Rui-Qi Wang

Synthesis of indazole based diarylurea derivatives and their antiproliferative activity against tumor cell lines.

New series of indazole based diarylureas were synthesized and their anticancer activity against cancer cells H460, A549, OS-RC-2, HT-29, Lovo, HepG2, Bel-7402, SGC-7901 and MDA-MB-231 were examined. These derivatives of diarylureas, except azaindazole based diarylureas 5f, 5l and 5m, showed superior or similar activity against most of these selected cancer cell lines to the reference compound sorafenib. The effect of substituents on the indazole ring was also investigated. Derivatives with trifluoromenthy or halogen substituent on the indazole ring showed higher activity against the selected cancer cell lines than sorafenib. The acute toxicity assay showed that compounds 5a, 5b and 5i possessed lower toxicity than sorafenib. Compound 5i with 4-(trifluoromenthy)-1H-indazole and 4-(trifluoromenthy) benzene moieties exhibited the most potent anticancer activity.

Riccardin D-26, a synthesized macrocyclic bisbibenzyl compound, inhibits human hepatocellular carcinoma growth through induction of apoptosis in p53-dependent way

Riccardin D-26 is a synthesized macrocyclic bisbibenzyl compound. We investigated the effect of Riccardin D-26 on human hepatocellular carcinomas. Riccardin D-26 possessed stronger activity against SMMC-7721 cells than human normal liver cells. Riccardin D-26 injection effectively delayed the growth of SMMC-7721 xenografts in mice without significant toxicity. This effect of Riccardin D-26 was associated with the status of p53 and its targets, bax and p21(Waf1)(/)(Cip1). Riccardin D-26 activated p53 expression and induced cancer cells to apoptosis through the p53-mediated transcription-dependent and -independent pathway. Overall, Riccardin D-26 may inhibit hepatocellular carcinoma growth through induction of apoptosis in p53-dependent pathway.

RETRACTED: Acetyl-11-keto-β-boswellic acid (AKBA) inhibits human gastric carcinoma growth through modulation of the Wnt/β-catenin signaling pathway

BACKGROUNDnAcetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid, an active component of Boswellia serrata gum resin. We examined the effect of AKBA on human gastric carcinoma growth and explored the underlying molecular mechanisms.nnnMETHODSnInhibition of cancer cell growth was estimated by colorimetric and clonogenic assays. Cell cycle distribution was analyzed by flow cytometry and apoptosis determined using Annexin V-FITC/PI staining and DNA ladder quantification. After three weeks of oral AKBA administration in nude mice bearing cancer xenografts, animals were sacrificed and xenografts removed for TUNEL staining and western blot analysis.nnnRESULTSnAKBA exhibited anti-cancer activity in vitro and in vivo. With oral application in mice, AKBA significantly inhibited SGC-7901 and MKN-45 xenografts without toxicity. This effect might be associated with its roles in cell cycle arrest and apoptosis induction. The results also showed activation of p21(Waf1/Cip1) and p53 in mitochondria and increased cleaved caspase-9, caspase-3, and PARP and Bax/Bcl-2 ratio after AKBA treatment. Further analysis suggested that these effects might arise from AKBAs modulation of the aberrant Wnt/β-catenin signaling pathway. Upon AKBA treatment, β-catenin expression in nuclei was inhibited, and membrane β-catenin was activated. In the same sample, active GSK3β was increased and its non-active form decreased. Levels of cyclin D1, PCNA, survivin, c-Myc, MMP-2, and MMP-7, downstream targets of Wnt/β-catenin, were inhibited.nnnCONCLUSIONSnAKBA effects on human gastric carcinoma growth were associated with its activity in modulating the Wnt/β-catenin signaling pathway.nnnGENERAL SIGNIFICANCEnAKBA could be useful in the treatment of gastric cancers.

Riccardin D-26, a synthesized macrocyclic bisbibenzyl compound, inhibits human oral squamous carcinoma cells KB and KB/VCR: In vitro and in vivo studies.

BACKGROUNDnRiccardin D-26, a synthesized macrocyclic bisbibenzyl compound, might possess anti-cancer properties. We aimed to evaluate the efficacy of Riccardin D-26 as a candidate compound for treatment of cancers with sensitive or drug resistant cells.nnnMETHODSnExperiments were performed on human oral squamous carcinoma KB cells and vincristin-selected MDR KB/VCR cells. The inhibition of cell growth was evaluated by colorimetric and clonogenic assays. The apoptotic cells were determined by the Annexin V-FITC/PI staining assay. JC-1 fluorescence probe was used to examine the mitochondria membrane potential (MMP). Further experiments were performed in nude mice bearing KB or KB/VCR xenografts. Riccardin D-26 was administered by injection for 2weeks. The specimens of KB and KB/VCR xenografts were removed for TUNEL staining and Western blotting analysis.nnnRESULTSnRiccardin D-26 significantly inhibited cancer growth in both KB and KB/VCR cells. Riccardin D-26s activity in cancer cells was greater than that in human normal liver cells. In mice, Riccardin D-26 effectively prevented the growth of KB and KB/VCR xenografts without significant toxicity. Further studies suggested that Riccardin D-26 inhibited cancer growth by inducing apoptosis in the activation of mitochondria-mediated intrinsic apoptosis pathway. Riccardin D-26 also possessed this activity in regulation of mitogen-related protein kinases such as MAPK and PI3K/Akt, which is associated with its inhibitory effect on KB/VCR cells.nnnCONCLUSIONSnRiccardin D-26 possessed an anti-proliferation activity against both sensitive KB and MDR KB/VCR cancer cells.nnnGENERAL SIGNIFICANCEnRiccardin D-26 could be a promising agent for treatment of cancers with sensitive or drug resistant cells.

RETRACTED: Acetyl-11-keto-beta-boswellic acid (AKBA) prevents human colonic adenocarcinoma growth through modulation of multiple signaling pathways

BACKGROUNDnAcetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid. We have previously reported that AKBA can reduce the number and size of colonic adenomatous polyps in the APC(Min/+) mouse model. In this study, we evaluated the effect of AKBA on human colonic adenocarcinoma growth. Its efficacy and toxicity were compared with those of the non-steroidal anti-inflammatory drug aspirin.nnnMETHODSnThe inhibition of cancer cell growth was estimated by colorimetric and clonogenic assay. Cell cycle distribution was analyzed by the flow cytometry assay. Annexin V-FITC/PI staining and JC-1 fluorescence probe assays were performed to determine the apoptotic cells. Further experiment was carried out in mice with HT-29 xenografts. AKBA was orally administered for 24days. The HT-29 xenografts were removed for TUNEL staining and western blotting analysis. Blood was obtained for clinical chemical analysis, and samples of organs were sectioned for microscopic assessment.nnnRESULTSnAKBA significantly inhibited human colon adenocarcinoma growth, showing arrest of the cell cycle in G1-phase and induction of apoptosis. AKBA administration in mice effectively delayed the growth of HT-29 xenografts without signs of toxicity. The activity of AKBA was more potent than that of aspirin. Western blotting suggested that this activity may arise from its multiple effects on the activation of apoptotic proteins, suppression of inflammatory cytokines and modulation of EGFR and ATM/P53 signaling pathways in the HT-29 xenografts.nnnCONCLUSIONSnAKBA prevents the growth of colonic adenocarcinoma through modulation of multiple signaling pathways.nnnGENERAL SIGNIFICANCEnAKBA could be a promising agent in the prevention of colonic adenocarcinomas.

1082-39, an analogue of sorafenib, inhibited human cancer cell growth more potently than sorafenib.

PURPOSEn1082-39, an analogue of sorafenib, is a derivative of indazole diarylurea. We evaluated the activity of 1082-39 against human cancer cell growth. Its effects and mechanisms of action were then compared with those of sorafenib. The experiments were performed in human melanoma M21 cells.nnnMETHODSnCell viability was estimated by using the colorimetric assay. Annexin V-FITC/PI staining assay was used to recognize the apoptotic cells. Further analysis of the mitochondria membrane potential (MMP) was performed by the JC-1 fluorescence probe staining. The levels of apoptotic proteins and kinases related to cancer proliferation were determined by western blotting assay.nnnRESULTSn1082-39 possessed the activity against cancer cell proliferation with time- and dose-dependent manner. 1082-39 induced M21 cell to apoptosis, showing the increase of annexin V-FITC/PI staining cells, the MMP collapse and releasing cytochrome c from mitochondria. Western blotting analysis showed the activation of the mitochondria-mediated intrinsic pathway, showing the increase of cleaved caspase-9, cleaved caspase-3 and cleaved PARP. Statistical analysis suggested that 1082-39 possessed greater activities than sorafenib in the inhibition of M21 proliferation and induction of apoptosis. These effects of 1082-39 might arise from its activity of regulation the PI3K/Akt and Wnt/β-catenin signaling pathways.nnnCONCLUSIONSn1082-39 is a promising candidate compound which could develop as a potent anticancer agent.

Pharmacokinetics and metabolism of SL-01, a prodrug of gemcitabine, in rats

PurposeSL-01, dodecyl-3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl) carbamoyl) pyrazine-2-carboxylate, is a prodrug of gemcitabine. Our previous reports suggested that SL-01 possesses superior bioavailability and anticancer activity to gemcitabine in mice. In this study, its pharmacokinetics and metabolisms were investigated in rats.MethodsThe pharmacokinetics of SL-01 was studied following intravenous or oral administration of SL-01 to Sprague–Dawley rats. The metabolites profile of SL-01 was further determined in rats receiving intravenous administration of SL-01. Blood samples were analyzed by using LC–MS or LC–MS/MS assay.ResultsFollowing administration with SL-01 intravenously or orally, SL-01, plasma gemcitabine released from SL-01 as well as the sum of gemcitabine (gemcitabine converted from SL-01 and plasma gemcitabine) exhibited higher values of Vz/F and CLz/F, and longer MRT and t1/2 than those of gemcitabine administered intravenously. The Cmax of gemcitabine produced by intravenous SL-01 was higher than that of gemcitabine dosed intravenously. The absolute bioavailability for the sum of gemcitabine was 32.2xa0% for intravenous and 22.2xa0% for oral administration with SL-01, respectively. After a single intravenous administration, a total of 5 components (M1, M2, M3, M4, and M5) were detected and identified as the metabolites of SL-01 in the plasma of rats. M1 and M2 were formed from the methylation and reduction of SL-01, respectively. Hydrolysis of the amide bond of SL-01 gave M3 and M4. M5 was produced from further dealkylation of M3.ConclusionsSL-01 displayed improved absorption, good distribution, high clearance, long mean residence time, and moderate bioavailability after administered intravenously or orally to rats. The major metabolic pathways of SL-01 involved methylation, reduction, hydrolysis, and dealkylation. These results suggested that SL-01 acts as a prodrug of gemcitabine in rats.

A novel anticancer diarylurea derivative HL-40 as a multi-kinases inhibitor with good pharmacokinetics in Wistar rats

HL-40, N-(4-(1-(4-chlorine indazole)) phenyl)-N-(4-chloro-3-three fluorine methyl phenyl) urea, is a novel diarylurea derivative. In this study, we investigated the kinases activities and binding constants, pharmacokinetics of HL-40, and then evaluated its anticancer efficacy by both in vitro and in vivo methods. Enzyme activities assays in vitro were employed to identify eight candidate kinase targets. The competition binding assays against eight candidate kinases suggested that HL-40 showed strong affinity to c-Kit, PDGFRβ and FLT3. The pharmacokinetic studies in Wistar rats showed that HL-40 could maintain high compound concentration and long residence time in the blood circulation. HL-40 possessed strong inhibition activities against 12xa0human cancer cells. Meanwhile, HL-40 effectively delayed the growth of cancer xenografts without significant toxicity to mice. Based on these in vitro and in vivo results, we suggested that HL-40 might be developed as a potential multi-kinases inhibitor for cancer treatment.

SL-01, an oral derivative of gemcitabine, inhibited human breast cancer growth through induction of apoptosis

UNLABELLEDnSL-01 is an oral derivative of gemcitabine that was synthesized by introducing the moiety of 3-(dodecyloxycarbonyl) pyrazine-2-carbonyl at N4-position on cytidine ring of gemcitabine. We aimed to evaluate the efficacy of SL-01 on human breast cancer growth. SL-01 significantly inhibited MCF-7 proliferation as estimated by colorimetric assay. Flow cytometry assay indicated the apoptotic induction and cell cycle arrest in G1 phase. SL-01 modulated the expressions of p-ATM, p53 and p21 and decrease of cyclin D1 in MCF-7 cells. Further experiments were performed in a MCF-7 xenografts mouse model. SL-01 by oral administration strongly inhibited MCF-7 xenografts growth. This effect of SL-01 might arise from its roles in the induction of apoptosis. Immunohistochemistry assay showed the increase of TUNEL staining cells. Western blotting indicated the modulation of apoptotic proteins in SL-01-treated xenografts. During the course of study, there was no evidence of toxicity to mice. In contrast, the decrease of neutrophil cells in peripheral and increase of AST and ALT levels in serum were observed in the gemcitabine-treated mice.nnnCONCLUSIONnSL-01 possessed similar activity against human breast cancer growth with gemcitabine, whereas, with lower toxicity to gemcitabine. SL-01 is a potent oral agent that may supplant the use of gemcitabine.