ABSTRACT
ß-Elemene, a compound extracted from Chinese herb Curcuma wenyujin, has been demonstrated with antitumor effects in various cancers, including glioblastoma (GBM), a primary brain tumor with high morbidity and mortality. In this study, we reported a bisamino derivative of ß-Elemene, 2, 2'-((1R, 3R, 4S)-4-methyl-4-vinylcyclohexane-1, 3-diyl) bis(prop-2-en-1-amine) (compound 1), displayed a better anti-GBM effect than ß-Elemene with lower concentration. GBM cell lines (C6 and U87) were treated with compound 1 and subsequently analyzed by several assays. Compound 1 significantly inhibited the migration of C6 and U87 cells based on wound healing assay, transwell assay and inverted migration assay. Furthermore, colony formation assay, immunostaining and flow cytometry assays revealed that compound 1 significantly inhibited the proliferation of GBM cells. In addition, compound 1 induced the apoptosis of GBM cells. Mechanistically, we found Yes-associated protein (YAP) was down-regulated in compound 1-treated GBM cells, and the overexpression of YAP partially rescued the anti-GBM effects of compound 1. Finally, compound 1 suppresses the GBM growth in xenograft model through inactivation YAP signaling. Taken together, these results reveal that a novel derivative of ß-Elemene, compound 1, exhibits more potent anti-GBM activity than ß-Elemene through inactivating YAP signaling pathway, which will provide novel strategies for the treatment of GBM.
ABSTRACT
Herein, we report the first access of ß-elemene derivatives through the SeO2-mediated oxidation reaction. Several new compounds were isolated through such a one-step reaction, and their structures were elucidated using various 2D-NMR techniques. This method provides easy access to multiple oxidative ß-elemene derivatives in one single step and represents the first modifications on cyclohexyl ring of ß-elemene. It is expected to open up the opportunity for future derivatization on cyclohexyl ring of ß-elemene. The new compounds obtained above showed better anti-proliferation activities than ß-elemene itself on several cancer cell lines. Among them, compound 17 shows the best activity in antiproliferation assays of A549 and U-87MG cell lines.
ABSTRACT
BACKGROUND: Many human diseases are associated with dysregulation of HDACs. HDAC6 exhibits deacetylase activity not only to histone protein but also to non-histone proteins such as α- tubulin, HSP90, cortactin, and peroxiredoxin. These unique functions of HDAC6 have gained significant attention in the medicinal chemistry community in recent years. Thus a great deal of effort has devoted to developing selective HDAC6 inhibitors for therapy with the hope to minimize the side effects caused by pan-HDAC inhibition. OBJECTIVE: The review intends to analyze the structural feature of the scaffolds, to provide useful information for those who are interested in this field, as well as to spark the future design of the new inhibitors. METHODS: The primary tool used for patent searching is SciFinder. All patents are retrieved from the following websites: the World Intellectual Property Organization (WIPO®), the United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. The years of patents covered in this review are between 2016 and 2019. RESULTS: Thirty-six patents from seventeen companies/academic institutes were classified into three categories based on the structure of ZBG: hydroxamic acid, 1,3,4-oxadiazole, and 1,2,4-oxadiazole. ZBG connects to the cap group through a linker. The cap group can tolerate different functional groups, including amide, urea, sulfonamide, sulfamide, etc. The cap group appears to modulate the selectivity of HDAC6 over other HDAC subtypes. CONCLUSION: Selectively targeting HDAC6 over other subtypes represents two fold advantages: it maximizes the pharmacological effects and minimizes the side effects seen in pan-HDAC inhibitors. Many small molecule selective HDAC6 inhibitors have advanced to clinical studies in recent years. We anticipate the approval of selective HDAC6 inhibitors as therapeutic agents in the near future.
Subject(s)
Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Patents as Topic , Drug Development , Histone Deacetylase 6/physiology , Histone Deacetylase Inhibitors/adverse effects , HumansABSTRACT
Economic and practical advantages are offered by the iron(III)-catalyzed and air-mediated tandem coupling/hydroarylation/dehydrogenation of simple readily available aldehydes, alkynes, and amines for the synthesis of 2, 4-disubstituted quinolines (see scheme).
