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.
Highlights
Oleanolic acid, which can be isolated from many foods and medicinal plants, has been reported to possess diverse biological activities
The struc‐ ture–activity relationships (SAR) analysis of oleanolic acid derivatives modified at C-3 and C-28 indicated that hydrogen-bond acceptor substitution at the C-3 position of oleanolic acid may be advantageous for the improvement of cytotoxicity against human prostatic carcinoma cell line (PC-3), human alveolar adenocarcinoma cell line (A549) and human breast adenocarcinoma cell line (MCF-7) cell lines [12]
Gnoatto found that the derivative with an acetylation at C-3 of the oleanolic acid backbone had much better activity against the L. amazonensis strain [17]. 3-Oxo oleanolic acid (3-oxo-olea-12-en-28-oic acid), a derivative of oleanolic acid modified at C-3, was found to significantly inhibit the growth of cancer cells derived from different tissues, on melanoma in vivo [18]
Summary
Oleanolic acid, which can be isolated from many foods and medicinal plants, has been reported to possess diverse biological activities. Some other acyl compounds, generated from the modification of the hydroxyl groups of the A-ring in the triterpene skeleton of oleanolic acid and maslinic acid (MA, Fig. 1) with 10 different acyl groups, displayed cytotoxic effects against b16f10 murine melanoma cells and showed apoptotic effects with high levels of early and total apoptosis (up to 90%). These acyl compounds exhibited better inhibition effects to anti-HIV-1-protease, with IC50 values between 0.31 and 15.6 μM, which are 4–186 times lower than their non-acylated precursors [19]. Compound 2 (Fig. 1), un benzyl (2α,3β) 2,3-diacetoxy-olean-12-en-28-amide, exhibited much better cytotoxicity against human tumor cell lines compared with its deacylation product, while it showed a rather low cytotoxicity for human fibroblasts (WW030272) [20]
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