Design and Synthesis of Novel Betulin Derivatives Containing Thio-/Semicarbazone Moieties as Apoptotic Inducers through Mitochindria-Related Pathways

Abstract

Two new series of betulin derivatives with semicarbazone (7a–g) or thiosemicarbazone (8a–g) groups at the C-28 position were synthesized. All compounds were evaluated for their in vitro cytotoxicities in human hepatocellular carcinoma cells (HepG2), human breast carcinoma cells (MCF-7), human lung carcinoma cells (A549), human colorectal cells (HCT-116) and normal human gastric epithelial cells (GES-1). Among these compounds, 8f displayed the most potent cytotoxicity with an IC50 value of 5.86 ± 0.61 μM against MCF-7 cells. Furthermore, the preliminary mechanism studies in MCF-7 cells showed that compound 8f could trigger the intracellular mitochondrial-mediated apoptosis pathway by losing MMP level, which was related with the upregulation of Bax, P53 and cytochrome c expression; the downregulation of Bcl-2 expression; activation of the expression levels of caspase-3, caspase-9, cleaved caspase-3 and cleaved caspase-9; and an increase in the amounts of intracellular reactive oxygen species. These results indicated that compound 8f may be used as a valuable skeleton structure for developing novel antitumor agents.

Synthesis, Pharmacological Properties, and Potential Molecular Mechanisms of Antitumor Activity of Betulin and Its Derivatives in Gastrointestinal Cancers

“…In contrast, in an experiment conducted by Wang et al [ 79 ], betulin derivatives containing a thio/-semicabazone group showed low cytotoxic activity against colon cancer cells of the HCT-116 line. Interestingly, only the obtained derivative lup-20(29)-ene-3β-ol-28-N-((3-trifluoromethyl-4-chloro)phenyl)semicarbazide 20g displayed significant cytotoxic activity against the CRC line [ 79 ].…”

“…Studies of the cytotoxic effect on HCT-116 cells conducted for this group of derivatives showed that the hydrazide and hydrazine derivatives containing a 4-trifluoromethylphenyl substituent ( 22d and 23h ) were the most active (IC 50 equal to 13.70 and 12.55 μM). Derivatives containing the pyridine ring 22i (IC 50 = 9.30 μM) and 23k (IC 50 = 9.32 μM) had the strongest effects on human hepatocellular carcinoma cells (HepG2) [ 79 , 80 , 81 ].…”

“…Interestingly, only the obtained derivative lup-20(29)-ene-3β-ol-28-N-((3-trifluoromethyl-4-chloro)phenyl)semicarbazide 20g displayed significant cytotoxic activity against the CRC line [ 79 ]. This may indicate that the introduction of the thiosemicarbazide grouping has a minor effect on colorectal cancer, which may be due to a different expression profile of receptors on the cell surface or impaired transport across the cell membrane [ 79 ].…”

New Betulin Derivatives with Nitrogen Heterocyclic Moiety—Synthesis and Anticancer Activity In Vitro

“…Betulin ( Figure 1 ), pentacyclic lupane-structure triterpenoid which occurs abundantly in the birch bark, is one such compound since it has been shown to inhibit growth and migration as well as induce apoptosis of various types of cancer cells. Moreover, betulin can been utilized as a precursor compound for the synthesis of novel derivatives with improved pharmacological properties and potential use in cancer treatment [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”

N-Rich, Polyphenolic Porous Organic Polymer and Its In Vitro Anticancer Activity on Colorectal Cancer

“…Covalently bonded networks of POPs are utilized in various biomedical applications because of their cell penetration compatibility, cell viability, and large-scale synthesis facilities [ 26 , 27 , 28 ]. Anticancer activity studies have been carried out on a colorectal carcinoma cell line (HCT 116), where these porous nanomaterials act as cell destroyer or drug delivery systems [ 29 , 30 , 31 ]. Functionalized POP materials having small particle sizes mean they are effective for target-specific cell death.…”