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    Enhanced anti-tumor effect of combination therapy with gemcitabine and apigenin in pancreatic cancer. Lee Sang Hyub,Ryu Ji Kon,Lee Kyeung-Yeup,Woo Sang Myung,Park Joo Kyung,Yoo Ji Won,Kim Yong-Tae,Yoon Yong Bum Cancer letters Apigenin is a dietary flavonoid possessing therapeutic potential against cancers. This study was designed to investigate whether combination therapy with gemcitabine and apigenin enhanced anti-tumor efficacy in pancreatic cancer. In vitro, the combination treatment resulted in more growth inhibition and apoptosis through the down-regulation of NF-kappa B activity with suppression of Akt activation in pancreatic cancer cell lines (MiaPaca-2, AsPC-1). In vivo, the combination therapy augmented tumor growth inhibition through the down-regulation of NF-kappa B activity with the suppression of Akt in tumor tissue. The combination of gemcitabine and apigenin enhanced anti-tumor efficacy through Akt and NF-kappa B activity suppression and apoptosis induction. 10.1016/j.canlet.2007.09.015
    Modulation of multidrug resistance protein 1 (MRP1/ABCC1)-mediated multidrug resistance by bivalent apigenin homodimers and their derivatives. Wong Iris L K,Chan Kin-Fai,Tsang Ka Hing,Lam Chi Yin,Zhao Yunzhe,Chan Tak Hang,Chow Larry Ming Cheung Journal of medicinal chemistry Here we showed that bivalency approach is effective in modulating multidrug resistance protein 1 (MRP1/ABCC1)-mediated doxorubicin (DOX) and etoposide (VP16) resistance in human 2008/MRP1 ovarian carcinoma cells. Flavonoid dimers bearing five or six ethylene glycol (EG) units with 6-methyl (4e, 4f) or 7-methyl (5e, 5f) substitution on the ring A of flavonoid dimers have the highest modulating activity for DOX against MRP1 with an EC(50) ranging from 73 to 133 nM. At 0.5 microM, the flavonoid dimer 4e was sufficient to restore DOX accumulation in 2008/MRP1 to parental 2008/P level. Lineweaver-Burk and Dixon plot suggested that it is likely a competitive inhibitor of DOX transport with a K(i) = 0.2 microM. Our data suggest that flavonoid dimers have a high affinity toward binding to DOX recognition site of MRP1. This results in inhibiting DOX transport, increasing intracellular DOX retention, and finally resensitizing 2008/MRP1 to DOX. The present study demonstrates that flavonoid dimers can be employed as an effective modulator of MRP1-mediated drug resistance in cancer cells. 10.1021/jm900194w
    Design, synthesis, and biological evaluation of scutellarein carbamate derivatives as potential multifunctional agents for the treatment of Alzheimer's disease. Sang Zhi-Pei,Qiang Xiao-Ming,Li Yan,Wu Bei,Zhang Hui,Zhao Ming-Gao,Deng Yong Chemical biology & drug design A series of scutellarein carbamate derivatives were designed and synthesized based on the multitarget-directed drug design strategy for treatment of Alzheimer's disease. Their acetylcholinesterase and butyrylcholinesterase inhibitory activities, antioxidant activities, metals chelation, and neuroprotective effects against hydrogen peroxide-induced PC12 cell injury were evaluated in vitro. The preliminary results indicated that compound 7b exhibited good inhibitory potency toward AChE and BuChE with IC50 values of 1.2 ± 0.03 μm and 22.1 ± 0.15 μm, respectively, possessed the strong antioxidant potency (10.3 trolox equivalents), as well as acted as a selective metal chelator and neuroprotective agent. Furthermore, 7b could improve memory impairment induced by scopolamine, ethanol, and sodium nitrite using the step-down passive avoidance task in vivo and could remarkably decrease the activity of acetylcholinesterase in mice brain. This study indicated that 7b could be considered as a potential multitarget agent against AD. 10.1111/cbdd.12580
    Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer's Agents: Design, Synthesis and Biological Evaluation. Spilovska Katarina,Korabecny Jan,Sepsova Vendula,Jun Daniel,Hrabinova Martina,Jost Petr,Muckova Lubica,Soukup Ondrej,Janockova Jana,Kucera Tomas,Dolezal Rafael,Mezeiova Eva,Kaping Daniel,Kuca Kamil Molecules (Basel, Switzerland) A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (AChE) and human butyrylcholinesterase (BChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid , bearing two methylene tether between two basic scaffolds, was found to be very potent AChE inhibitor (IC = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on AChE with the most active compound in the study, , pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies. 10.3390/molecules22061006
    Comparison of the molecular interactions of 7'-carboxyalkyl apigenin derivatives with S. cerevisiae α-glucosidase. Qi Y J,Lu H N,Liang J X,Zhao Y M,Wang X E,Jin N Z Computational biology and chemistry As one of the most investigated flavonoids, apigenin, is considered to be a strong α-glucosidase inhibitor. However, the clinical utility of apigenin is limited due to its low solubility. It was reported that the solubility and biological activity can be improved by introducing sole carboxyalkyl group into apigenin, especially the 7'-substitution. With the increase of length of the alkyl chain in carboxyalkyl group, B ring of the apigenin derivative is embedded much more deeply into the binding cavity while the carboxyalkyl stretches to the neighboring cavity. All of the terminal carboxyl groups form hydrogen bonding interactions easily with the surrounding polar amino acids, such as His239, Ser244, Arg312 and Asp349. Thus, the electron density values of the carbonyl in the carboxyl group become higher than the solution status due to the strong molecular interactions. In fact, electron densities of most of the chemical bonds are decreased after molecular docking procedure. On compared with the solution phase, however, dipole moments of most of these molecules are increased, and their vectors are reoriented distinctly in the active sites. It is noticed that all of the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) are distributed throughout the whole parent apigenin ring in solution phase, whereas the disappeared situation happened on the B rings of some molecules (II-IV) in the active site, leading to higher energy gaps. 10.1016/j.compbiolchem.2017.01.007
    Synthesis of scutellarein derivatives to increase biological activity and water solubility. Shi Zhi-Hao,Li Nian-Guang,Shi Qian-Ping,Zhang Wei,Dong Ze-Xi,Tang Yu-Ping,Zhang Peng-Xuan,Gu Ting,Wu Wen-Yu,Fang Fang,Xin-Xue ,Li He-Min,Yang Jian-Ping,Duan Jin-Ao Bioorganic & medicinal chemistry In order to improve the biological activity and water solubility of scutellarin (1), some derivatives of its main metabolite (scutellarein) were designed and synthesized. All the compounds were tested for their thrombin inhibition activity through the analyzation of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity, their water solubility were also assessed by ultraviolet (UV) spectrophotometer. The results showed that compound 8b demonstrated stronger anticoagulant and antioxidant activity, better water solubility compared with scutellarein (2), which warrants it as a promising agent for the treatment of ischemic cerebrovascular disease. 10.1016/j.bmc.2015.09.047
    Scutellarin derivatives as apoptosis inducers: Design, synthesis and biological evaluation. Han Tong,Li Jia,Xue Jingjing,Li He,Xu Fanxing,Cheng Keguang,Li Dahong,Li Zhanlin,Gao Ming,Hua Huiming European journal of medicinal chemistry To explore novel antitumor agents with high efficiency and low toxicity, a series of NO-donating scutellarin derivatives (14-17) were synthesized and the antiproliferative activities against MCF-7, HCT-116, PC-3 and HepG2 cancer cell lines were assessed. Among them, compound 14b was the strongest with IC values of 2.96 μM, 7.25 μM, 0.09 μM and 0.50 μM, respectively, and displayed low toxicity against normal human liver L-O2 cells with an IC of 47.96 μM, showing good selectivity between normal and malignant liver cells. Moreover, NO releasing ability of the derivatives has been studied. Mechanism studies of the most promising compounds 14b and 15a were carried out. The results indicated that 14b and 15a could induce apoptosis, cell cycle arrest at the S phase and led to mitochondrial dysfunction in the HepG2 and PC-3 cell lines, respectively. Furthermore, Human Apoptosis Protein Array kit assay demonstrated that 14b could induce apoptosis through down-regulating the levels of procaspase-3 and inhibiting the expression of survivin, c-IAP1, HSP27, HSP60, HSP70, HO-1/HMOX1/HSP32 and HO-2/HMOX2 in HepG2 cell line. These results guaranteed compound 14b to be a drug candidate against liver cancer for further investigation. 10.1016/j.ejmech.2017.03.020
    Synthesis of Scutellarein Derivatives with a Long Aliphatic Chain and Their Biological Evaluation against Human Cancer Cells. Ni Guanghui,Tang Yanling,Li Minxin,He Yuefeng,Rao Gaoxiong Molecules (Basel, Switzerland) Scutellarin is the major active flavonoid extracted from the traditional Chinese herbal medicine (Vant.) Hand-Mazz., which is widely used in China. Recently, accumulating evidence has highlighted the potential role of scutellarin and its main metabolite scutellarein in the treatment of cancer. To explore novel anticancer agents with high efficiency, a series of new scutellarein derivatives with a long aliphatic chain were synthesized, and the antiproliferative activities against Jurkat, HCT-116 and MDA-MB-231 cancer cell lines were assessed. Among them, compound exhibited the strongest antiproliferative effects on Jurkat (IC = 1.80 μM), HCT-116 (IC = 11.50 μM) and MDA-MB-231 (IC = 53.91 μM). In particular, even showed stronger antiproliferative effects than the positive control NaAsO₂ on Jurkat and HCT-116 cell lines. The results showed that a proper long aliphatic chain enhanced the antiproliferative activity of scutellarein. 10.3390/molecules23020310
    Design, Synthesis, and Biological Evaluation of Scutellarein Derivatives Based on Scutellarin Metabolic Mechanism In Vivo. Dong Ze-Xi,Shi Zhi-Hao,Li Nian-Guang,Zhang Wei,Gu Ting,Zhang Peng-Xuan,Wu Wen-Yu,Tang Yu-Ping,Fang Fang,Xue Xin,Li He-Min,Cheng Hai-Bo,Yang Jian-Ping,Duan Jin-Ao Chemical biology & drug design Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. Their thrombin inhibition activities were tested through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay and the ability to protect PC12 cells against H2 O2 -induced cytotoxicity, and their solubilities were evaluated by ultraviolet (UV) spectrophotometer. The results showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment. 10.1111/cbdd.12727
    Synthesis and biological evaluation of apigenin derivatives as antibacterial and antiproliferative agents. Liu Rui,Zhang Hongchi,Yuan Maosen,Zhou Jiao,Tu Qin,Liu Jian-Jun,Wang Jinyi Molecules (Basel, Switzerland) Two series of apigenin [5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one] derivatives, 3a-3j and 4a-4j, were synthesized. The apigenin and alkyl amines moieties of these compounds were separated by C₂ or C₃ spacers, respectively. The chemical structures of the apigenin derivatives were confirmed using ¹H-NMR, ¹³C-NMR, and electrospray ionization mass spectroscopy. The in vitro antibacterial and antiproliferative activities of all synthesized compounds were determined. Among the tested compounds, 4a-4j displayed significant antibacterial activity against the tested strains (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa). Additionally, 4i showed the best inhibitory activity with minimum inhibitory concentrations of 1.95, 3.91, 3.91, and 3.91 μg/mL against S. aureus, B. subtilis, E. coli, and P. aeruginosa, respectively. The antiproliferative activity of the apigenin derivatives was evaluated by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. We determined that 4a-4j displayed better growth inhibition activity against four human cancer cell lines, namely, human lung (A549), human cervical (HeLa), human hepatocellular liver (HepG2), and human breast (MCF-7) cancer cells, than the parent apigenin. Compound 4j was found to be the most active antiproliferative compound against the selected cancer cells. Structure-activity relationships were also discussed based on the obtained experimental data. 10.3390/molecules180911496
    Synthesis and Biological Evaluation of Scutellarein Alkyl Derivatives as Preventing Neurodegenerative Agents with Improved Lipid Soluble Properties. Li He-Min,Gu Ting,Wu Wen-Yu,Yu Shao-Peng,Fan Tian-Yuan,Zhong Yue,Li Nian-Guang Medicinal chemistry (Shariqah (United Arab Emirates)) BACKGROUND:Exogenous antioxidants are considered as a promising therapeutic approach to treat neurodegenerative diseases since they could prevent and/or minimize the neuronal damage by oxidation. OBJECTIVE:Three series of lipophilic compounds structurally based on scutellarein (2), which is one metabolite of scutellarin (1) in vivo, have been designed and synthesized. METHODS:Their antioxidant activity was evaluated by detecting the 2-thiobarbituric acid reactive substance (TBARS) produced in the ferrous salt/ascorbate-induced autoxidation of lipids, which were present in microsomal membranes of rat hepatocytes. The lipophilicity of these compounds indicated as partition coefficient between n-octanol and buffer was investigated by ultraviolet (UV) spectrophotometer. RESULTS:This study indicated that compound 5e which had a benzyl group substituted at the C4'- OH position showed a potent antioxidant activity and good lipophilicity. CONCLUSION:5e could be an effective candidate for preventing or reducing the oxidative status associated with the neurodegenerative processes. 10.2174/1573406414666181015143551
    Effects of C-glycosylation on anti-diabetic, anti-Alzheimer's disease and anti-inflammatory potential of apigenin. Choi Jae Sue,Islam Md Nurul,Ali Md Yousof,Kim Eon Ji,Kim Young Myeong,Jung Hyun Ah Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Apigenin has gained particular interests in recent years as a beneficial and health promoting agent because of its low intrinsic toxicity. Vitexin and isovitexin, naturally occurring C-glycosylated derivatives of apigenin, have been known to possess potent anti-diabetic, anti-Alzheimer's disease (anti-AD), and anti-inflammatory activities. The present study was designed to investigate the anti-diabetic, anti-AD, and anti-inflammatory potential of apigenin and its two C-glycosylated derivatives, vitexin and isovitexin by in vitro assays including rat lens aldose reductase (RLAR), human recombinant aldose reductase (HRAR), advanced glycation endproducts (AGEs), protein tyrosine phosphatase 1B (PTP1B), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), β-site amyloid precursor (APP) cleaving enzyme 1 (BACE1), and nitric oxide (NO), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Among them, isovitexin was found as the most potent inhibitor against RLAR, HRAR, AGE, AChE, and BChE while vitexin showed the most potent PTP1B inhibitory activity. Despite the relatively weak anti-diabetic and anti-AD potentials, apigenin showed powerful antiinflammatory activity by inhibiting NO production and iNOS and COX-2 expression while vitexin and isovitexin were inactive. Therefore, it could be speculated that C-glycosylation of apigenin at different positions might be closely linked to relative intensity of anti-diabetic, anti-AD, and anti-inflammatory potentials. 10.1016/j.fct.2013.11.020
    Evidence for activation of mutated p53 by apigenin in human pancreatic cancer. King Jonathan C,Lu Qing-Yi,Li Gang,Moro Aune,Takahashi Hiroki,Chen Monica,Go Vay Liang W,Reber Howard A,Eibl Guido,Hines O Joe Biochimica et biophysica acta Pancreatic cancer is an exceedingly lethal disease with a five-year survival that ranks among the lowest of gastrointestinal malignancies. Part of its lethality is attributable to a generally poor response to existing chemotherapeutic regimens. New therapeutic approaches are urgently needed. We aimed to elucidate the anti-neoplastic mechanisms of apigenin-an abundant, naturally-occurring plant flavonoid-with a particular focus on p53 function. Pancreatic cancer cells (BxPC-3, MiaPaCa-2) experienced dose and time-dependent growth inhibition and increased apoptosis with apigenin treatment. p53 post-translational modification, nuclear translocation, DNA binding, and upregulation of p21 and PUMA were all enhanced by apigenin treatment despite mutated p53 in both cell lines. Transcription-dependent p53 activity was reversed by pifithrin-α, a specific DNA binding inhibitor of p53, but not growth inhibition or apoptosis suggesting transcription-independent p53 activity. This was supported by immunoprecipitation assays which demonstrated disassociation of p53/BclXL and PUMA/BclXL and formation of complexes with Bak followed by cytochrome c release. Treated animals grew smaller tumors with increased cellular apoptosis than those fed control diet. These results suggest that despite deactivating mutation, p53 retains some of its function which is augmented following treatment with apigenin. Cell cycle arrest and apoptosis induction may be mediated by transcription-independent p53 function via interactions with BclXL and PUMA. Further study of flavonoids as chemotherapeutics is warranted. 10.1016/j.bbamcr.2011.12.008
    Discovery of xanthine oxidase inhibitors and/or α-glucosidase inhibitors by carboxyalkyl derivatization based on the flavonoid of apigenin. Su Zhuo-Ran,Fan Shi-Yong,Shi Wei-Guo,Zhong Bo-Hua Bioorganic & medicinal chemistry letters Three series of apigenin derivatives have been prepared by coupling the carboxyl alkyl group to 4'-, 5- or 7-hydroxyl groups of apigenin respectively. Preliminary biological evaluation in vitro revealed that xanthine oxidase inhibitory activity was improved by modifications at 4'-position and decreased by similar modifications at 5-, 7-positions while α-glucosidase inhibitory activity was maintained by modifications at 5-, 7-positions but lost by modifications at 4'-position. Administration (ip) of 7e markedly lowered serum uric acid levels in potassium oxonate induced hyperuricemic mouse model and administration (p.o.) of 11d or 11e effectively suppressed the elevation of serum glucose in the oral sucrose tolerance test in mice, while apigenin were not significantly effective in both tests. 10.1016/j.bmcl.2015.05.016
    Oxidation pathways underlying the pro-oxidant effects of apigenin. Andueza Aitor,García-Garzón Antonia,Ruiz de Galarreta Marina,Ansorena Eduardo,Iraburu María J,López-Zabalza María J,Martínez-Irujo Juan J Free radical biology & medicine Apigenin, a natural flavone, is emerging as a promising compound for the treatment of several diseases. One of the hallmarks of apigenin is the generation of intracellular reactive oxygen species (ROS), as judged by the oxidation of reduced dichlorofluorescein derivatives seen in many cell types. This study aimed to reveal some mechanisms by which apigenin can be oxidized and how apigenin-derived radicals affect the oxidation of 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein (H(2)DCF), a probe usually employed to detect intracellular ROS. Apigenin induced a rapid oxidation of H(2)DCF in two different immortalized cell lines derived from rat and human hepatic stellate cells. However, apigenin did not generate ROS in these cells, as judged by dihydroethidium oxidation and extracellular hydrogen peroxide production. In cell-free experiments we found that oxidation of apigenin leads to the generation of a phenoxyl radical, which directly oxidizes H(2)DCF with catalytic amounts of hydrogen peroxide. The net balance of the reaction was the oxidation of the probe by molecular oxygen due to redox cycling of apigenin. This flavonoid was also able to deplete NADH and glutathione by a similar mechanism. Interestingly, H(2)DCF oxidation was significantly accelerated by apigenin in the presence of horseradish peroxidase and xanthine oxidase, but not with other enzymes showing peroxidase-like activity, such as cytochrome c or catalase. We conclude that in cells treated with apigenin oxidation of reduced dichlorofluorescein derivatives does not measure intracellular ROS and that pro- and antioxidant effects of flavonoids deduced from these experiments are inconclusive and must be confirmed by other techniques. 10.1016/j.freeradbiomed.2015.06.003
    Apigenin-induced apoptosis is enhanced by inhibition of autophagy formation in HCT116 human colon cancer cells. Lee Yujin,Sung Bokyung,Kang Yong Jung,Kim Dong Hwan,Jang Jung-Yoon,Hwang Seong Yeon,Kim Minjung,Lim Hyun Sook,Yoon Jeong-Hyun,Chung Hae Young,Kim Nam Deuk International journal of oncology Apigenin (4',5,7-trihydroxyflavone) is a natural flavonoid, shown to have chemopreventive and/or anticancer properties in a variety of human cancer cells. The involvement of autophagy in apigenin-induced apoptotic cell death of HCT116 human colon cancer cells was investigated. Apigenin induced suppression of cell growth in a concentration-dependent manner in HCT116 cells. Flow cytometric analyses indicated that apigenin resulted in G2/M phase arrest. This flavone also suppressed the expression of both cyclin B1 and its activating partners, Cdc2 and Cdc25c, whereas the expression of cell cycle inhibitors, such as p53 and p53-dependent p21(CIP1/WAF1), was increased after apigenin treatment. Apigenin induced poly (ADP-ribose) polymerase (PARP) cleavage and decreased the levels of procaspase-8, -9 and -3. In addition, the apigenin-treated cells exhibited autophagy, as characterized by the appearance of autophagosomes under fluorescence microscopy and the accumulation of acidic vesicular organelles by flow cytometry. Furthermore, the results of the western blot analysis revealed that the levels of LC3-II, the processed form of LC3-I, was increased by apigenin. Treatment with the autophagy inhibitor 3-methyladenine (3-MA) significantly enhanced the apoptosis induced by apigenin, which was accompanied by an increase in the levels of PARP cleavage. These results indicate that apigenin has apoptosis- and autophagy-inducing effects in HCT116 colon cancer cells. Autophagy plays a cytoprotective role in apigenin-induced apoptosis, and the combination of apigenin and an autophagy inhibitor may be a promising strategy for colon cancer control. 10.3892/ijo.2014.2339
    Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo. Chen Haijun,Mrazek Amy A,Wang Xiaofu,Ding Chunyong,Ding Ye,Porro Laura J,Liu Huiling,Chao Celia,Hellmich Mark R,Zhou Jia Bioorganic & medicinal chemistry Accumulating evidence suggests that activated pancreatic stellate cells (PSC) play an important role in chronic pancreatitis (CP), and inhibition of the activated PSC is considered as a potential strategy for the treatment and prevention of CP. Herein, we disclose our findings that apigenin and its novel analogues suppress the proliferation and induce apoptosis in PSC, which reduce the PSC-mediated fibrosis in CP. Chemical modifications of apigenin have been directed to build a focused library of O-alkylamino-tethered apigenin derivatives at 4'-O position of the ring C with the attempt to enhance the potency and drug-like properties including aqueous solubility. A number of compounds such as 14, 16, and 24 exhibited potent antiproliferative effects as well as improved aqueous solubility. Intriguingly, apigenin, new analogues 23 and 24 displayed significant efficacy to reduce pancreatic fibrosis even at a low dose of 0.5mg/kg in our proof-of-concept study using a preclinical in vivo mouse model of CP. 10.1016/j.bmc.2014.04.043
    Plant flavone apigenin binds to nucleic acid bases and reduces oxidative DNA damage in prostate epithelial cells. Sharma Haripaul,Kanwal Rajnee,Bhaskaran Natarajan,Gupta Sanjay PloS one Oxidative stress has been linked to prostate carcinogenesis as human prostate tissue is vulnerable to oxidative DNA damage. Apigenin, a dietary plant flavone, possesses anti-proliferative and anticancer effects; however, its antioxidant properties have not been fully elucidated. We investigated sub-cellular distribution of apigenin, it's binding to DNA and protective effects against H2O2-induced DNA damage using transformed human prostate epithelial RWPE-1 cells and prostate cancer LNCaP, PC-3 and DU145 cells. Exposure of cells to apigenin exhibited higher accumulation in RWPE-1 and LNCaP cells, compared to PC-3 and DU145 cells. The kinetics of apigenin uptake in LNCaP cells was estimated with a Km value of 5 µmole/L and Vmax of 190 pmoles/million cells/h. Sub-cellular fractionation demonstrated that nuclear matrix retains the highest concentration of apigenin (45.3%), followed by cytosol (23.9%), nuclear membranes (17.9%) and microsomes (12.9%), respectively. Spectroscopic analysis of apigenin with calf-thymus DNA exhibited intercalation as the dominant binding mode to DNA duplex. Apigenin exposure resulted in significant genoprotective effects in H2O2-stressed RWPE-1 cells by reduction in reactive oxygen species levels. In addition, apigenin exposure suppressed the formation of 8-hydroxy-2' deoxyguanosine and protected exposed cells from apoptosis. Our studies demonstrate that apigenin is readily taken up by normal prostatic epithelial cells and prostate cancer cells, and is incorporated into their nuclei, where its intercalation with nucleic acid bases may account for its antioxidant and chemopreventive activities. 10.1371/journal.pone.0091588
    Traversal of the Blood-Brain Barrier by Cleavable l-Lysine Conjugates of Apigenin. Wong Tsung-Yun,Tsai Ming-Shian,Hsu Lih-Ching,Lin Shu-Wha,Liang Pi-Hui Journal of agricultural and food chemistry Apigenin, a flavone abundant in parsley and celery, is known to act on several CNS receptors, but its very poor water solubility (<0.001 mg/mL) impedes its absorption in vivo and prevents clinical use. Herein, apigenin was directly conjugated with glycine, l-phenylalanine, and l-lysine to give the corresponding carbamate derivatives, all of which were much more soluble than apigenin itself (0.017, 0.018, and 0.13 mg/mL, respectively). The Lys-apigenin carbamate 10 had a temporary sedative effect on the mice within 5 min of intraperitoneal administration (single dose of 0.4 mg/g) and could be detected in the mice brain tissues at a concentration of 0.82 μg/g of intact Lys-apigenin carbamate 10 and 0.42 ug/g of apigenin at 1.5 h. This study accomplished the delivery of apigenin across the BBB in a manner that might be applicable to other congeners, which should inform the future development of BBB-crossing flavonoids. 10.1021/acs.jafc.8b01187
    Mutual Interaction of Phenolic Compounds and Microbiota: Metabolism of Complex Phenolic Apigenin-C- and Kaempferol-O-Derivatives by Human Fecal Samples. Vollmer Maren,Esders Selma,Farquharson Freda M,Neugart Susanne,Duncan Sylvia H,Schreiner Monika,Louis Petra,Maul Ronald,Rohn Sascha Journal of agricultural and food chemistry Human colonic bacteria have an important impact on the biotransformation of flavonoid glycosides and their conversion can result in the formation of bioactive compounds. However, information about the microbial conversion of complex glycosylated flavonoids and the impact on the gut microbiota are still limited. In this study, in vitro fermentations with selected flavonoid O- and C-glycosides and three different fecal samples were performed. As a result, all flavonoid glycosides were metabolized via their aglycones yielding smaller substances. Main metabolites were 3-(4-hydroxyphenyl)propionic acid, 3-phenylpropionic acid, and phenylacetic acid. Differences in the metabolite formation due to different time courses between the donors were determined. Therefore, from all fermentations, the ones with a specific donor were always slower resulting in a lower number of metabolites compared to the others. For example, tiliroside was totally degraded from 0 h (105 ± 13.2 μM) within the first 24 h, while in the fermentations with fecal samples from other donors, tiliroside (107 ± 52.7 μM at 0 h) was not detected after 7 h anymore. In general, fermentation rates of C-glycosides were slower compared to the fermentation rates of O-glycosides. The O-glycoside tiliroside was degraded within 4 h while the gut microbiota converted the C-glycoside vitexin within 13 h. However, significant changes (p < 0.05) in the microbiota composition and short chain fatty acid levels as products of carbohydrate fermentation were not detected between incubations with different phenolic compounds. Therefore, microbiota diversity was not affected and a significant prebiotic effect of phenolic compounds cannot be assigned to flavonoid glycosides in food-relevant concentrations. 10.1021/acs.jafc.7b04842
    Total synthesis of scutellarin and apigenin 7-O-β-d-glucuronide. Liu Xin,Wen Guo-En,Liu Jian-Chao,Liao Jin-Xi,Sun Jian-Song Carbohydrate research A general protocol for direct glucuronic linkages formation featuring Au(I)-catalyzed appropriately protected glucuronyl o-alkynylbenzoate-involved glycosylation reaction, as well as a concise approach for easy access of scutellarein prominent for the mild and efficient hydroxyl group installation via borylation-oxidation sequence from flavanone derivative, has been established, based on which a novel route for scutellarin derivatives preparation has been devised. The developed strategies, among which the stepwise deprotection process was also included, guarantee the high whole synthetic efficiency, and definitely will find broad application in diversity-oriented synthesis of bioactive flavonoid glycosides. 10.1016/j.carres.2019.02.005
    Synthesis and anti-cancer activities of apigenin derivatives. Zheng Xing,Yu Liuying,Yang Jing,Yao Xu,Yan Wenna,Bo Shaowei,Liu Ya,Wei Yun,Wu Zhiyi,Wang Guan Medicinal chemistry (Shariqah (United Arab Emirates)) A novel series of apigenin derivatives with phloroglucinol or resorcinol as raw materials were synthesized according to Baker-Venaktaraman reaction and their in vitro inhibitory activities on colorectal adenocarcinoma (HT-29) and leucocythemia (HL-60) cell lines were evaluated by the standard methyl thiazole tetrazolium (MTT) method. The results of biological test showed that some of apigenin derivatives possessed stronger anti-cancer activities than apigenin. Compound 6 showed the strongest activity against colorectal adenocarcinoma (HT-29) and leucocythemia (HL-60) cell lines with IC50 valure of 2.03±0.22 µM, 2.25±0.42 µM, it was better than 5-FU (12.92±0.61 µM, 9.56±0.16 µM), which shows a potential compound for colorectal adenocarcinoma and leucocythemia. 10.2174/1573406410666140307152557
    Direct semi-synthesis of the anticancer lead-drug protoapigenone from apigenin, and synthesis of further new cytotoxic protoflavone derivatives. Hunyadi Attila,Chuang Da-Wei,Danko Balazs,Chiang Michael Y,Lee Chia-Lin,Wang Hui-Chun,Wu Chin-Chung,Chang Fang-Rong,Wu Yang-Chang PloS one Protoapigenone, a natural flavonoid possessing an unusual p-quinol moiety on its B-ring, is a novel prospective anticancer agent with low toxicity that is currently in development. The first economical, one-step synthesis of protoapigenone from apigenin is described on up to gram scale. 13 new 1'-O-alkylflavone analogs were also synthesized, either from apigenin or β-naphthoflavone. The in vitro cytotoxic activity of each compound was tested on six human cancer cell lines (HepG2, Hep3B, Ca9-22, A549, MCF-7 and MDA-MB-231). In the case of 1'-O-alkyl-protoapigenone derivatives, structure-activity relationships were found depending on the side-chain, and protoapigenone 1'-O-butyl ether was found to exert significantly stronger activity against three of the cell lines (Hep3B, MCF-7 and MDA-MB-231) than its non-substituted analog, protoapigenone itself. In contrast to this, all β-naphthoflavone derivatives bearing the same pharmacophore on their B-ring showed decreased cytotoxic activities when substituted with an O-alkyl side-chain at position 1', comparing to that of the non-substituted compound. 10.1371/journal.pone.0023922
    Synthesis, nitric oxide release, and α-glucosidase inhibition of nitric oxide donating apigenin and chrysin derivatives. Wang Qi-Qin,Cheng Ning,Yi Wen-Bing,Peng Sheng-Ming,Zou Xiao-Qing Bioorganic & medicinal chemistry α-Glucosidase (AG) play crucial roles in the digestion of carbohydrates. Inhibitors of α-glucosidase (AGIs) are promising candidates for the development of anti-diabetic drugs. Here, five series of apigenin and chrysin nitric oxide (NO)-donating derivatives were synthesised and evaluated for their AG inhibitory activity and NO releasing capacity in vitro. Except for 9a-c, twelve compounds showed remarkable inhibitory activity against α-glucosidase, with potency being better than that of acarbose and 1-deoxynojirimycin. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure activity relationship studies indicated that 5-OH, hydrophobic coupling chain, and carbonyl groups of the coupling chain could enhance the inhibitory activity. Apigenin and chrysin derivatives therefore represents a new class of promising compounds that can inhibit α-glucosidase activity and supply moderate NO for preventing the development of diabetic complications. 10.1016/j.bmc.2014.01.038
    A comparison of the effects of apigenin and seven of its derivatives on selected biomarkers of oxidative stress and coagulation in vitro. Kowalska Iwona,Adach Weronika,Stochmal Anna,Olas Beata Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Apigenin is a phenolic compound widely present in many fruits, vegetables and herbs. Its name originates from Apium: a genus of the Apiaceae. The aim of the present study was to determine the antioxidant or pro-oxidant properties of apigenin and seven of its derivatives, isolated from the aerial parts of barrel medic (Medicago truncatula) and common wheat (Triticum aestivum), in human plasma treated with a hydroxyl radical donor (OH) in vitro. It also examines their influence on the parameters of coagulation. The compounds were found to demonstrate different effects on oxidative stress and coagulation which may be related to differences in their structure. In particular, apigenin 7-O-{2'-O-feruloyl-[β-D-glucuronopyranosyl(1 → 3)]-β-D- glucuronopyranosyl(1 → 2)-O-β-D-glucopyranoside} demonstrates both antioxidant and anticoagulant activities, and may offer the most promise for the prevention and treatment of cardiovascular disorders of all the phenolic compounds tested so far. 10.1016/j.fct.2019.111016