IC50 = 41 nM) cancer cell lines. Cellular infiltration assays revealed that minor structural modifications have significant effects on the ability of our PIs to inhibit intracellular proteasomes, and we identified 5k as a promising candidate for continued therapeutic studies. Our novel drug lead 5k is a more potent proteasome inhibitor than carfilzomib with mid-to-low nanomolar IC50 measurements and it is cytotoxic against multiple cancer cell lines at levels approaching those of carfilzomib.