共查询到20条相似文献,搜索用时 46 毫秒
1.
James McNulty Jerald J. Nair Mohini Singh Denis J. Crankshaw Alison C. Holloway 《Bioorganic & medicinal chemistry letters》2009,19(19):5607-5612
Two total syntheses of fully functionalized seco-analogs of the anticancer compound pancratistatin are reported. Structure–activity relationship (SAR) studies identified potent and selective inhibitors of human cytochrome P450 3A4 (CYP3A4) and revealed several core pharmacophoric elements. These studies identify potential roadblocks and will guide the further development of a viable selective clinical pancratistatin derivative. 相似文献
2.
James McNulty Jerald J. Nair Mohini Singh Denis J. Crankshaw Alison C. Holloway 《Bioorganic & medicinal chemistry letters》2010,20(7):2335-2339
seco-Derivatives of the anticancer agent pancratistatin bearing the 2S,3S,4S,5S configuration were accessed via a novel, highly diastereoselective anti-aldol reaction. Structure–activity relationships reveal important insights into the seco-pancratistatin pharmacophore as a potent and selective inhibitor of human cytochrome P450 3A4 (CYP3A4), and highlight features of concern in advancing a potent, selective anticancer agent in the pancratistatin series. 相似文献
3.
McNulty J Mao J Gibe R Mo R Wolf S Pettit GR Herald DL Boyd MR 《Bioorganic & medicinal chemistry letters》2001,11(2):169-172
Two deoxy-analogues of the anticancer/antiviral agent pancratistatin containing functionality complementary to the minimum structural pharmacophore were synthesized and subjected to anticancer screening. One of the analogues exhibited selective inhibition of certain tumor cell lines but was significantly less potent than the natural products. The minimum structural pharmacophore has now been refined from eight to three possible structures. 相似文献
4.
Parveen Khan Sayara Abbas Bob Petit Robert Caffrey Victoria Megram Alan McGown 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1999,726(1-2)
The stability of the experimental anti-tumour agent pancratistatin in human plasma has been investigated. A solid-phase extraction technique and an HPLC assay with external standards have been developed and validated. Extraction was performed using C18 cartridges and HPLC, analysis was performed on a 15 cm Hypersil BDS column using isocratic elution with 13% acetonitrile and aqueous solution of 1% (w/v) acetic acid. The lower limit of quantification for pancratistatin in 5% DMF–95% water was found to be 0.58 ng/ml (±10.58%) and 2.3 ng/ml (±9.2%) following extraction from human plasma. Mean recovery of 89.4% (±4.73%) was obtained over the concentration range 0.0023–9.45 μg/ml for a five day validation study. Pancratistatin was stable at room temperature in light or dark for at least 15 days, in the refrigerator at 4°C for at least 16 days and in the freezer at −20°C or −80°C for at least 28 days. Under all conditions monitored, % recovery of pancratistatin from human plasma was greater than 95% and no evidence of degradation had occurred. There also was no loss of pancratistatin after three cycles of freezing and thawing. 相似文献
5.
Idso SB Kimball BA Pettit Iii GR Garner LC Pettit GR Backhaus RA 《American journal of botany》2000,87(6):769-773
Two 2-yr crops of tropical spider lily (Hymenocallis littoralis) plants were grown in field soil in clear-plastic-wall open-top enclosures in the Sonoran Desert environment of central Arizona. Half of the plants were exposed to ambient air of 400 ppm atmospheric CO(2) concentration and half of them were exposed to air of 700 ppm CO(2). This 75% increase in the air's CO(2) content resulted in a 48% increase in aboveground plant biomass and a 56% increase in belowground (bulb) biomass. It also increased the concentrations of five bulb constituents that have been demonstrated to possess anticancer and antiviral activities. Mean percentage increases in these concentrations were 6% for a two-constituent (1:1) mixture of 7-deoxynarciclasine and 7-deoxy-trans-dihydronarciclasine, 8% for pancratistatin, 8% for trans-dihydronarciclasine, and 28% for narciclasine, for a mean active ingredient percentage concentration increase of 12%. Combined with the 56% increase in bulb biomass, these percentage concentration increases resulted in a mean active ingredient increase of 75% for the 75% increase in the air's CO(2) concentration used in our experiments. 相似文献
6.
Anticancer evaluation of structurally diverse Amaryllidaceae alkaloids and their synthetic derivatives 总被引:1,自引:0,他引:1
Plants of the Amaryllidaceae family have been under intense scrutiny for the presence of the specific metabolites responsible
for the medicinal properties associated with them. The study began in 1877 with the isolation of alkaloid lycorine from Narcissus pseudonarcissus and since then more than 100 alkaloids, exhibiting diverse biological activities, have been isolated from the Amaryllidaceae
plants. Based on the present scientific evidence, it is likely that isocarbostyril constituents of the Amaryllidaceae, such
as narciclasine, pancratistatin and their congeners, are the most important metabolites responsible for the therapeutic benefits
of these plant species in the folk medical treatment of cancer. Notably, Narcissus poeticus L., used by the ancient Greek physicians, is now known to contain about 0.12 g of narciclasine per kg of fresh bulbs. The
focus of the present research work is the chemistry and biology of these compounds as specifically relevant to their potential
use in medicine. In particular, the anticancer evaluation of lycorine, narciclasine as well as of other Amaryllidaceae alkaloids
and their synthetic derivatives are presented in this paper. The structure–activity relationships among some groups of Amaryllidaceae
alkaloids will be discussed. 相似文献
7.
James McNulty Jerald J. Nair Mohini Singh Denis J. Crankshaw Alison C. Holloway Jaume Bastida 《Bioorganic & medicinal chemistry letters》2009,19(12):3233-3237
A library of natural and semi-synthetic Amaryllidaceae alkaloids was screened for cytochrome P450 3A4 (CYP3A4) inhibitory activity. Of the crinane, lycorane and galanthamine representatives examined two semi-synthetic silylated lycorane analogues, accessed via a chemoselective silylation strategy from lycorine, and the natural compound narciclasine exhibited low micromolar activities. Important pharmacological features uncovered include the lack of CYP3A4 inhibitory activity seen for galanthamine and the selective activity that is seen with narciclasine over pancratistatin. 相似文献
8.
Background
Pancratistatin, a natural compound extracted from Hymenocallis littoralis, can selectively induce apoptosis in several cancer cell lines. In this ex vivo study, we evaluated the effect of pancratistatin on peripheral blood mononuclear cells obtained from 15 leukemia patients prior to clinical intervention of newly diagnosed patients, as well as others of different ages in relapse and at various disease progression states. 相似文献9.
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11.
Cisplatin resistance and mechanism in a viral test system: SV40 isolates that resist inhibition by the antitumor drug have lost regulatory DNA 总被引:1,自引:0,他引:1
Isolates of SV40 that have enhanced ability to survive inhibition by the antitumor drug cisplatin were selected by serial drug challenge in vivo. These mutant viruses have acquired specific deletions within the repeated regulatory motif (GGGCGG)6 or GC box. This DNA element was shown previously to be a strong target of drug attack by cisplatin and other anticancer drugs in vitro and is an important viral and cellular DNA control sequence. Thus, drug resistance in this viral test system is dependent on the loss of important target DNA sequences. The results also indicate that drug efficacy may be related to the ability of certain anticancer drugs to attack regulatory DNA sequences containing strings of guanosines. 相似文献
12.
Vshyvenko S Scattolon J Hudlicky T Romero AE Kornienko A 《Bioorganic & medicinal chemistry letters》2011,21(16):4750-4752
The synthesis of two C-1 analogues of pancratistatin has been accomplished in 17 steps from bromobenzene. The key steps involved the enzymatic dihydroxylation, regioselective opening of epoxyaziridine 9 with the alane derived from 8, a solid-state silica-gel-catalyzed intramolecular opening of aziridine to produce phenanthrene 13 whose oxidative cleavage and recyclization provided the full skeleton of the Amaryllidaceae constituents. The new analogues 5 and 6 exhibited promising activity in several human cancer cell lines. 相似文献
13.
Komeda S 《Metallomics : integrated biometal science》2011,3(7):650-655
Platinum coordination compounds are among the most utilized anticancer agents, even though platinum has not been determined to be an essential trace element in any living organism. The success of platinum-based drugs has catalyzed research on other metal-containing agents that can be used to achieve therapeutic goals that cannot be achieved with organic compounds. The antitumor activities of recently reported platinum(ii) complexes indicate that further modification of platinum coordination compounds will lead to the development of anticancer agents with higher efficacies against chemotherapy-insensitive tumors. 相似文献
14.
JJ Nair L Rárová M Strnad J Bastida J van Staden 《Bioorganic & medicinal chemistry letters》2012,22(19):6195-6199
Several of the Amaryllidaceae alkaloids are known for their cytotoxic properties, of which the lycorine group representatives are prominent for potent and cell line specific antiproliferative activities. As a distinct niche within the lycorine group, the phenanthridones, exemplified by narciclasine and pancratistatin, have shown much promise as remarkably selective cytotoxic agents and are presently at various stages of development, with a clinical candidate likely to appear on the market within the next decade. The crinane group of the Amaryllidaceae has also spawned several molecules, such as crinamine and haemanthamine, with promising cytotoxic activities. In the present study, the β-crinane distichamine as well as the phenanthridone narciprimine, both rare constituents of the Amaryllidaceae, are revealed as novel antiproliferative agents. Apoptosis-inducing effects are demonstrated for distichamine in human acute lymphoblastic leukemia (CEM) cells. These findings provide further insights to the structural details of the apoptosis-inducing pharmacophores resident within both series of alkaloids. 相似文献
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16.
Wang W Goswami S Sahai E Wyckoff JB Segall JE Condeelis JS 《Trends in cell biology》2005,15(3):138-145
Invasion of neighboring extracellular matrix tissue, the lymphatic system and blood vessels is a key element of tumor cell metastasis in many epithelial tumors. Understanding the cell motility pathways that contribute to invasion can provide new approaches and targets for anticancer therapy. The recent convergence of technologies for expression profiling and intravital imaging has revealed the identities of some of the genes that contribute to motility and chemotaxis of cancer cells in tumors. In particular, the genes encoding a minimum motility machine are coordinately upregulated in tumor cells collected by an in vivo invasion assay. These results support a "tumor microenvironment invasion model" and provide new target opportunities for cancer therapy. 相似文献
17.
Selenium is an essential trace element, the deficiency of which leads to the development of several serious diseases, including male infertility, prostate cancer, etc. It has been shown that oxidative stress contributes to the progression of prostate cancer, and antioxidants such as selenium and vitamin E can significantly reduce the risk of this disease. Sodium selenite, one of the selenium compounds that induce the formation of reactive oxygen species, is considered as a potential anticancer agent. The SS concentrations that lead to a decrease in the viability of human prostate adenocarcinoma cells (line Du-145) have been selected, and the effect of sodium selenite on the expression of mRNA of the SELV, SELW, and TGR selenocysteine proteins in these cells has been analyzed. 相似文献
18.
Hast MA Nichols CB Armstrong SM Kelly SM Hellinga HW Alspaugh JA Beese LS 《The Journal of biological chemistry》2011,286(40):35149-35162
Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals, including AIDS patients and transplant recipients. Few antifungals can treat C. neoformans infections, and drug resistance is increasing. Protein farnesyltransferase (FTase) catalyzes post-translational lipidation of key signal transduction proteins and is essential in C. neoformans. We present a multidisciplinary study validating C. neoformans FTase (CnFTase) as a drug target, showing that several anticancer FTase inhibitors with disparate scaffolds can inhibit C. neoformans and suggesting structure-based strategies for further optimization of these leads. Structural studies are an essential element for species-specific inhibitor development strategies by revealing similarities and differences between pathogen and host orthologs that can be exploited. We, therefore, present eight crystal structures of CnFTase that define the enzymatic reaction cycle, basis of ligand selection, and structurally divergent regions of the active site. Crystal structures of clinically important anticancer FTase inhibitors in complex with CnFTase reveal opportunities for optimization of selectivity for the fungal enzyme by modifying functional groups that interact with structurally diverse regions. A substrate-induced conformational change in CnFTase is observed as part of the reaction cycle, a feature that is mechanistically distinct from human FTase. Our combined structural and functional studies provide a framework for developing FTase inhibitors to treat invasive fungal infections. 相似文献
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Hongzhi Wang Yuanyuan Yin Peiqi Wang Chenyu Xiong Lingyu Huang Sijia Li Xinyi Li Leilei Fu 《Apoptosis : an international journal on programmed cell death》2016,21(7):778-794
Cancer is a deadly disease with increasing incidence and mortality rates and affects the life quality of millions of people per year. The past 15 years have witnessed the rapid development of targeted therapy for cancer treatment, with numerous anticancer drugs, drug targets and related gene mutations been identified. The demand for better anticancer drugs and the advances in database technologies have propelled the development of databases related to anticancer drugs. These databases provide systematic collections of integrative information either directly on anticancer drugs or on a specific type of anticancer drugs with their own emphases on different aspects, such as drug–target interactions, the relationship between mutations in drug targets and drug resistance/sensitivity, drug–drug interactions, natural products with anticancer activity, anticancer peptides, synthetic lethality pairs and histone deacetylase inhibitors. We focus on a holistic view of the current situation and future usage of databases related to anticancer drugs and further discuss their strengths and weaknesses, in the hope of facilitating the discovery of new anticancer drugs with better clinical outcomes. 相似文献