Synthesis of acyl oleanolic acid-uracil conjugates and their anti-tumor activity

Abstract

BackgroundOleanolic acid, which can be isolated from many foods and medicinal plants, has been reported to possess diverse biological activities. It has been found that the acylation of the hydroxyl groups of the A-ring in the triterpene skeleton of oleanolic acid could be favorable for biological activities. The pyrimidinyl group has been constructed in many new compounds in various anti-tumor studies.ResultsFive acyl oleanolic acid-uracil conjugates were synthesized. Most of the IC50 values of these conjugates were lower than 10.0 μM, and some of them were even under 0.1 μM. Cytotoxicity selectivity detection revealed that conjugate 4c exhibited low cytotoxicity towards the normal human liver cell line HL-7702. Further studies revealed that 4c clearly possessed apoptosis inducing effects, could arrest the Hep-G2 cell line in the G1 phase, induce late-stage apoptosis, and activate effector caspase-3/9 to trigger apoptosis.ConclusionsConjugates of five different acyl OA derivatives with uracil were synthesized and identified as possessing high selectivity toward tumor cell lines. These conjugates could induce apoptosis in Hep-G2 cells by triggering caspase-3/9 activity.Graphical abstractFive acyl oleanolic aicd-uracil conjugates were synthesized. These conjugates exhibited selective cytotoxicity toward tumor cells achieved via inducing apoptosis by activation of caspase-3/9. Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-016-0217-5) contains supplementary material, which is available to authorized users.

Cytotoxic and Antimigration Activity of Etlingera alba (A.D.) Poulsen Rhizome

“…Several compounds in fraction B, such as rengyolone [ 22 ], licochalcone A [ 23 ], sugiol [ 24 , 25 ], and spinasterol [ 26 ], have been known to have activity against cancer cells. For fraction E, thymine [ 27 ], aschantin [ 28 ], lirioresinol B dimethyl ether [ 29 ], and others have potency as anticancer, as well.…”

Recent advancements in Uracil and 5-Fluorouracil hybrids as potential anticancer agents: A review

“…Moreover, unlike other compounds, compound 71c was found to be the least cytotoxic to healthy liver cell line (HL-7702). Further cell cycle analysis depicted that compound 71c could trigger apoptosis by activating caspase-3/9 and arrest the G1 phase of HEP-G2 cells (Mo et al, 2016).…”

“…SAR studies of oleanolic acid showed that structural modification at C-3 and C-28 improves cytotoxic properties against prostate cancer (PC-3), lung cancer (A549), and breast cancer (MCF-7) cell lines (Hao et al, 2013). Being inspired by the evidence, Mo et al (2016) synthesized the conjugates of Acyl-oleanolic acid and Uracil. Synthetic pathway starts with the treatment of oleanolic acid (69) (1 equiv) with anhydride (1.5 equiv) and DMAP (0.1 equiv) in anhydrous CH 2 Cl 2 /pyridine at room temperature to yield 3-O-acyl derivatives (70a-c).…”

Anti-Cancer Potential of Synthetic Oleanolic Acid Derivatives and Their Conjugates with NSAIDs

“…Moreover, impairment of melanoma mitochondrial function was observed, in contrast to the effect observed in the non-tumor keratinocytes cell line [ 57 ]. High selectivity of conjugates with uracil, particularly in hepatoma HepG2 cells, in the induction of apoptosis (triggering caspase-3/9 activity), was claimed [ 58 ].…”