A novel synthetic oleanolic acid derivative with amino acid conjugate suppresses tumour growth by inducing cell cycle arrest

ArticleinJournal of Pharmacy and Pharmacology 59(8):1087-93 · September 2007with3 Reads
DOI: 10.1211/jpp.59.8.0005 · Source: PubMed
Abstract
Oleanolic acid (3beta-hydroxy-olean-12-en-28-oic acid; OA) has a wide variety of bioactivities and is used for medicinal purposes in many Asian countries. Various derivatives of OA have been synthesized in attempts to improve the potency. Here we describe the anti-tumour activity of a novel OA derivative, N-[(3beta)-3-(acetyloxy)-28-oxoolean-12-en-28-yl]-glycine methyl ester (AOA-GMe). AOAGMe was a more potent inhibitor of the growth of B16 melanoma cells than its parent compound OA, both in-vitro and in-vivo. AOA-GMe also exhibited dose-dependent inhibition of human K562 leukaemia cells, but had almost no toxicity in normal human peripheral blood mononuclear cells. AOA-GMe induced cell cycle arrest in G0/G1 and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D, cyclin-dependent kinase CDK4 and phosphorylated retinoblastoma protein, and increases in the cyclin-dependent kinase inhibitor p15. OA did not show such activities. These results suggest that AOA-GMe may induce growth arrest in tumour cells through regulation of proteins involved in the cell cycle.
    • "Increasing the solubility of a compound usually can improve its bioavailability. For example, conjugation of an amino acid to oleanolic acid has been to shown to improve its water solubility as well as its anti-melanoma activity [16]. It is reported that a hydrogen donor group at either the C-3 position and/or C-28 positions of ursolic acid is essential for its cytotoxic activity [10]. "
    [Show abstract] [Hide abstract] ABSTRACT: Fifteen semi-synthetic derivatives of asiatic acid (AA) have been synthesized and evaluated for their biological activities. The successful modification of these compounds at the C-2, C-3, C-23 and C-28 positions was confirmed using NMR, MS and IR spectra. Further, their anti-tumor effects were evaluated in vitro using different cancer cell lines (HeLa, HepG2, B16F10, SGC7901, A549, MCF7 and PC3), while their anti-angiogenic activities were evaluated in vivo using a larval zebrafish model. Among the derivatives, compounds 4-10 showed more potent cytotoxic and anti-angiogenic effects than AA, while compounds 11-17 had significantly less effects. The new derivative 10 was also included in finished formulations to evaluate its stability using HPLC due to its potential topical use. The derivative 10 had markedly better anti-tumor activities than both AA and other derivatives, with similar stability as its parent compound AA.
    Full-text · Article · Apr 2015
    • "As essential nutrients of the human body, amino acids have favorable hydrophilicity. Numerous studies have showed that by introducing amino acid groups into the structures of insoluble drugs, the hydrophilicity and the bioactivity could be enhanced1213141516171819202122. In addition, some studies have indicated that low aqueous-solubility drugs conjugated with amino acids or dipeptides could be selectively identified and taken up by certain transporters, thus significantly improving their membrane permeability and cytotoxicity [22,23]. "
    [Show abstract] [Hide abstract] ABSTRACT: A series of novel ligustrazine-oleanolic acid (TOA) derivatives were designed, and synthesized by conjugating amino acids to the 3-hydroxy group of TOA by ester bonds. Their cytotoxicity was evaluated on four cancer cell lines (HepG2, HT-29, Hela and BGC-823) by standard MTT assays. The ClogP values were calculated by means of computer simulation, and logP values of both 3β-glycine ester olean-12-en-28-oic acid-3,5,6-trimethylpyrazin-2-methyl ester (6a) and TOA were determined using a shake flask-ultraviolet spectrophotometry method. It was found that 6a and the 3β-L-lysine ester-6g not only displayed good cytotoxicity (IC50 < 3.5 μM) but also possessed better hydrophilicity than TOA. Moreover, 6a (IC50 = 4.884 μM) had lower nephrotoxicity than both 6g (IC50 = 2.310 μM) and cisplatin (CDDP, IC50 = 3.691 μM) on MDCK cells. Combining Giemsa and DAPI staining, it was further verified that 6a could induce HepG2 apoptosis via nuclei fragmentation and had lower nephrotoxicity. In addition, the structure-activity relationships of these derivatives are briefly discussed.
    Full-text · Article · Nov 2014
    • "Oleanolic acid (3β-hydroxy-olean-12-en-28-oic acid; OA) is a naturally occurring pentacyclic triterpenoid found in more than 1600 species (Yeung et al., 2010). Literature demonstrates that oleanolic acid and its derivatives are reported to exhibit a wide range of biological and pharmacological properties including anti-inflammatory (Lee et al., 2013), antitumor (Lu et al., 2007), Anti HIV (Zhu et al., 2001), antioxidant (Gao et al., 2009), cardiotonic (Somova et al., 2004), diuretic (Jadhav et al., 2010) and hepatoprotective properties (Jeong., 1999). Further structural conversion of C-3 hydroxyl group in to acetoxy, oxo or hydroxy imino group showed strong cytotoxic activity as compare to oleanolic acid (Bednarczyk-Cwynar et al., 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Oleanolic acid (3 β -hydroxy-olean-12-en-28-oic acid; OA-01), a pentacyclic triterpene, exhibit a wide range of pharmacological ad biological activities. We have isolated oleanolic acid from methanolic extract of Periploca aphylla, collected from surroundings of Karachi in the month of February. Furthermore, four known and two new C-28 amino acid conjugates of oleanolic acid were prepared to explore potential of these compounds on HCCs and one breast cancer cell line. Cytotoxic effects revealed that as compare to parent compound (OA-01), two derivatives OA-04 (p<0.0001) and OA-06 (p<0.01) showed significantly increased /higher inhibition rates.
    Full-text · Article · Sep 2014
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