An efficient methodology for the synthesis of α-Kdo glycosidic bonds has been developed with 5,7-O-di-tert-butylsilylene (DTBS) protected Kdo ethyl thioglycosides as glycosyl donors. The approach permits a wide scope of acceptors to be used, thus affording biologically significant Kdo glycosides in good to excellent chemical yields with complete α-selectivity. The synthetic utility of an orthogonally protected Kdo donor has been demonstrated by concise preparation of two α-Kdo-containing oligosaccharides.
Proteostasis is the process of regulating intracellular proteins to maintain the balance of the cell proteome, which is crucial for cancer cell survival. Several proteases located in the cytoplasm, mitochondria, lysosome, and extracellular environment have been identified as potential antitumor targets because of their involvement in proteostasis. Although the discovery of small-molecule inhibitors targeting proteases faces particular challenges, rapid advances in chemical biology and structural biology, and the new technology of drug discovery have facilitated the development of promising protease modulators. In this review, the protein structure and function of important tumor-related proteases and their inhibitors are presented. We also provide a prospective on advances and the outlook of new drug strategies that target these proteases.
Homo sapiens caseinolytic protease
P (HsClpP) plays an important role in maintaining mitochondrial proteostasis.
Activating HsClpP has been proved to be a potential strategy for cancer
therapy. In this paper, a novel class of HsClpP agonists is designed
and synthesized using a position shift strategy based on the imipridone ONC201. Among these newly synthesized imipridone derivatives,
compound 16z exhibits remarkably enhanced antitumor activity
(IC50 = 0.04 μM against HCT116 cells). It can improve
HsClpP thermal stability and induce mitochondrial dysfunction, reactive
oxygen species production, cell cycle arrest in the G0/G1 phase, and
apoptosis of HCT116 cells. Moreover, compound 16z possesses
excellent pharmacokinetic profiles and significantly inhibits tumor
growth in HCT116 cell-inoculated xenograft nude mouse models. Our
study demonstrates that 16z has potential to be an antitumor
drug candidate for further development and provides insights for the
design of the next generation of HsClpP agonists for cancer treatment.
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