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

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, 210093, China.
Journal of Pharmacy and Pharmacology (Impact Factor: 2.26). 09/2007; 59(8):1087-93. DOI: 10.1211/jpp.59.8.0005
Source: PubMed


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.

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    • "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). "
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    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.
    Pakistan journal of pharmaceutical sciences 09/2014; 27(5):1491. · 0.68 Impact Factor
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    • "Recent progress has been made to improve the efficacy of OA against leukemia through generation of its derivatives [19], [41]. For example, a synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces differentiation and apoptosis in myeloid leukemia cells [20], [41], [42], while another synthetic oleanolic acid derivative N-[(3beta)-3-(acetyloxy)-28-oxoolean-12-en-28-yl]-glycine methyl ester (AOA-GMe) inhibits cell growth in K562 and B16 melanoma cells by inducing cell cycle arrest [19]. Here, we report that OEOA, an oxadiazole carboxylic acid derivative of OA, exhibits promising inhibitory effect on human leukemia cell proliferation. "
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    ABSTRACT: Oleanolic acid (3β-hydroxy-olea-12-en-28-oic acid) is a natural pentacyclic triterpenoic acid found in many fruits, herbs and medicinal plants. In the past decade, increasing evidence has suggested that oleanolic acid exhibits inhibitory activities against different types of cancer including skin cancer and colon cancer, but not leukemia. We report here that a derivative of oleanolic acid, olean-12-eno[2,3-c] [1], [2], [5]oxadiazol-28-oic acid (designated OEOA) effectively blocks the proliferation of human leukemia cells. OEOA significantly reduces cell proliferation without inducing cell death in three types of leukemia cell lines, including K562, HEL and Jurket. Moreover, exposure of K562 cells to OEOA results in G1 cell cycle arrest, with a concomitant induction of cyclin-dependent kinase inhibitor p27 and downregulation of cyclins and Cdks that are essential for cell cycle progression. Interestingly, OEOA also enhances erythroid differentiation in K562 cells through suppressing the expression of Bcr-Abl and phosphorylation of Erk1/2. These findings identify a novel chemical entity for further development as therapeutics against leukemia.
    PLoS ONE 05/2013; 8(5):e63580. DOI:10.1371/journal.pone.0063580 · 3.23 Impact Factor
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    ABSTRACT: Two series, a and b, of 3-cyclopentyl or (3-cyclohexyl)-5-substituted-3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTT) 2a-9a and 3b, 4b, 6b-9b, were synthesized to develop new cell cycle inhibitors. Variable and promising in vitro antiproliferative activities were shown with the synthesized THTT derivatives. Compound 5a with a 5-cyclopentyl group on position-3 and a glutamine residue on position-5 of the THTT moiety showed maximum activity (IC(50) = 8.98 μM). Compound 5a possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. There is no evident relationship between the cytotoxic activity of the tested compounds and their lipophilicity. In addition, a pharmacophore based study was performed to explain the biological activity on structural bases. A successful model was generated with a good correlation with the observed activity.
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