1,721,177 research outputs found
Evaluation of anticancer properties of thiosugars
No full textThe “sugar code” concept assumes the interaction of carbohydrates with inter and intra cellular
components. This concept is the basis of a therapy employing carbohydrate-derived chemicals as drugs
(Gabius, 2004). The “CARB” pharmacological potential is enhanced by the addition of pharmacophores and
other functional groups. We proposed an idea of “functional carb-pharmacophores” (FCP) as a new approach
to compose functionalized sugar derivatives that have therapeutic potential (Witczak, Poplawski, 2014) and
designed the collection of FCP. For further investigation we choose sugar derivatives including thisugar and
1-4-S-thiodisacharide motifs. Our preliminary data suggest their anticancer properties, and the most sensitive
was astrocytoma (HTB-14) and breast cancer (MCF-7) cell lines. The aim of this project is to determine
mechanisms of anticancer activities of functional carb-pharmacophores (FCPs). Taking into account the
results of our research we set the following hypotheses:
The selected FCPs kills cancer cells by activating one of the cellular death pathway.
The selected FCPs induce expression of the key genes in biological pathways activated in
response to toxic drugs in cancer and normal cells
The selected FCPs induce oxidative stress in cancer cells.
The selected FCPs have inhibitory effect on proliferation cancer cells in vitro
The uptake of selected FCPs is mediated by facilitative glucose transporter proteins
(GLUTs)
Development of C-Methyl Branched Purine Ribonucleoside Analogs: Chemistry, Biological Activity and Therapeutic Potential
No full textIn this review, we first highlighted on C-methyl-branched nucleosides and nucleotides approved as anti-hepatitis C infection (HCV) drugs, their mechanism of action and recent progress in the development of new clinical candidates. Then, we report on our attempt to develop several C-methyl nucleosides/tides potentially useful for treatment of various diseases such cancer, pain, epilepsy and glaucoma. Design, synthesis and
pharmacological screening of 1′-C-, 2′-C-, 3'-C-methyladenosine or other purine/pyrimidine nucleosides allowed us to discover some promising new
molecules. 3'-C-Methyladenosine showed antitumor activity against several
human tumor cell lines. We have investigated the mechanism of action of
3'-C-methyladenosine that proved to be an effective inhibitor of ribonucleotide reductase.
Moreover, we will also summarize the chemical and biological properties of some of the
recent N6-substituted and 5', N6-disubstituted 2'-C-methyladenosine derivatives that were synthetized in our laboratory and evaluated as A1 adenosine receptor agonists. 2-Chloro-2'- C-methyl-N6-cyclopentyladenosine (2'-Me-CCPA), 5′-chloro-5′-deoxy-N6-(±)-(endo-norborn-2-yl)adenosine (5′Cl5′d-(±)-ENBA) and 2'-C-methyl-5'-chloro-5'-deoxy-N6-(±)-(endo-norborn-2-yl)adenosine (2'-Me-5′Cl5′d-(±)-ENBA) displayed high hA1AR affinity and selectivity. 2'-Me-CCPA and 5′Cl5′d-(±)-ENBA showed significant analgesic properties
Nicotinamide Adenine Dinucleotide Based Therapeutics, Update
No full textAbout 500 NAD (P)-dependent enzymes in the cell use NAD (P) as a cofactor or a substrate. This family of broadly diversified enzymes is crucial for maintaining homeostasis of all living organisms. The NAD binding domain of these enzymes is conserved and it was believed that NAD mimics would not be of therapeutic value due to lack of selectivity. Consequently, only mycophenolic acid which selectively binds at the cofactor pocket of NAD-dependent IMP-dehydrogenase (IMPDH) has been approved as an immunosuppressant. Recently, it became clear that the NAD (P)-binding domain was structurally much more diversified than anticipated and numerous highly potent and selective inhibitors of NAD (P) dependent enzymes have been reported. It is likely, that as in the case of protein kinases inhibitors, inhibitors of NAD (P)-dependent enzymes would find soon their way to the clinic. In this review, recent developments of selective inhibitors of NAD-dependent human IMPDH, as well as inhibitors of IMPDHs from parasites, and from bacterial sources are reported. Therapies against Cryptosporidium parvum and the development of new antibiotics that are on the horizon will be discussed. New inhibitors of bacterial NAD-ligases, NAD-kinases, NMN-adenylyl transferases, as well as phosphoribosyl transferases are also described. Although none of these compounds has yet to be approved, the progress in revealing and understanding crucial factors that might allow for designing more potent and efficient drug candidates is enormous and highly encouraging
Synthesis and antitumor activity of a heterodinucleotide of BVDU and Gemcitabine
No full textA heterodinucleotide comprising BVDU and Gemcitabine bound together by a 5',5'-pyrophospate bridge (BVDUp(2)dFdC) has been synthesized and evaluated as antitumor agent against AH13 rat sarcoma cells. BVDUp(2)dFdC showed a cytotoxicity similar to that of Gemcitabine
NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK) inhibitors: chemistry and potential therapeutic applications
No full textNicotinamide adenine dinucleotide (NAD+) has a crucial role in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Thus, enzymes involved in NAD+ metabolism are attractive targets for drug discovery against a variety of human diseases. Herein we focus on two of them: NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK). NMNAT is a key enzyme in all organisms catalyzing coupling of ATP and NMN or NaMN yielding NAD or NaAD, respectively. NADKs are ubiquitous enzymes involved in the last step of the biosynthesis of NADP. They phosphorylate NAD to produce NADP using ATP (or inorganic polyphosphates) in the presence of Mg2+. No other pathway of NADP biosynthesis has been found in prokaryotic or eukaryotic cells. In this review we provide a comprehensive summary of NMNAT and NADK inhibitors highlighting their chemical modifications by different synthetic approaches, and structure-activity relationships depending on their potential therapeutic application
New N6-substituted adenosine and 3’-C-methyl-adenosine derivatives as antitumor agents
No full textMany analogues of the natural nucleosides modified at nucleobase or at sugar moiety have been developed on the basis of their therapeutic potential as antitumor antiviral and antiprotozoal agents. Among the N6-modified adenosine analogues, N6-hydroxy, N6-methoxy, and N6-amino derivatives have proved to be potent cytotoxic agents acting through letal mutagenesis. Moreover, modification at the ribose moiety of purine nucleosides resulted in potent antitumor agents, such as in the case of 3'-C-methyladenosine (3'-MeAdo), recently developed by us as a mechanism-based ribonucleotide reductase (RR) inhibitor, that displayed a significant cytotoxicity against a panel of human leukemia and carcinoma cell lines.1 We now report on the synthesis and antitumor activity of a series of 3'-C-methyladenosine derivatives substituted at N6 with a hydroxy, methoxy or amino group. Furthmore, azinyl hydrazone containing a N*-N*-N* structural motif able to inhibit RR were also prepared starting from N6-.amino-adenosine or N6-amino-3'-C-methyladensine. The stereochemistry of these compounds was established to be Z by means of NMR spectroscopy. The antiproliferative activity of the substituted purine nucleosides against a panel of human tumor cell lines will be presented.
1 (a) Franchetti P et al J Med Chem 2005, 48, 4983-89; (b) Cappellacci et al J Med Chem 2008, 51, 4260-6
5'-CHLORO-5'-DEOXY-N6-(±)-endo-NORBORNYLADENOSINE, A POTENT AND HIGHLY SELECTIVE HUMAN A1 ADENOSINE RECEPTOR AGONIST, PREVENTS HYPERALGESIA/ALLODYNIA AND EARLY OVER-EXPRESSION OF PRO-APOPTOTIC AND PRO-INFLAMMATORY GENES IN A MICE MODEL OF NEUROPATHIC PAIN
No full textA1 adenosine receptor (A1AR) is a promising drug target for neuropathic pain treatment. Some N6-substituted adenosine derivatives as A1AR agonists have shown to modulate nociception in vivo. Recently, we reported 5'-chloro-5'-deoxy-N6-(±)-endo-norbornyladenosine (5'Cl5'd-(±)-ENBA) as a very potent and highly selective human A1AR agonist with antinociceptive effects in mice.1 In this study we used mice with sciatic nerve injury (spared nerve injury, SNI) and combined behavioural, molecular and morphological approaches to assess the involvement of A1AR in neuropathic pain-associated hyperalgesia and allodynia and spinal cord gliosis and neuro-inflammation.
Mechanical allodynia and thermal hyperalgesia developed 2-3 days after surgery. Morphological changes in the ipsilateral L4-L6 laminae I-II consisted of: i) increased TUNEL-positive profiles, ii) increased microglia activity, and iii) astrogliosis. Molecular expression data showed: 1) increased expression of pro-apoptotic and pro-inflammatory genes (bax, 325 ± 12%; caspase 7, 109 ± 17%; caspase 8, 133 ± 17%), 7 days after SNI. The selective A1AR agonist 5'Cl5'd-(±)-ENBA (1 mg/Kg i.p. once daily), reduced the development of thermal hyperalgesia and mechanical allodynia. This treatment in part normalized the spinal cord expression of bax, bcl-2 and caspases in SNI mice, and proved to be cytoprotective at 7 days post-SNI. This study shows that: a) allodynia and hyperalgesia developed with spinal cord glia activation, b) over-expression of pro-apoptotic or pro-inflammatory genes may be critical for maintaining gliosis in the spinal cord, and c) adenosine A1 receptor stimulation was capable to protect neuropathic mice from the observed biomolecular and morphological modifications.
(1) Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.; Grifantini, M. J. Med. Chem. 2009, 52, 2393-2406
Development of a LC-MS-MS method for the simultaneous determination of natural steroidal hormones and synthetic anabolic steroids in equine and bovine blood matrix
No full textMonitoring the hormones in equine matrix is crucial to understanding the health status of horses , and also to monitoring the abuse of these substances before a race or a horse transaction. Few analytical procedures exist which are “self made methods”, generally based on immunoassay analysis, often impossible to replicate in other laboratories or too complex for the staff. On that, it is necessary to develop new sensitive analytical methods, that can be diffused to external vets and give correct and comparable results. Furthermore, the few analytical procedures involving an HPLC-MS-MS system reported in literature allow for simultaneous quantification of no more than three or four hormones [1][2]. The proposed method makes it possible to detect and quantify seventeen hormones and metabolites in a single assay, in just ten minutes. Quantifiable hormones with the proposed method are: Pregnenolon, 17-OH-Pregnenolon, Progesteron, 17-OH-Progesteron, Androsteron, Androstenedion, DHEA, DHEAS, Testosteron, Cortisol, Corticosteron, Aldosteron, 11-Deossicortisol, 11-Deossicorticosteron, Diidrotestosteron, Estron, Estradiol. A deuterated hormone ( Testosteron-D3) has been used as internal standards in order to set a more accurate and precise procedure. The method was developed using the Agilent UHPLC chromatographic system (1290) using a Zorbax RRHD C18 – 1,8 μm column and a 6420 Agilent Mass Spectrometer . The procedure is fast and intuitive; the sample preparation is very easy, with the serum deproteinized in vials using a deproteinizing solution, centifuged and injected into the system. The mobile phases are made of water and acetonitrile, both containing formic acid.
Overall, the method is very simple and robust and it brings about a remarkable saving of time and money with respect to previously reported methods; in fact, using the UHPLC–Tandem Mass spectrometer enables simultaneous quantification of seventeen Steroidal Hormones. The method has been applied to a number of equine and bovine blood samples supplied from different breeding farms and territorial vests
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
- …
