Semisynthesis and biological evaluation of novel honokiol thioethers against colon cancer cells HCT116 via inhibiting the transcription and expression of YAP protein.

Honokiol, derived from Magnolia officinalis (a traditional Chinese medicine), has been reported to have anticancer activity. Here, a series of novel honokiol thioethers bearing a 1,3,4-oxadiazole moiety were prepared and evaluated for their anticancer activities against three types of digestive system tumor cells. Biological evaluation showed that honokiol derivative 3k exhibited the best antiproliferative activity against HCT116 cells with an IC50 value of 6.1 µmol/L, superior to the reference drug 5-fluorouracil (IC50: 9.63 ± 0.27 µmol/L). The structure-activity relationships (SARs) indicated that the introduction of -(4-NO2)Ph, 3-pyridyl, -(2-F)Ph, -(4-F)Ph, -(3-F)Ph, -(4-Cl)Ph, and -(3-Cl)Ph groups was favorable for enhancing the anticancer activity of the title honokiol thioethers. Further study revealed that honokiol thioether 3k can well inhibit the proliferation of colon cancer cells HCT116, arresting the cells in G1 phase and inducing cell death. Moreover, a preliminary mechanism study indicated that 3k directly inhibits the transcription and expression of YAP protein without activating the Hippo signaling pathway. Thus, honokiol thioether 3k could be deeply developed for the development of honokiol-based anticancer candidates.

Semisynthesis and neurotrophic activity studies of novel neomajucin/majucin derivatives as neurotrophin small molecule mimetics.

Majucin-type Illicium sesquiterpenes with potent neurotrophic activity are considered to be promising candidates for the treatment of various neurodegenerative disease. Owing to the low-abundance metabolites in Illicium genus, there are few studies on their structural modifications, structure-activity relationships, and pharmacophoric motif. Herein, structural modifications were conducted on the hydroxyl groups at C-3 and C-6 positions of two majucin-type compounds neomajucin (1) and majucin (2), and 39 neomajucin/majucin based esters were synthesized and evaluated for their neurite outgrowth-promoting activities. Among all the target derivatives, compounds 1a, 1j, 1r, 2b, 2d, 3a, 3b, 3d and 3h displayed more potent neurite outgrowth-promoting activity than their precursors. Some interesting structure-activity relationships (SARs) were also observed. Moreover, compound 1a showed good neuroprotective effect on MPP+-induced PC12 cell damage. Finally, compounds 1a and 3a exhibited relatively no cytotoxicity to normal human H9C2 cardiac cells. This work will shed light on the development of neomajucin/majucin derivatives as potential neurotrophic agents.