Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs

Abstract

Ursolic acid (UA) is a natural product which has been shown to possess a wide range of pharmacological activities, in particular those with anticancer activity. In this study, 13 novel ursolic acid derivatives were designed and synthesized in an attempt to further improve compound potency. The structures of the newly synthesized compounds were confirmed using mass spectrometry, infrared spectroscopy, and (1) H NMR. The ability of the UA derivatives to inhibit cell growth was assayed against both various tumor cell lines and a non-pathogenic cell line, HELF. Analysis of theoretical toxicity risks for all derivatives was performed using OSIRIS and indicated that the majority of compounds would present moderate to low risks. Pharmacological results indicated that the majority of the derivatives were more potent growth inhibitors than UA. In particular, 5b demonstrated IC50 values ranging from 4.09 ± 0.27 to 7.78 ± 0.43 μm against 12 different tumor cell lines. Flow cytometry analysis indicated that 5b induced G0/G1 arrest in three of these cell lines. These results were validated by structural docking studies, which confirmed that UA could bind to cyclins D1 (Cyc D1) and cyclin-dependent kinases (CDK6), the key regulators of G0/G1 transition in cell cycle, while the piperazine moiety of 5b could bind with glucokinase (GK), glucose transporter 1 (GLUT1), and ATPase, which are the main proteins involved in cancer cell metabolism. Acridine orange/ethidium bromide staining confirmed that 5b was capable of inducing apoptosis and decreasing cell viability in a dose-dependent manner.

Selective killing of cancer cells with triterpenoic acid amides - The substantial role of an aromatic moiety alignment

“…A C C E P T E D The cytotoxic activities of acetylated amides of ursolic acid [21][22][23][24][25][26] has already been investigated by several groups in detail while for asiatic acid mainly amides without additional acetyl groups in ring A have been investigated so far. 27,28 Screening of our analogs for their cytotoxic activity showed (cf.…”

A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment

“…It exhibits comprehensive biologic properties, such as anti-inflammatory [9], anti-angiogenesis [10], anti-cancer [11, 12] and liver protection [13], in a variety of human diseases. Recently, it has attracted considerable attention for its activities towards different cancers [14, 15]. In particular, it has the advantage of low toxicity, which makes it suitable for cancer metastatic chemoprevention.…”

Anti-hepatocellular carcinoma activity and mechanism of chemopreventive compounds: ursolic acid derivatives

“…Dong et al (2014) showed that piperazine moiety-modified UA (compound 8, Table 2) further enhanced the therapeutic effects of 2-DG probably through synergistic suppression of cancer cell glucose metabolism. Subsequently, Yang et al (2015) demonstrated that UA bound to cyclins D1 (Cyc D1) and cyclindependent kinases (CDK6), while compound 9 targeted at glucokinase (GK), glucose transporter 1 (GLUT1) and ATPase. Therefore, modification at the C-28 position of UA with the piperazine moiety (compounds 9-11) exhibited better anticancer activity than against HepG2 by interfering with glucose metabolism in a dose-dependent manner.…”