The Experts below are selected from a list of 174 Experts worldwide ranked by ideXlab platform
G E Trantor - One of the best experts on this subject based on the ideXlab platform.
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isosteres of the dna polymerase inhibitor Aphidicolin as potential antiviral agents against human herpes viruses
Journal of Medicinal Chemistry, 1993Co-Authors: David L Selwood, J N Champness, J Gillam, D K Hibberd, Karamjit Singh Jandu, D Lowe, M Pether, J Selway, G E TrantorAbstract:: A variety of isosteres of the DNA polymerase inhibitor Aphidicolin were synthesized as potential antiherpes agents. Modeling studies indicated that the bicyclooctane C, D rings of Aphidicolin could be replaced by an aromatic moiety while maintaining the spatial arrangement of the hydroxyl group equivalent to the essential C18 hydroxyl group of Aphidicolin. Of the racemic isosteres synthesized only 13, the compound with the greatest structural similarity to Aphidicolin, showed any significant antiviral activity in primary assays. An enantioselective synthesis of the compound was carried out and the 4aS isomer 36 was shown to account for the observed antiviral activity noted against herpes simplex virus 1 and human cytomegalovirus.
David L Selwood - One of the best experts on this subject based on the ideXlab platform.
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isosteres of the dna polymerase inhibitor Aphidicolin as potential antiviral agents against human herpes viruses
Journal of Medicinal Chemistry, 1993Co-Authors: David L Selwood, J N Champness, J Gillam, D K Hibberd, Karamjit Singh Jandu, D Lowe, M Pether, J Selway, G E TrantorAbstract:: A variety of isosteres of the DNA polymerase inhibitor Aphidicolin were synthesized as potential antiherpes agents. Modeling studies indicated that the bicyclooctane C, D rings of Aphidicolin could be replaced by an aromatic moiety while maintaining the spatial arrangement of the hydroxyl group equivalent to the essential C18 hydroxyl group of Aphidicolin. Of the racemic isosteres synthesized only 13, the compound with the greatest structural similarity to Aphidicolin, showed any significant antiviral activity in primary assays. An enantioselective synthesis of the compound was carried out and the 4aS isomer 36 was shown to account for the observed antiviral activity noted against herpes simplex virus 1 and human cytomegalovirus.
Olivier Hyrien - One of the best experts on this subject based on the ideXlab platform.
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Aphidicolin triggers a block to replication origin firing in xenopus egg extracts
Journal of Biological Chemistry, 2001Co-Authors: Kathrin Marheineke, Olivier HyrienAbstract:Abstract DNA replication origins are located at random with respect to DNA sequence in Xenopus early embryos and on DNA replicated in Xenopus egg extracts. We have recently shown that origins fire throughout the S phase in Xenopusegg extracts. To study the temporal regulation of origin firing, we have analyzed origin activation in sperm nuclei treated with the DNA polymerase inhibitor Aphidicolin. Sperm chromatin was incubated inXenopus egg extracts in the presence of Aphidicolin and transferred to a fresh extract, and digoxigenin-dUTP and biotin-dUTP were added at various times after Aphidicolin release to selectively label early and late replicating DNA. Molecular combing analysis of single DNA fibers showed that only a fraction of potential origins were able to initiate in the presence of Aphidicolin. After release from Aphidicolin, the remaining origins fired asynchronously throughout the S phase. Therefore, initiation during the S phase depends on the normal progression of replication forks assembled at earlier activated origins. Caffeine, an inhibitor of the checkpoint kinases ATR and ATM, did not relieve the Aphidicolin-induced block to origin firing. We conclude that a caffeine-insensitive intra-S phase checkpoint regulates origin activation when DNA synthesis is inhibited inXenopus egg extracts.
Jaroslav Cinatl - One of the best experts on this subject based on the ideXlab platform.
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increased systemic efficacy of Aphidicolin encapsulated in liposomes
Oncology Reports, 2005Co-Authors: Martin Michaelis, Andreas Zimmer, Nganou Handjou, Jaroslav CinatlAbstract:Aphidicolin, a tetracyclic diterpene antibiotic produced by Cephalosporium aphidicola, is under investigation as anti-cancer drug. Because of its poor solubility in water, it cannot be administered directly in vivo. Systemic application of Aphidicolin glycinate or Aphidicolin gamma-cyclodextrin complexes resulted in tumour growth inhibition but not in cures. To improve the pharmacokinetics, a liposomal preparation of Aphidicolin was developed and tested in neuroblastoma-bearing (UKF-NB-3) mice. The loading capacity of these liposomes was limited. Therefore, 4.5 mg Aphidicolin/kg body weight was the maximum Aphidicolin dose that could be applied as liposomal preparation in this approach. Comparison of effects on tumour growth exhibited by Aphidicolin liposomes (4.5 mg Aphidicolin/kg) given for 15 consecutive days to those of gamma-cyclodextrin inclusion complexes (15 mg Aphidicolin/kg) revealed comparable tumour growth inhibition, although Aphidicolin concentrations were approximately 3-fold lower. This shows that liposomal encapsulation is a promising strategy for the improvement of systemic anti-cancer activity of Aphidicolin.
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Aphidicolin selectively kills neuroblastoma cells in vitro.
Cancer Letters, 1992Co-Authors: Jindrich Cinatl, Jaroslav Cinatl, M. Mainke, Albrecht Weißflog, Gabriele Steigmann, Holger F. Rabenau, Hans-wilhelm Doerr, Bernhard KornhuberAbstract:Abstract Aphidicolin is a tetracyclic diterpene antibiotic which is known to inhibit the growth of eucaryotic cells by reversible binding to DNA polymerase α without significant effect on cell viability in most common human cell lines. We observed that Aphidicolin at a concentration of 5 × 10 −7 M kills all cells of four human neuroblastoma cell lines. In contrast, viability of normal human embryonal cells and of human continuous cell lines including HeLa, H9, A549 and Caco-2 was influenced only moderately by Aphidicolin. In addition, neuroblastoma cells were killed after treatment with 5 × 10 −7 M Aphidicolin in cocultures with normal embryonal cells which continued to proliferate after removal of Aphidicolin. These results show that Aphidicolin provides an agent which selectively kills neuroblastoma cells in vitro.
Carol M. Warner - One of the best experts on this subject based on the ideXlab platform.
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The effects of Aphidicolin and α-amanitin on DNA synthesis in preimplantation mouse embryos
Gamete Research, 2005Co-Authors: Karen M. Cozad, Carol M. WarnerAbstract:The effects of Aphidicolin and α-amanitin on DNA synthesis by preimplantation mouse embryos were studied. It was found that both blastocyst and 8-cell embryos showed marked inhibition of 3H-thymidine incorporation into DNA by Aphidicolin at concentrations of 20–50 μg/ml. However, Aphidicolin did not inhibit the conversion of morula embryos to blastocyst embryos, although Aphidicolin-treated blastocysts lost their blastocoel and collapsed into a compact form after prolonged exposure to the drug. Both 8-cell and blastocyst embryos were found to be susceptible to inhibition of DNA synthesis by α-amanitin.
