97 research outputs found
Enzymatic synthesis of 2’-O-acyl-prodrugs of 1-(beta-D-arabinofuranosyl)-5(E)-(2-bromovinyl)uracil (sorivudine, BV-araU) and of 2’-O-acyl-araU, -araC and -araA.
No full textPig liver esterase (EC 3.1.1.1) catalysed regioselective hydrolysis of 1-(2,3,5-tri-O-acyl-beta-D-arabinofuranosyl)uracil, -cytosine and -adenine to give the corresponding 2'-monoesters effectively and in high yield. This methodology enabled the preparation of 1-(2-O-acyl-beta-D-arabinofuranosyl)-5-[(E)-(2-bromovinyl)]uracil prodrugs which, although slightly less active than the parent 1-(beta-D-arabinofuranosyl)-5-(E)-(2 bromovinyl)uracil (sorivudine; BV-araU), were strongly active in vitro against varicella-zoster virus (ED50 2.4-45 ng/ml). The retarded rates of enzymatic hydrolysis of the 2'-esters imply that they might function as lipophilic prodrugs, leading to increased plasma and cellular concentrations. In view of the marked in vitro activity, they represent an interesting approach to arabinofuranosyl nucleoside prodrugs with improved pharmacokinetics and enzymatic stability
Geiparvarin Analogs. 4.1. Synthesis and Cytostatic Activity of Geiparvarin Analogs Bearing a Carbamate Moiety or a Furocoumarin Fragment on the Alkenyl Side Chain
No full textAs a continuation of previous studies on the synthesis and antitumor activity of geiparvarin
analogues bearing a carbamate moiety in the alkyl side chain, a series of N-substituted [(E)-
3-(4,5-dihydro-5,5-dimethyl-4-oxo-2-furanyl)-2-butenyllcarbama(t1e5s a-f) were synthesized
and tested with the objective to investigate the reason for the marked difference of cytostatic
activity found between alkyl and phenyl derivatives. A series of compounds, characterized by
different physicochemical properties, were designed in order to study this hypothesis. Moreover,
to further investigate the modification of the alkenyl side chain, (E)- and (2)-[2-(4,5-dihydro-
5,5-dimethy1-4-oxo-2-furany1)propeny11-7~-furo[3,2-g][11benzop~an-7-o(nllea ,b) were synthesized,
the latter compounds being the combination of two units, namely, the 3(2H)-furanone
ring system endowed with potent alkylating properties and the furocoumarin portion which
binds to DNA resulting in potential DNA-targeted alkylating agents. The compounds were
tested for their cytostatic activity against proliferation of murine (L1210) and human (Molt/
4F, CEM, or MT-4) tumor cells. The highest cytostatic activity found within both series of
carbamic derivatives (15a-d,k and 15e,g-j) was associated with the highest global lipophilicity.
With regard to compounds lla,b, the cytostatic activity of (Z)-furocoumarin llb might be related
to a specific interaction with DNA (Le., intercalation)
Distributions of energy, luminosity, duration, and waiting times of gamma-ray burst pulses with known redshift detected by Fermi/GBM
No full textDiscovered more than 50 years ago, gamma-ray burst (GRB) prompt emission remains the most puzzling aspect of GRB physics. Its complex and irregular nature should reveal how newborn GRB engines release their energy. In this respect, the possibility that GRB engines could operate as self-organized critical (SOC) systems has been put forward. Here, we present the energy, luminosity, waiting time, and duration distributions of individual pulses of GRBs with known redshift detected by the Fermi Gamma-ray Burst Monitor (GBM). This is the first study of this kind in which selection effects are accounted for. The compatibility of our results with the framework of SOC theory is discussed. We found evidence for an intrinsic break in the power-law models that describe the energy and the luminosity distributions
Design, synthesis and antiproliferative activity of methyl 4-iodo-1-b-D-ribofuranosyl-pyrazole-3-carboxylate and related compounds
No full textContinuing our studies on the structure-activity relationships of some pyrazole nucleosides (1a-h) structurally related to ribavirin, tiazofurin and selenazofurin, we describe here the synthesis and antitumor/antiviral/antimicrobial activity of a new series of 1-tetrahydropyranyl-4-substituted pyrazoles. In this study, the tetrahydropyranyl moiety (THP), designed as a mimic of the glycosidic portion of the parent compounds 1a-h, has led to a few derivatives with moderate cytotoxic activity against leukemia/lymphoma and solid tumor-derived cell lines (IC50 14-100 microM). The compounds obtained through substitution of the ribofuranosyl moiety by the THP moiety were still active, the free heterocyclic bases were devoid of any activity.In a SAR study on azole-related nucleosides we have designed some pyrazole-nucleoside analogs characterised, for the first time, by a carboxylic ester moiety. 4-Iodo-1-β-D-ribofuranosyl-pyrazole-3-carboxylate showed a wide spectrum of antiproliferative activity and a particularly low cytotoxicity against resting PBL, being, unlike the other azole nucleosides, more active than the corresponding primary amide. Copyright © 1996 Elsevier Science Ltd
New isoxazole derivatives of retinoids: Synthesis and activity on growth and differentiation of tumor cells
No full textThe effects of several newly synthesized isoxazole analogues of retinoids on differentiation and proliferation of 'in vitro' cultured tumor cell lines are reported. Some of the tested compounds exhibit significative differentiating action, inducing adipogenic conversion of the Chinese hamster FH06T1-1 cell line in a range of 2-10 times the activity of retinoic acid and retinol
Synthesis of isoxazole and isoxazoline derivatives of retinoids: effects on growth and differentiation of tumor cells
No full textThe authors studied the effects of several newly synthesized isoxazole and isoxazoline analogs of retinoids on induction of terminal differentiation and "in vitro" growth of tumor cell lines. Some of the tested compds. exhibit: (a) ability to induce adipogenic conversion of Ha-ras-1 transformed FH06T1-1 chinese hamster fibroblasts: (b) antiproliferative activity toward tumor cell lines, including the erythroleukemic K562 and FL cell lines and the FH06T1-1 cell line. This data could be of interest in identifying drugs of possible application in exptl. anticancer therapy
Design, synthesis and antiproliferative activity of methyl 4-iodo-1-β-D-ribofuranosyl-pyrazole-3-carboxylate and related compounds
No full textIn a SAR study on azole-related nucleosides we have designed some pyrazole-nucleoside analogs characterised, for the first time, by a carboxylic ester moiety. 4-Iodo-1-beta-D-ribofuranosyl-pyrazole-3-carboxylate showed a wide spectrum of antiproliferative activity and a particularly low cytotoxicity against resting PBL, being, unlike the other azole nucleosides, more active than the corresponding primary amide
Distribution of the number of peaks within a long gamma-ray burst: The full
No full textContext. The dissipation process responsible for the long gamma-ray burst (GRB) prompt emission and the kind of dynamics that drives the release of energy as a function of time are still key open issues. We recently found that the distribution of the number of peaks per GRB is described by a mixture of two exponentials, suggesting the existence of two behaviours that turn up as peak-rich and peak-poor time profiles.
Aims. Our aims are to study the distribution of the number of peaks per GRB of the entire catalogue of about 3000 GRBs observed by the Fermi Gamma-ray Burst Monitor (GBM) and to make a comparison with previous results obtained from other catalogues.
Methods. We identified GRB peaks using the MEPS
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