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Peter C Dedon - One of the best experts on this subject based on the ideXlab platform.

  • The DNA-damage signature in Saccharomyces cerevisiae is associated with single-strand breaks in DNA
    BMC Genomics, 2006
    Co-Authors: Rebecca C. Fry, Michael S. Demott, Joseph P. Cosgrove, Thomas J. Begley, Leona D. Samson, Peter C Dedon
    Abstract:

    Background Upon exposure to agents that damage DNA, Saccharomyces cerevisiae undergo widespread reprogramming of gene expression. Such a vast response may be due not only to damage to DNA but also damage to proteins, RNA, and lipids. Here the transcriptional response of S. cerevisiae specifically induced by DNA damage was discerned by exposing S. cerevisiae to a panel of three "radiomimetic" enediyne antibiotics (calicheamicin γ_1^I, Esperamicin A1 and neocarzinostatin) that bind specifically to DNA and generate varying proportions of single- and double-strand DNA breaks. The genome-wide responses were compared to those induced by the non-selective oxidant γ-radiation. Results Given well-controlled exposures that resulted in similar and minimal cell death (~20–25%) across all conditions, the extent of gene expression modulation was markedly different depending on treatment with the enediynes or γ-radiation. Exposure to γ-radiation resulted in more extensive transcriptional changes classified both by the number of genes modulated and the magnitude of change. Common biological responses were identified between the enediynes and γ-radiation, with the induction of DNA repair and stress response genes, and the repression of ribosomal biogenesis genes. Despite these common responses, a fraction of the response induced by gamma radiation was repressed by the enediynes and vise versa , suggesting that the enediyne response is not entirely "radiomimetic." Regression analysis identified 55 transcripts with gene expression induction associated both with double- or single-strand break formation. The S. cerevisiae "DNA damage signature" genes as defined by Gasch et al . [ 1 ] were enriched among regulated transcripts associated with single-strand breaks, while genes involved in cell cycle regulation were associated with double-strand breaks. Conclusion Dissection of the transcriptional response in yeast that is specifically signaled by DNA strand breaks has identified that single-strand breaks provide the signal for activation of transcripts encoding proteins involved in the DNA damage signature in S. cerevisiae , and double-strand breaks signal changes in cell cycle regulation genes.

  • The DNA-damage signature in Saccharomyces cerevisiae is associated with single-strand breaks in DNA.
    BMC genomics, 2006
    Co-Authors: Rebecca C. Fry, Michael S. Demott, Joseph P. Cosgrove, Thomas J. Begley, Leona D. Samson, Peter C Dedon
    Abstract:

    Background Upon exposure to agents that damage DNA, Saccharomyces cerevisiae undergo widespread reprogramming of gene expression. Such a vast response may be due not only to damage to DNA but also damage to proteins, RNA, and lipids. Here the transcriptional response of S. cerevisiae specifically induced by DNA damage was discerned by exposing S. cerevisiae to a panel of three "radiomimetic" enediyne antibiotics (calicheamicin γ1I, Esperamicin A1 and neocarzinostatin) that bind specifically to DNA and generate varying proportions of single- and double-strand DNA breaks. The genome-wide responses were compared to those induced by the non-selective oxidant γ-radiation.

  • Modulation of enediyne-induced DNA damage by chromatin structures in transcriptionally active genes.
    Biochemistry, 1999
    Co-Authors: Peter C Dedon
    Abstract:

    To better understand how the cellular environment of DNA affects it as a target for genotoxins, we have used ligation-mediated PCR to map DNA damage produced by two DNA-cleaving enediyne antibiotics, Esperamicins A1 and C, in the transcriptionally active human p53 and phosphoglycerate kinase (pgk1) genes in vivo. Esperamicin A1, which is limited to damaging the linker region between nucleosome cores due to intercalation of an anthranilate moiety, did not detect the presence of a nucleosome proposed to reside between exons 5 and 6 of p53. This may be due to the absence of a nucleosome at this site in the p53 gene or to the altered structure of nucleosomes in transcriptionally active genes. In studies of the upstream region of the active pgk1 gene, we found that DNA damage produced by both enediynes was enhanced in sequences located between several transcription factor binding sites, while patterns of DNA damage within the binding sites were consistent with known drug binding modes and structures of the protein-DNA complexes. For both drugs, the DNA sequence appeared to be the major determinant of the location of DNA damage, with chromatin structures modulating the quantity of DNA damage.

  • dna damage produced by enediynes in the human phosphoglycerate kinase gene in vivo Esperamicin a1 as a nucleosome footprinting agent
    Biochemistry, 1998
    Co-Authors: Jinghai Xu, Jiongru Wu, Peter C Dedon
    Abstract:

    : We have used both conventional and a modified version of ligation-mediated polymerase chain reaction (LMPCR) to study the role of chromatin structure in the selection of DNA targets by three DNA-cleaving enediynes in whole cells. On the basis of previous studies of enediyne target selection in nucleosomes, we focused on nucleosomes present in the human X-linked phosphoglycerate kinase (PGK1) gene. Damage produced by Esperamicin A1 in cells containing a transcriptionally inactive copy of the X-chromosome is reduced compared to that in naked DNA in two regions that encompass approximately 130 and approximately 150 base pairs upstream of the PGK1 gene. These sizes are consistent with nucleosome core DNA. Damage produced by Esperamicin A1 in the transcriptionally active form of the gene, in which nucleosomes are not apparent, did not show such a pattern. Esperamicin C, an analogue of Esperamicin A1 lacking an intercalating anthranilate moiety, and calicheamicin, both groove binders, were found to cleave DNA throughout the nucleosome core and linker. These results confirm hypotheses generated from studies in isolated chromatin and reconstituted nucleosomes and suggest that enediynes may prove useful as chromatin footprinting agents.

  • Cytosine methylation enhances DNA damage produced by groove binding and intercalating enediynes: studies with Esperamicins A1 and C.
    Biochemistry, 1997
    Co-Authors: Pradeep Mathur, Xu J, Peter C Dedon
    Abstract:

    Methylation of the C5 position of cytosine in CG dinucleotides represents an important element in the control of gene expression in eukaryotic cells. This major groove modification of DNA causes ch...

Terrence W. Doyle - One of the best experts on this subject based on the ideXlab platform.

  • Synthesis of an Esperamicin core analog with an epoxide trigger
    Tetrahedron Letters, 1996
    Co-Authors: Harold Mastalerz, John F. Kadow, Terrence W. Doyle, Dolatrai M. Vyas
    Abstract:

    Abstract An Esperamicin core analog 4 with an epoxide trigger like that found in the related enediyne, dynemicin, was prepared. Surprisingly, it was found to be relatively stable; the p -aminophenyl substituent did not facilitate epoxide solvolysis to the extent that had been anticipated. A mild acid, pyridinium p -toluenesulfonate, was found to induce solvolysis of 4 and led to the formation of the cycloaromatized product 25 .

  • Synthesis of a hybrid analog of the Esperamicin and dynemicin cores
    Tetrahedron Letters, 1996
    Co-Authors: Harold Mastalerz, John F. Kadow, Terrence W. Doyle, Dolatrai M. Vyas
    Abstract:

    Abstract An enediyne analog ( 2 , R=H) that is a hybrid of the core structures of Esperamicin and dynemicin was prepared. The key step in its synthesis was a Reissert-type reaction that involved intramolecular addition of the anion of a Z-1,3-diyn-2-ene to an N-acyl tetrahydrophenathridinium intermediate. It was found that 2 (R=H) readily undergoes epoxide rearrangement to an allylic alcohol ( 16 ). Both 2 (R=H) and 16 form the same cycloaromatized product 17 when heated in MeOH at 45 °C.

  • Synthesis of intermediates for the preparation of core analogs of Esperamicin
    Tetrahedron Letters, 1995
    Co-Authors: Harold Mastalerz, John F. Kadow, Terrence W. Doyle, Kinwa Leung, Dolatrai M. Vyas
    Abstract:

    Bicyclo[7.3.1]enediyne intermediates for the synthesis of analogs of BMY-46108 (5), a simple core analog of Esperamicin, were prepared by two different routes. One involved fluoride-promoted cyclization of 1 followed by epoxide rearrangement. The other proceeded by a base-promoted cyclization of the aldehyde 8 and was subject to thermodynamic control. The stereochemistry of the C-12 asymmetric center in the favored cyclization product (9) was established by its conversion into 5 and its isomer, 14.

  • facile synthesis of a simplified bicyclo 7 3 1 Esperamicin calicheamicin enediyne core
    Tetrahedron, 1994
    Co-Authors: John F. Kadow, Donald Cook, Kahnie M Pham, D M Vyas, Terrence W. Doyle, David R Langley, Michael D. Wittman
    Abstract:

    Abstract An efficient non cobalt mediated route for the synthesis of a simplified bicyclo[7.3.1]enediyne core of the naturally occurring calicheamicins and espe

  • The DNA-Esperamicin A1 complex. A model based on solvated molecular dynamics simulations
    Journal of the American Chemical Society, 1994
    Co-Authors: David R Langley, Terrence W. Doyle, Jerzy Golik, B. Krishman, David L. Beveridge
    Abstract:

    A solvated model for the DNA-Esperamicin complex has been constructed and shown to be thermodynamically stable over a 300-ps molecular dynamics simulation. The dynamical model is consistent with all of the available experimental data. The model has been used to gain insights into (1) how Esperamicin is activated into a DNA-cleaving molecule, (2) its mode of binding to DNA, (3) how the individual Esperamicin residues contribute to its ability to bind with and cleave DNA, (4) the fate of the carbon-centered radicals, and (5) its DNA-cleavage patterns and cleavage sequence specificity

Yukio Sugiura - One of the best experts on this subject based on the ideXlab platform.

  • A new non-protein enediyne antibiotic N1999A2: Unique enediyne chromophore similar to neocarzinostatin and DNA cleavage feature
    Tetrahedron Letters, 1998
    Co-Authors: Toshihiko Ando, Makoto Ishii, Takayuki Kajiura, Toshiyuki Kameyama, Kiyoshi Miwa, Yukio Sugiura
    Abstract:

    Abstract The present NMR and X-ray structural studies demonstrated that the new antibiotic N1999A2 isolated from the broth filtrate of Streptomyces sp. AJ9493, possesses a novel 9-membered ring enediyne chromophore similar to neocarzinostatin, but is not chromoprotein. Of special interest is the fact that stable N1999A2 exists as enediyne chromophore alone as well as dynemicin A, Esperamicin A 1 and calicheamicin γ 1 . The major difference between N1999A2 and neocarzinostatin chromophore is lack of the amino sugar in N1999A2. The antibiotic N1999A2 revealed more random DNA cutting profile than neocarzinostatin chromophore.

  • Selective cleavages of tRNAPhe with secondary and tertiary structures by enediyne antitumor antibiotics.
    Bioorganic & medicinal chemistry, 1997
    Co-Authors: Yukio Sugiura, Ryuichi Totsuka, Michihiro Araki, Yasushi Okuno
    Abstract:

    Some enediyne antitumor antibiotics induce site-selective cleavages for yeast tRNAPhe with three-dimensional structure. Of special interest is the fact that tRNAPhe is specifically cleaved at the anticodon arm regions by C-1027 and Esperamicin Al in the presence of Mg2+ ions. Although neocarzinostatin strongly breaks tRNAPhe at 5′-GPu steps in the absence of magnesium ions, its cleavage ability is completely lost in the presence of 100 μM Mg2+ ions. Dynemicin A, which favors an intercalative binding, causes no strand scissions for the RNA with secondary and tertiary structures. This cutting of tRNAPhe may reveal that RNA as well as DNA constitutes a therapeutically relevant target for certain enediyne antitumor antibiotics.

  • Hydrophobic DNA binding of Esperamicin requires conformational distortion of the host DNA.
    Biochimica et biophysica acta, 1995
    Co-Authors: Motonari Uesugi, Tetsuya Kusakabe, Yukio Sugiura
    Abstract:

    Evidence is presented that the sequence-specific DNA binding of Esperamicin is accompanied by structural distortion of the host DNA that depends on hydrophobic interactions. In the first part of this paper, we describe the effects of conformational freedom of DNA on the DNA-cutting efficiency of Esperamicin. If conformational distortion of DNA is significantly required for binding of the drug, then the drug should possess a lower binding/cleaving efficiency for conformationally more restricted DNAs. Our results on model DNAs reveal a substantial decrease in the DNA-cleaving efficiency of Esperamicin as the conformational freedom of DNA decrease. In the second part we demonstrate that Esperamicin binds to DNA with considerably higher affinity in solutions containing organic solvents. This observation indicates that the required distortion of DNA depends on hydrophobic interactions. Molecular origins of the sequence-specific binding are also discussed on the basis of all available data.

  • DNA Recognition by Esperamicin and Calicheamicin
    Journal of Japan Oil Chemists Society, 1994
    Co-Authors: Motonari Uesugi, Yukio Sugiura
    Abstract:

    Esperamicin and calicheamicin are among the most prominent members of enediyne antibiotics. Combining highly unusual molecular structures, potent biological activities, and fascinating modes of action, these DNA-cleaving compounds elicited extensive research activities in chemistry, biology, and medicine. This review weights the oligo (purine/pyrimidine) recognition by Esperamicin and calicheamicin. We begin by consideration of the experimental approaches that have been used to provide insights into the recognition process. Next we summarize the recent interpretations of the sources of the specificity to oligo (purine/pyrimidine) sequences.

  • DNA Recognition by Esperamicin and Calicheamicin
    Journal of Japan Oil Chemists Society, 1994
    Co-Authors: Motonari Uesugi, Yukio Sugiura
    Abstract:

    Esperamicin and calicheamicin are among the most prominent members of enediyne antibiotics. Combining highly unusual molecular structures, potent biological activities, and fascinating modes of action, these DNA-cleaving compounds elicited extensive research activities in chemistry, biology, and medicine. This review weights the oligo (purine/pyrimidine) recognition by Esperamicin and calicheamicin. We begin by consideration of the experimental approaches that have been used to provide insights into the recognition process. Next we summarize the recent interpretations of the sources of the specificity to oligo (purine/pyrimidine) sequences.

Jean-marie Beau - One of the best experts on this subject based on the ideXlab platform.

David S. Grierson - One of the best experts on this subject based on the ideXlab platform.

  • Imine-Enamina
    2009
    Co-Authors: Gerard Ulibani, Hélène Audrain, Hervé Lhermitte, David S. Grierson, William Nadler, Ullbarrl G. Eta
    Abstract:

    Abstract: Two strategies for the construction of the calicheamicin/Esperamicin core structure are presented. The first is based upon the 2.3-Wittig ring contraction of a 13-membered macrocycle 3 (X = CH2 or NCaMe). The aza 2,3-Wittig rearrangement of 3 (X = NCaMe) is of particular interest, as it can potentially lead to compound 6 in one operation. The objective in the second enediyne synthesis project is to obtain both enantiomers of the Esperamicin A1 aglycone (Esperamicinone) via a highly concise route using the 3,4-cyclohexylidene derivative 17 of (-)-quinic acid as a common starting synthon. The discovery of the "enediyne " antitumor antibiotics calicheamicin ylI(1) and Esperamicin A1 (2) (Figure 1) has provided both new possibilities for the treatment of cancer, and a challenge to synthetic chemists to construct the highly strained bicyclo[7.3.l]tridecenediyne unit present as a common feature in the aglycone portion of each molecule. Already, the total synthesis of both molecules have been independently achieved by the Nicolaou and Danishefsky teams, and further work by other groups is leading in the same direction. In our laboratory, two distinct approaches to the synthesis of the aglycone portion of 1 and 2 are under study

  • STUDIES TOWARD THE CONSTRUCTION OF THE ALLYLTRISULFIDE COMPONENT IN Esperamicin-A1 FROM 5-KETOSHIKIMIC ACID DERIVATIVES : PART 1
    Tetrahedron Letters, 1999
    Co-Authors: Sandrine Piguel, Gerardo Ulibarri, David S. Grierson
    Abstract:

    The conversion of keto ester 1, obtained in either enantiomeric form from (−)-quinic acid, to its corresponding enol silyl ether 4 was examined as the first step to construct the allyl trisulfide unit found in Esperamicin A1. Under different conditions a very facile dimerization of either 4 or enolate 10 to give compound 14 was observed.

  • Studies toward the construction of the allyltrisulfide component in Esperamicin-A1 from 5-ketoshikimic acid derivatives: Part 2
    Tetrahedron Letters, 1999
    Co-Authors: Sandrine Piguel, Gerardo Ulibarri, David S. Grierson
    Abstract:

    Abstract The MOM protected keto alcohol 7 was successfully converted to the silyl enol ether 4 by reaction with BSA. Reaction of this intermediate with dioxirane led to formation of allylic alcohol 10 . Lactone 15 was obtained by reaction of tosylate 14 with the cuprate reagent derived from ethyl bromoacetate. Through a short sequence of reactions this 5-membered lactone was isomerized to the target lactone product 18 .

  • Synthesis of the 'enediyne' antibiotic Esperamicin-A 1 , and novel analogues for tumor targeting
    Pure and Applied Chemistry, 1996
    Co-Authors: G. Ulibarri, Hélène Audrain, William R. Nadler, Hervé Lhermitte, David S. Grierson
    Abstract:

    Two strategies for the construction of the calicheamicin/Esperamicin core structure are presented. The first is based upon the 2.3-Wittig ring contraction of a 13- membered macrocycle 3 (X = CH2 or NCaMe). The aza 2,3-Wittig rearrangement of 3 (X = NCaMe) is of particular interest, as it can potentially lead to compound 6 in one operation. The objective in the second enediyne synthesis project is to obtain both enantiomers of the Esperamicin A1 aglycone (Esperamicinone) via a highly concise route using the 3,4-cyclohexylidene derivative 17 of (-)-quinic acid as a common starting synthon.

  • Toward the synthesis of the Esperamicin-A1/calicheamicin γI1 aglycone : the study of an 'azoxy' version of the [2,3]-Wittig rearrangement
    Bulletin de la Société Chimique de France, 1996
    Co-Authors: H. Audrain, C. Riche, A. Chiaroni, David S. Grierson
    Abstract:

    Une strategie basee sur une version «azoxy» du rearrangement de Wittig-[2,3] a ete etudiee dans le but d'acceder a la partie aglycone des enediynes Esperamicine-A 1 et calicheamicine γ I 1 , antibiotiques antitumoraux. Bien que l'enamine N-methoxycarbonylee 8 ne puisse pas etre preparee, les enamides correspondantes 22 et 23 ont ete obtenues tres efficacement grâce a la reaction de l'ether d'oxime bicyclique 12 respectivement avec le bromure d'acetyl et l'anhydride trifluoroacetique en l'absence de base. La reaction du compose 22 avec des amidures de lithium a conduit soit a la formation du dimere 37, soit au produit 1,5-diyne acyclique 40. L'aldehyde 36, genere par coupure de la liaison N-O du compose 34, etait un intermediaire dans ces deux reactions. De facon similaire, le traitement de l'enamide 23 avec LiTMP a entraine la formation de l'aldehyde 1,5-diyne acyclique 41 au lieu du produit issu du rearrangement de Wittig-[2,3]. Des essais de fermeture de cycle de cet intermediaire en vue de l'obtention de 43 ont resulte de la formation de l'alcyne decarbonyle 46.