Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance.

Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking platinum(II) agents and glycyrrhetinic acid (GA) were designed and synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including cisplatin resistance cells than cisplatin and simultaneously displayed good liver-targeting ability. Moreover, complex 20 can significantly cause DNA damage and mitochondrial dysfunction, promote reactive oxygen species generation, activate endoplasmic reticulum stress, and eventually induce apoptosis. Additionally, complex 20 can effectively inhibit cell migration and invasion and trigger autophagy and ferroptosis in HepG-2 cells. More importantly, complex 20 demonstrated stronger tumor inhibition ability than cisplatin or the combo of cisplatin/GA with almost no systemic toxicity in HepG-2 or A549 xenograft models. Collectively, complex 20 could be developed as a potential anti-HCC agent for cancer treatment.

Synthesis and anti-inflammatory activities of glycyrrhetinic acid derivatives containing disulfide bond.

A series of glycyrrhetinic acid (GA, aglycone of glycyrrhizic acid) derivatives containing disulfide bond were synthesized and their anti-inflammatory and anti-fibrosis activities were evaluated in vivo and in vitro. Among them, compound 7 displayed the highest toxicity to all the tested cell lines including macrophages. Compounds 3 and 4 showed higher activities than GA in the cell and animal model. In the anti-inflammatory tests, compounds 3 and 4 down-regulated the expressions of several inflammatory factors, such as HMGB1, TLR4, IL-1ß, TNF-α and TGF-ß1 in LPS-treated RAW264.7 cells in a dose-dependent manner. Compounds 3 and 4 at 30 µM respectively reduced the levels of HMGB1 in the LPS group to 42.7% and 38.2%. In addition, the level of TLR4 decreased to close to that of control group when treated by compound 4 at the concentration of 30 µM. In the process of anti-fibrosis tests using TGF-ß1-induced A549 cell line as the model, compounds 3 and 4 also decreased the expression levels of Col1 and α-SMA in a dose-dependent manner. Compound 3 and 4 at 30 µM respectively reduced the expression of α-SMA level by 2.2-fold and 2.6-fold compared to the TGF-ß1-treated control group. Moreover, they influenced the ROS level and mitochondrial membrane potential (MMP) in A549 cells. In the paraquat-induced pulmonary fibrosis mice model, the symptoms of inflammation and fibrosis of mice were alleviated after administration of compound 3 or 4. The above results suggest that compounds 3 and 4 may be promising candidates for inflammation and lung fibrosis treatment.

Indole- and Pyrazole-Glycyrrhetinic Acid Derivatives as PTP1B Inhibitors: Synthesis, In Vitro and In Silico Studies.

Regulating insulin and leptin levels using a protein tyrosine phosphatase 1B (PTP1B) inhibitor is an attractive strategy to treat diabetes and obesity. Glycyrrhetinic acid (GA), a triterpenoid, may weakly inhibit this enzyme. Nonetheless, semisynthetic derivatives of GA have not been developed as PTP1B inhibitors to date. Herein we describe the synthesis and evaluation of two series of indole- and N-phenylpyrazole-GA derivatives (4a-f and 5a-f). We measured their inhibitory activity and enzyme kinetics against PTP1B using p-nitrophenylphosphate (pNPP) assay. GA derivatives bearing substituted indoles or N-phenylpyrazoles fused to their A-ring showed a 50% inhibitory concentration for PTP1B in a range from 2.5 to 10.1 µM. The trifluoromethyl derivative of indole-GA (4f) exhibited non-competitive inhibition of PTP1B as well as higher potency (IC50 = 2.5 µM) than that of positive controls ursolic acid (IC50 = 5.6 µM), claramine (IC50 = 13.7 µM) and suramin (IC50 = 4.1 µM). Finally, docking and molecular dynamics simulations provided the theoretical basis for the favorable activity of the designed compounds.

Glycyrrhetinic acid derivatives as Zika virus inhibitors: Synthesis and antiviral activity in vitro.

Zika virus (ZIKV) is an arbovirus of the Flaviviridae family (Flavivirus genus), causing serious neurological complications, such as Guillain-Barre Syndrome (GBS) in adults and fetal microcephaly. Licensed vaccines or specific antiviral agents against ZIKV do not currently exist. Therefore, the search and development of anti-ZIKV agents are particularly relevant and necessary. Glycyrrhetinic (3ß-hydroxy-11-oxo-18ßH-Olean-12-en-30-oic acid) (GA) 1 is one of the well-known pentacyclic triterpenoids isolated from licorice root (Glycyrrhiza glabra L., Gl. uralensis Fisher) (Leguminosae) possessing many biological features, including antiviral activity. This paper is devoted to the synthesis and studies of a number of nitrogen and sulfur-containing GA derivatives as ZIKV inhibitors. Sixteen GA and related triterpenoids (3ß-hydroxy-18ßH-Olean-12-en-30-oic acid and 3ß-hydroxy-11-oxo-18ßH-Olean-12(13),18(19)-dien-30-oic acid) derivatives were synthesized (amides, semi- and thiosemicarbazones, and 1,2,3-thiadiazoles) and antiviral activity against ZIKV was studied in vitro, including the inhibitory assays on cytopathic effect (CPE), viral protein synthesis, and replication stages. Four active compounds were found among GA derivatives tested, 13 (3-O-acetyl-30-aminopyridine GA), 16 (3-semicarbazone-30-butyl GA), 18 (1,2,3-thiadiazole-30-methyl GA), and 19 (1,2,3-thiadiazole-30-butyl GA) with IC50 < 1 µM against ZIKV replication. These compounds had a stronger inhibitory activity on ZIKV-induced CPE and viral protein translation in infected cells as compared to derivatives of 11-desoxo-GA. The most active compound was amide 13 (IC50 0.13 µM, TI ˃ 384). Time-of-addition assays indicated that 1,2,3-thiadiazole ring is important for inhibiting viral entry stage (compounds 18 and 19), while the 30-butyl ester group influenced on post-entry stage (compound 19). The molecular docking analysis demonstrated that lead compounds 13 and 19 forms a hydrogen-bond interaction with the catalytic triad (His51-Asp75-Ser135) of ZIKV NS2B-NS3 protease. Therefore, the active GA derivatives are promising for developing new antiviral agents against ZIKV infection.

Design and synthesis of novel glycyrrhetin ureas as anti-inflammatory agents for the treatment of acute kidney injury.

To develop new anti-inflammatory drugs for the prevention and treatment of acute kidney injury, a series of novel glycyrrhetic ureas were designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. Compounds 5r-5u (2.04, 2.50, 3.25 and 2.48 µM, respectively) with acidic or neutral amino acid showed potent anti-inflammatory activity (IC50 = 2-3 µM for NO inhibition), amongst them, compound 5r also inhibited tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in a dose-dependent manner. In cisplatin-induced AKI mice model, compound 5r significantly reduced the level of pro-inflammatory factors, ameliorated the pathological damage of kidney tissue, and maintained the normal metabolic capacity.

Structurally modified glycyrrhetinic acid derivatives as anti-inflammatory agents.

With the aim of finding new anti-inflammatory drugs, a series of new Glycyrrhetinic acid derivatives (1-34) have been designed and synthesized by structural modification, and their anti-inflammatory activities in vitro have been evaluated. The anti-inflammatory activities assay demonstrated that compound 5b suppressed the expression of pro-inflammatory cytokines including IL-6, TNF-α and NO, it also suppressed the expression of iNOS and COX-2 in LPS-induced RAW264.7 cells in a dose-dependent manner. Additionally, western blot results indicated that the suppressing effect of compound 5b on pro-inflammatory cytokines were correlated with the suppression of NF-κB and MAPK signaling pathways. The results attained in this study indicated that compound 5b had the potential to be developed into an anti-inflammation agent and it may be applied to the prevention and treatment of inflammatory diseases.

Synthesis, anti-microbial and anti-inflammatory activities of 18ß-glycyrrhetinic acid derivatives.

Thirteen 18ß-glycyrrhetinic acid (GA) derivatives were obtained by reduction at C-11 position, oxidation at C-3 position and condensation at C-2 position of GA. Anti-microbial activity evaluation indicated that compounds 04, 05, 10, 13 and 14 showed more potent inhibitory activity against Staphylococcus aureus subsp. aureus, Staphylococcus epidermidis, Staphylococcus aureus than GA, especially compound 10, the inhibitory activity against Staphylococcus epidermidis was equaled with Ampicillin. Moreover, in vivo experiments exhibited that compound 10 also has anti-inflammatory effect, which could decrease about 59.69% TPA-induced ear edema of mice with the gavage treatment of 40.0 mg/mL. Immunohistochemistry results revealed that the effect of inhibition was related to inhibition of TPA-induced upregulation of the pro-inflammatory cytokines TNF-α and IL-1ß. Furthermore, compound 10 also significantly decreased the expression level of p65 in NF-κB signaling pathway. In general, compound 10, both with antibacterial and anti-inflammatory activities, was expected to become a promising bio-functional agent.

Novel 3'-Substituted-1',2',4'-Oxadiazole Derivatives of 18ßH-Glycyrrhetinic Acid and Their O-Acylated Amidoximes: Synthesis and Evaluation of Antitumor and Anti-Inflammatory Potential In Vitro and In Vivo.

A series of novel 18ßH-glycyrrhetinic acid (GA) derivatives containing 3'-(alkyl/phenyl/pyridin(-2″, -3″, and -4″)-yl)-1',2',4'-oxadiazole moieties at the C-30 position were synthesized by condensation of triterpenoid's carboxyl group with corresponding amidoximes and further cyclization. Screening of the cytotoxicity of novel GA derivatives on a panel of tumor cell lines showed that the 3-acetoxy triterpenoid intermediates-O-acylated amidoxime 3a-h-display better solubility under bioassay conditions and more pronounced cytotoxicity compared to their 1',2',4'-oxadiazole analogs 4f-h (median IC50 = 7.0 and 49.7 µM, respectively). Subsequent replacement of the 3-acetoxy group by the hydroxyl group of pyridin(-2″, 3″, and -4″)-yl-1',2',4'-oxadiazole-bearing GA derivatives produced compounds 5f-h, showing the most pronounced selective toxicity toward tumor cells (median selectivity index (SI) > 12.1). Further detailed analysis of the antitumor activity of hit derivative 5f revealed its marked proapoptotic activity and inhibitory effects on clonogenicity and motility of HeLa cervical carcinoma cells in vitro, and the metastatic growth of B16 melanoma in vivo. Additionally, the comprehensive in silico study revealed intermediate 3d, bearing the tert-butyl moiety in O-acylated amidoxime, as a potent anti-inflammatory candidate, which was able to effectively inhibit inflammatory response induced by IFNγ in macrophages in vitro and carrageenan in murine models in vivo, probably by primary interactions with active sites of MMP9, neutrophil elastase, and thrombin. Taken together, our findings provide a basis for a better understanding of the structure-activity relationship of 1',2',4'-oxadiazole-containing triterpenoids and reveal two hit molecules with pronounced antitumor (5f) and anti-inflammatory (3d) activities.

Trioxolone Methyl, a Novel Cyano Enone-Bearing 18ßH-Glycyrrhetinic Acid Derivative, Ameliorates Dextran Sulphate Sodium-Induced Colitis in Mice.

Semi-synthetic triterpenoids, bearing cyano enone functionality in ring A, are considered to be novel promising therapeutic agents with complex inhibitory effects on tissue damage, inflammation and tumor growth. Previously, we showed that the cyano enone-containing 18ßH-glycyrrhetinic acid derivative soloxolone methyl (SM) effectively suppressed the inflammatory response of macrophages in vitro and the development of influenza A-induced pneumonia and phlogogen-stimulated paw edema in vivo. In this work, we reported the synthesis of a novel 18ßH-glycyrrhetinic acid derivative trioxolone methyl (TM), bearing a 2-cyano-3-oxo-1(2)-en moiety in ring A and a 12,19-dioxo-9(11),13(18)-dien moiety in rings C, D, and E. TM exhibited a high inhibitory effect on nitric oxide (II) production by lipopolysaccharide-stimulated J774 macrophages in vitro and dextran sulfate sodium (DSS)-induced colitis in mice, displaying higher anti-inflammatory activity in comparison with SM. TM effectively suppressed the DSS-induced epithelial damage and inflammatory infiltration of colon tissue, the hyperproduction of colonic neutral mucin and TNFα and increased glutathione synthesis. Our in silico analysis showed that Akt1, STAT3 and dopamine receptor D2 can be considered as mediators of the anti-colitic activity of TM. Our findings provided valuable information for a better understanding of the anti-inflammatory activity of cyano enone-bearing triterpenoids and revealed TM as a promising anti-inflammatory candidate.

Synthesis and anti-hepaticfibrosis of glycyrrhetinic acid derivatives with inhibiting COX-2.

Many tests have shown cyclooxygenase-2 (COX-2) was closely related to the activation of hepatic stellate cells (HSCs), which further promoting the onset and development of hepatic fibrosis. According to these research findings, a series of glycyrrhetinic acid derivatives were designed and synthesized. Meanwhile, their anti-hepaticfibrotic activities were evaluated in vitro and in vivo. Firstly, in the tests of the cell models, all the compounds displayed anti-proliferative effect on the HSC-T6 activated by (transforming growth factor beta) TGF-ß1 (10 ng/mL). Among them, compounds 2 and 16 exhibited a stronger activity than the others, and their IC50 values were 17.6 µM and 30.3 µM, respectively; both of them were low toxicity to normal HSC-T6 cells and WI38 cells, and they inhibited the activated HSC-T6 cells proliferation by promoting apoptosis and resting them at the G0/G1 phase. Secondly, compounds 2 and 16 displayed strong inhibitory effect on activation of HSCs; they not only inhibited the expression of α-SMA and Col1 in the activated HSC-T6 cells, but also decreased the levels of COX-2, TGF-ß1 and (reactive oxygen species) ROS in a concentration-dependent manner; they down-regulated the levels of three biomarkers in the process of test, but this decrease did not change linearly with the action time of compound. Thirdly, for the rats which induced with (carbontetrachloride) CCl4, the symptoms of liver fibrosis in rats were significantly alleviated after successive administration the tested compound for 14d; the α-SMA level in liver tissue decreased in a concentration dependent manner; and the liver cell necrosis and the fat collagen fiber decreased significantly compared with the positive control group; furthermore, inflammatory infiltration was significantly lower than that of the control. This suggests the compounds possibly are candidates for hepatic fibrosis with promising application in clinic.

Synthesis and Evaluation of Glycyrrhetic Acid-aromatic Hybrids as Antiinflammatory Agents.

BACKGROUND: Inflammation is a biological response of body tissues to harmful stimuli, so it is desirable to search for novel anti-inflammatory agents with improved pharmaceutical profiles and reduced adverse effects. OBJECTIVE: This study was to explore natural anti-inflammatory agents and improve therapeutic application of glycyrrhetic acid (GA) through molecular hybridization with active aromatics. METHODS: Fourteen novel GA-aromatic hybrids were synthesized and evaluated for their antiinflammatory activities by inhibiting LPS-induced nitric oxide (NO) release in RAW264.7 cells. The synthesized compounds were characterized by single-crystal X-ray diffraction, 1H NMR, 13C NMR and HRMS. RESULTS: The structure-activity relationship (SAR) study indicated that compounds with styryl displayed better NO inhibitory activity. Among them, compounds 2a and 3c exhibited the most promising activity with IC50 values of 9.93 µM and 12.25 µM, respectively. In addition, X-ray singlecrystal diffraction data for compounds 2e and 3c showed that the absolute configuration of GA skeleton was consistent with that of natural 18 ß-glycyrrhetic acid. CONCLUSION: The results showed that GA-aromatic hybrids were a new class of anti-inflammatory agents and this study provided useful information on further optimization.

Design, Synthesis, Antibacterial Evaluation, and Induced Apoptotic Behaviors of Epimeric and Chiral 18ß-Glycyrrhetinic Acid Ester Derivatives with an Isopropanolamine Bridge against Phytopathogens.

Because only a handful of agrochemicals can manage bacterial infections, the discovery and development of innovative, inexpensive, and high-efficiency antibacterial agents targeting these infections are challenging. Herein, a series of novel epimeric and chiral 18ß-glycyrrhetinic acid (GA) ester derivatives with various tertiary amine pendants were designed, synthesized, and screened for pharmacological activity. Results showed that some of the title compounds were conferred with significantly enhanced antibacterial activity toward phytopathogens Xanthomonas oryzae pv oryzae (A2, B1-B3, and C1, EC50 values within 3.81-4.82 µg/mL) and Xanthomonas axonopodis pv citri (B1, EC50 = 3.18 µg/mL; B2, EC50 = 2.76 µg/mL). These activities are superior to those of GA (EC50 > 400 µg/mL), thiodiazole copper, and bismerthiazol. Pharmacophore studies revealed that the synergistic combination of GA skeleton and tertiary amine scaffolds contributed to the biological actions. In vivo experiments displayed their promising applications in controlling bacterial infections. Antibacterial mechanism studies revealed that the title compounds could trigger apoptosis in the tested pathogens, evident by bacteria morphological changes observed in scanning electron microscopy images. This outcome should motivate the development of various apoptosis inducers against plant bacterial diseases by a novel mode of action compared to that of existing agricultural chemicals.

Synthesis and Antiproliferative Activity of Novel A-Ring Cleaved Glycyrrhetinic Acid Derivatives.

A series of new glycyrrhetinic acid derivatives was synthesized via the opening of its ring A along with the coupling of an amino acid. The antiproliferative activity of the derivatives was evaluated against a panel of nine human cancer cell lines. Compound 17 was the most active compound, with an IC50 of 6.1 µM on Jurkat cells, which is 17-fold more potent than that of glycyrrhetinic acid, and was up to 10 times more selective toward that cancer cell line. Further biological investigation in Jurkat cells showed that the antiproliferative activity of compound 17 was due to cell cycle arrest at the S phase and induction of apoptosis.

Synthesis and biological activity of glycyrrhetinic acid derivatives as antitumor agents.

Glycyrrhetinic acid (GA) had been the star anticancer lead compound and appealed to many scientists all over the world; however, its antitumor activity was not potent enough. To improve GA's cytoxicity and explore the effect of bonding mode on antitumor activity, 32 compounds including GA-OH series (GO, esters in C-3 position) and GA-NH2 series (GN, with amide linkages in C-3 position) had been designed and synthesized. All the compounds were screened for in vitro cytotoxicity against A549, HepG2, MCF-7, Hela and MDCK cell lines. As a result, all the de-protected (without Boc group) derivatives showed much stronger cytotoxic activity than GA, and surprisingly enough, all the GN series of the compounds were more potent than GO series against various tumor cells. Among them, the compound 26 (amide linkages in C-3 position) exhibited stronger antitumor activity against A549 cell line (IC50 = 2.109 ±â€¯0.11 µM) than the positive drug cisplatin (IC50 = 9.001 ±â€¯0.37 µM). Further studies indicated that compound 26 could induce A549 apoptosis via nuclei fragmentation. The detection of apoptosis and cell cycle analysis indicated that compound 26 could induce the early apoptosis and prevent A549 cells transition from S to G2 phase. Furthermore, the structure-activity relationships were briefly discussed. Among which, current study displayed amide linkages in C-3 position could effectively enhance GA cytotoxicity, providing a new modification strategy for further study.

In Vitro and In Silico Studies of Glycyrrhetinic Acid Derivatives as Anti- Filarial Agents.

BACKGROUND: Lymphatic filariasis is one of the chronic diseases in many parts of the tropics and sub-tropics of the world despite the use of standard drugs diethylcarbamazine and ivermectin because they kill microfilaries and not the adult parasites. Therefore, new leads with activity on adult parasites are highly desirable. OBJECTIVE: Anti-filarial lead optimization by semi-synthetic modification of glycyrrhetinic acid (GA). METHODS: The GA was first converted into 3-O-acyl derivative, which was further converted into 12 amide derivatives. All these derivatives were assessed for their antifilarial potential by parasite motility assay. The binding affinity of active GA derivatives on trehalose-6-phosphate phosphatase (Bm-TPP) was assessed by molecular docking studies. RESULTS: Among 15 GA derivatives, GAD-2, GAD-3, and GAD-4 were found more potent than the GA and standard drug DEC. These derivatives reduced the motility of Brugia malayi adult worms by up to 74% while the GA and DEC reduced only up to 49%. Further, GA and most of its derivatives exhibited two times more reduction in MTT assay when compared to the standard drug DEC. These derivatives also showed 100% reduction of microfilariae and good interactions with Bm-TPP protein. CONCLUSION: The present study suggests that 3-O-acyl and linear chain amide derivatives of glycyrrhetinic acid may be potent leads against B. malayi microfilariae and adult worms. These results might be helpful in developing QSAR model for optimizing a new class of antifilarial lead from a very common, inexpensive, and non toxic natural product.

Liver-targeted liposomes for codelivery of curcumin and combretastatin A4 phosphate: preparation, characterization, and antitumor effects.

BACKGROUND: Recent efforts have been focused on combining two or more therapeutic approaches with different mechanisms to enhance antitumor therapy. Moreover, nanosize drug-delivery systems for codelivering two drugs with proapoptotic and antiangiogenic activities have exhibited great potential in efficient treatment of cancers. METHODS: Glycyrrhetinic acid (GA)-modified liposomes (GA LPs) for liver-targeted codelivery of curcumin (Cur) and combretastatin A4 phosphate (CA4P) were prepared and characterized. In vitro cellular uptake, cytotoxicity, cell migration, in vivo biodistribution, antitumor activity, and histopathological studies were performed. RESULTS: Compared with unmodified LPs (Cur-CA4P LPs), Cur-CA4P/GA LPs were taken up effectively by human hepatocellular carcinoma cells (BEL-7402) and showed higher cytotoxicity than free drugs. In vivo real-time near-infrared fluorescence-imaging results indicated that GA-targeted LPs increased accumulation in the tumor region. Moreover, Cur-CA4P/GA LPs showed stronger inhibition of tumor proliferation than Cur, Cur + CA4P, and Cur-CA4P LPs in vivo antitumor studies, which was also verified by H&E staining. CONCLUSION: GA-modified LPs can serve as a promising nanocarrier for liver-targeted co-delivery of antitumor drugs against hepatocellular carcinoma.

Synthesis and Antiproliferative Activity of Novel Heterocyclic Glycyrrhetinic Acid Derivatives.

A new series of glycyrrhetinic acid derivatives has been synthesized via the introduction of different heterocyclic rings conjugated with an α,ß-unsaturated ketone in its ring A. These new compounds were screened for their antiproliferative activity in a panel of nine human cancer cell lines. Compound 10 was the most active derivative, with an IC50 of 1.1 µM on Jurkat cells, which is 96-fold more potent than that of glycyrrhetinic acid, and was 4-fold more selective toward that cancer cell line. Further biological studies performed in Jurkat cells showed that compound 10 is a potent inducer of apoptosis that activates both the intrinsic and extrinsic pathways.

Synthesis and structure-activity relationship studies of water-soluble ß-cyclodextrin-glycyrrhetinic acid conjugates as potential anti-influenza virus agents.

Glycyrrhetinic acid (GA) is a major constituent of the herb Glycyrrhiza glabra, and many of its derivatives demonstrate a broad spectrum of antiviral activities. In the current study, 18 water-soluble ß-cyclodextrin (CD)-GA conjugates, in which GA was covalently coupled to the primary face of ß-CD using 1,2,3-triazole moiety along with varying lengths of linker, were synthesized via copper-catalyzed azide-alkyl cycloaddition reaction. Benefited from the attached ß-CD moiety, all these conjugates showed lower hydrophobicity (AlogP) compared with their parent compound GA. With the exception of per-O-methylated ß-CD-GA conjugate (35), all other conjugates showed no significant cytotoxicity to MDCK cells, and these conjugates were then screened against A/WSN/33 (H1N1) virus using the cytopathic effect assay. The preliminary results indicated that six conjugates showed promising antiviral activity, and the C-3 and C-30 of GA could tolerate some modifications. Our findings suggested that GA could be used as a lead compound for the development of potential anti-influenza virus agents.

Mitochondria-targeted triphenylphosphonium conjugated glycyrrhetinic acid derivatives as potent anticancer drugs.

Glycyrrhetinic acid has been usually studied for their anti-tumor activities. However, the low bioavailability and poor aqueous solubility as well as limited intracellular accumulation have limited their utility. In this present study, a series of new glycyrrhetinic acid conjugates with a triphenylphosphonium cation (TTP+) moiety, meant to specifically target them to tumor cells mitochondria, have been designed and synthesized. Among them, compound 2f possessed excellent antitumor activities against the tested human cancer cells, and simultaneously exhibited better cell selectivity between cancer cells and normal cells than glycyrrhetinic acid and HCPT. Moreover, 2f significantly induced cell cycle arrest at the G2/M phase, and effectively inhibited cancer cells proliferation and migration. Mechanism studies revealed that 2f triggered apoptosis through the mitochondrial pathway via the collapse of mitochondrial membrane potential, reactive oxygen species production and the activation of caspase-9 and caspase-3.

Design and preparation of derivatives of oleanolic and glycyrrhetinic acids with cytotoxic properties.

BACKGROUND: The structural modification of natural products with the aim to improve the anticancer activity is a popular current research direction. The pentacyclic triterpenoid compounds oleanolic acid (OA) and glycyrrhetinic acid (GA) are distributed widely in nature. METHODS: In this study, various oleanolic acids and glycyrrhetinic acids were designed and synthesized by using the combination principle. The in vitro anticancer activities of new OA and GA derivatives were tested by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) method with SGC-7901 (gastric cancer), MCF-7 (breast cancer), Eca-109 (esophageal cancer), HeLa (cervical cancer), Hep-G2 (hepatoma cancer) and HSF (normal human skin fibroblast) cells. RESULTS AND CONCLUSION: The screening results showed that the compound 3m presented the highest inhibitory activities against SGC-7901, MCF-7 and Eca-109 cell lines with IC50 values of 7.57±0.64 µM, 5.51±0.41 µM and 5.03±0.56 µM, respectively. In addition, this compound also showed effective inhibition of Hep-G2 cells with an IC50 value of 4.11±0.73 µM. Moreover, compound 5b showed the strongest inhibitory activity against Hep-G2 cells with an IC50 value of 3.74±0.18 µM and compound 3l showed strong selective inhibition of the HeLa cells with the lowest IC50 value of 4.32±0.89 µM. A series of pharmacology experiments indicated that compound 5b could induce Hep-G2 cells autophagy and apoptosis. These compounds will expand the structural diversity of anti-cancer targets and confirm the prospects for further research.