Synthesis and biological activity of DNA damaging agents that form decoy binding sites for the estrogen receptor.
Identifieur interne : 003E07 ( Main/Exploration ); précédent : 003E06; suivant : 003E08Synthesis and biological activity of DNA damaging agents that form decoy binding sites for the estrogen receptor.
Auteurs : S M Rink [États-Unis] ; K J Yarema ; M S Solomon ; L A Paige ; B M Tadayoni-Rebek ; J M Essigmann ; R G CroySource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 1996.
Descripteurs français
- KwdFr :
- ADN (), Altération de l'ADN, Antinéoplasiques alcoylants (), Antinéoplasiques alcoylants (synthèse chimique), Antinéoplasiques alcoylants (toxicité), Conception de médicament, Facteurs de transcription (), Facteurs de transcription (métabolisme), Femelle, Humains, Lignée cellulaire, Moutardes à l'azote (), Moutardes à l'azote (synthèse chimique), Moutardes à l'azote (toxicité), N,N-Bis(2-chloroéthyl)aniline (), N,N-Bis(2-chloroéthyl)aniline (synthèse chimique), N,N-Bis(2-chloroéthyl)aniline (toxicité), Oligodésoxyribonucléotides, Récepteurs des oestrogènes (), Récepteurs des oestrogènes (métabolisme), Sites de fixation, Structure moléculaire, Survie cellulaire (), Séquence nucléotidique, Tumeurs de l'ovaire (métabolisme), Tumeurs du sein (métabolisme).
- MESH :
- métabolisme : Facteurs de transcription, Récepteurs des oestrogènes, Tumeurs de l'ovaire, Tumeurs du sein.
- synthèse chimique : Antinéoplasiques alcoylants, Moutardes à l'azote, N,N-Bis(2-chloroéthyl)aniline.
- toxicité : Antinéoplasiques alcoylants, Moutardes à l'azote, N,N-Bis(2-chloroéthyl)aniline.
- ADN, Altération de l'ADN, Antinéoplasiques alcoylants, Conception de médicament, Facteurs de transcription, Femelle, Humains, Lignée cellulaire, Moutardes à l'azote, N,N-Bis(2-chloroéthyl)aniline, Oligodésoxyribonucléotides, Récepteurs des oestrogènes, Sites de fixation, Structure moléculaire, Survie cellulaire, Séquence nucléotidique.
English descriptors
- KwdEn :
- Aniline Mustard (chemical synthesis), Aniline Mustard (chemistry), Aniline Mustard (toxicity), Antineoplastic Agents, Alkylating (chemical synthesis), Antineoplastic Agents, Alkylating (chemistry), Antineoplastic Agents, Alkylating (toxicity), Base Sequence, Binding Sites, Breast Neoplasms (metabolism), Cell Line, Cell Survival (drug effects), DNA (chemistry), DNA (drug effects), DNA Damage, Drug Design, Female, Humans, Molecular Structure, Nitrogen Mustard Compounds (chemical synthesis), Nitrogen Mustard Compounds (chemistry), Nitrogen Mustard Compounds (toxicity), Oligodeoxyribonucleotides, Ovarian Neoplasms (metabolism), Receptors, Estrogen (chemistry), Receptors, Estrogen (metabolism), Transcription Factors (chemistry), Transcription Factors (metabolism).
- MESH :
- chemical , chemical synthesis : Aniline Mustard, Antineoplastic Agents, Alkylating, Nitrogen Mustard Compounds.
- chemical , chemistry : Aniline Mustard, Antineoplastic Agents, Alkylating, DNA, Nitrogen Mustard Compounds, Receptors, Estrogen, Transcription Factors.
- chemical , drug effects : DNA.
- chemical , metabolism : Receptors, Estrogen, Transcription Factors.
- chemical , toxicity : Aniline Mustard, Antineoplastic Agents, Alkylating, Nitrogen Mustard Compounds.
- drug effects : Cell Survival.
- metabolism : Breast Neoplasms, Ovarian Neoplasms.
- Base Sequence, Binding Sites, Cell Line, DNA Damage, Drug Design, Female, Humans, Molecular Structure, Oligodeoxyribonucleotides.
Abstract
It is a goal of cancer chemotherapy to achieve the selective killing of tumor cells while minimizing toxicity to normal tissues. We describe the design of selective toxins forming DNA adducts that attract the estrogen receptor (ER), a transcription factor that is overexpressed in many human breast and ovarian tumors. The compounds consist of 4-(3-aminopropyl)-N,N-(2-chloroethyl)-aniline linked to 2-(4'-hydroxyphenyl)-3-methyl-5-hydroxy-indole. The former moiety is a DNA damaging nitrogen mustard and the latter is a ligand for the ER. The connection between these groups was refined to permit DNA adducts formed by the mustard portion of the molecule to present the ligand domain so that it was able to interact efficiently with the ER. By using 16-mers containing specific DNA adducts, it was determined that monoadducts and putative intrastrand crosslinks were preferred targets for the ER over interstrand crosslinks. A series of structurally related 2-phenylindole mustards was prepared, some of which were selectively toxic to the ER-positive breast cancer cell line MCF-7, as compared with the ER(-) negative line MDA-MB231. The ability both to bind to DNA and to interact significantly with the ER were essential to achieve selective lethality toward ER(+) cells. Compounds forming DNA adducts without the ability to bind receptor showed similar toxicities in the two cell lines. Several models could explain the selective toxicity of the mustard-phenylindole compounds toward ER(+) cells. The favored model suggests that a mustard-DNA adduct is shielded by the ER from DNA repair enzymes and hence cells possessing an abundance of the ER selectively retain the adduct and are killed.
DOI: 10.1073/pnas.93.26.15063
PubMed: 8986764
Affiliations:
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Le document en format XML
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first="L A" last="Paige">L A Paige</name></author><author><name sortKey="Tadayoni Rebek, B M" sort="Tadayoni Rebek, B M" uniqKey="Tadayoni Rebek B" first="B M" last="Tadayoni-Rebek">B M Tadayoni-Rebek</name></author><author><name sortKey="Essigmann, J M" sort="Essigmann, J M" uniqKey="Essigmann J" first="J M" last="Essigmann">J M Essigmann</name></author><author><name sortKey="Croy, R G" sort="Croy, R G" uniqKey="Croy R" first="R G" last="Croy">R G Croy</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="1996">1996</date><idno type="RBID">pubmed:8986764</idno><idno type="pmid">8986764</idno><idno type="doi">10.1073/pnas.93.26.15063</idno><idno type="wicri:Area/PubMed/Corpus">002745</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002745</idno><idno type="wicri:Area/PubMed/Curation">002745</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002745</idno><idno 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xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139</wicri:regionArea><wicri:noRegion>Cambridge 02139</wicri:noRegion></affiliation></author><author><name sortKey="Yarema, K J" sort="Yarema, K J" uniqKey="Yarema K" first="K J" last="Yarema">K J Yarema</name></author><author><name sortKey="Solomon, M S" sort="Solomon, M S" uniqKey="Solomon M" first="M S" last="Solomon">M S Solomon</name></author><author><name sortKey="Paige, L A" sort="Paige, L A" uniqKey="Paige L" first="L A" last="Paige">L A Paige</name></author><author><name sortKey="Tadayoni Rebek, B M" sort="Tadayoni Rebek, B M" uniqKey="Tadayoni Rebek B" first="B M" last="Tadayoni-Rebek">B M Tadayoni-Rebek</name></author><author><name sortKey="Essigmann, J M" sort="Essigmann, J M" uniqKey="Essigmann J" first="J M" last="Essigmann">J M Essigmann</name></author><author><name sortKey="Croy, R G" sort="Croy, R G" uniqKey="Croy R" first="R G" last="Croy">R G Croy</name></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><imprint><date when="1996" type="published">1996</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aniline Mustard (chemical synthesis)</term><term>Aniline Mustard (chemistry)</term><term>Aniline Mustard (toxicity)</term><term>Antineoplastic Agents, Alkylating (chemical synthesis)</term><term>Antineoplastic Agents, Alkylating (chemistry)</term><term>Antineoplastic Agents, Alkylating (toxicity)</term><term>Base Sequence</term><term>Binding Sites</term><term>Breast Neoplasms (metabolism)</term><term>Cell Line</term><term>Cell Survival (drug effects)</term><term>DNA (chemistry)</term><term>DNA (drug effects)</term><term>DNA Damage</term><term>Drug Design</term><term>Female</term><term>Humans</term><term>Molecular Structure</term><term>Nitrogen Mustard Compounds (chemical synthesis)</term><term>Nitrogen Mustard Compounds (chemistry)</term><term>Nitrogen Mustard Compounds (toxicity)</term><term>Oligodeoxyribonucleotides</term><term>Ovarian Neoplasms (metabolism)</term><term>Receptors, Estrogen (chemistry)</term><term>Receptors, Estrogen (metabolism)</term><term>Transcription Factors (chemistry)</term><term>Transcription Factors (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ADN ()</term><term>Altération de l'ADN</term><term>Antinéoplasiques alcoylants ()</term><term>Antinéoplasiques alcoylants (synthèse chimique)</term><term>Antinéoplasiques alcoylants (toxicité)</term><term>Conception de médicament</term><term>Facteurs de transcription ()</term><term>Facteurs de transcription (métabolisme)</term><term>Femelle</term><term>Humains</term><term>Lignée cellulaire</term><term>Moutardes à l'azote ()</term><term>Moutardes à l'azote (synthèse chimique)</term><term>Moutardes à l'azote (toxicité)</term><term>N,N-Bis(2-chloroéthyl)aniline ()</term><term>N,N-Bis(2-chloroéthyl)aniline (synthèse chimique)</term><term>N,N-Bis(2-chloroéthyl)aniline (toxicité)</term><term>Oligodésoxyribonucléotides</term><term>Récepteurs des oestrogènes ()</term><term>Récepteurs des oestrogènes (métabolisme)</term><term>Sites de fixation</term><term>Structure moléculaire</term><term>Survie cellulaire ()</term><term>Séquence nucléotidique</term><term>Tumeurs de l'ovaire (métabolisme)</term><term>Tumeurs du sein (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Aniline Mustard</term><term>Antineoplastic Agents, Alkylating</term><term>Nitrogen Mustard Compounds</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Aniline Mustard</term><term>Antineoplastic Agents, Alkylating</term><term>DNA</term><term>Nitrogen Mustard Compounds</term><term>Receptors, Estrogen</term><term>Transcription Factors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>DNA</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Receptors, Estrogen</term><term>Transcription Factors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Aniline Mustard</term><term>Antineoplastic Agents, Alkylating</term><term>Nitrogen Mustard Compounds</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Survival</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Breast Neoplasms</term><term>Ovarian Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Facteurs de transcription</term><term>Récepteurs des oestrogènes</term><term>Tumeurs de l'ovaire</term><term>Tumeurs du sein</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antinéoplasiques alcoylants</term><term>Moutardes à l'azote</term><term>N,N-Bis(2-chloroéthyl)aniline</term></keywords><keywords scheme="MESH" qualifier="toxicité" xml:lang="fr"><term>Antinéoplasiques alcoylants</term><term>Moutardes à l'azote</term><term>N,N-Bis(2-chloroéthyl)aniline</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Base Sequence</term><term>Binding Sites</term><term>Cell Line</term><term>DNA Damage</term><term>Drug Design</term><term>Female</term><term>Humans</term><term>Molecular Structure</term><term>Oligodeoxyribonucleotides</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>ADN</term><term>Altération de l'ADN</term><term>Antinéoplasiques alcoylants</term><term>Conception de médicament</term><term>Facteurs de transcription</term><term>Femelle</term><term>Humains</term><term>Lignée cellulaire</term><term>Moutardes à l'azote</term><term>N,N-Bis(2-chloroéthyl)aniline</term><term>Oligodésoxyribonucléotides</term><term>Récepteurs des oestrogènes</term><term>Sites de fixation</term><term>Structure moléculaire</term><term>Survie cellulaire</term><term>Séquence nucléotidique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">It is a goal of cancer chemotherapy to achieve the selective killing of tumor cells while minimizing toxicity to normal tissues. We describe the design of selective toxins forming DNA adducts that attract the estrogen receptor (ER), a transcription factor that is overexpressed in many human breast and ovarian tumors. The compounds consist of 4-(3-aminopropyl)-N,N-(2-chloroethyl)-aniline linked to 2-(4'-hydroxyphenyl)-3-methyl-5-hydroxy-indole. The former moiety is a DNA damaging nitrogen mustard and the latter is a ligand for the ER. The connection between these groups was refined to permit DNA adducts formed by the mustard portion of the molecule to present the ligand domain so that it was able to interact efficiently with the ER. By using 16-mers containing specific DNA adducts, it was determined that monoadducts and putative intrastrand crosslinks were preferred targets for the ER over interstrand crosslinks. A series of structurally related 2-phenylindole mustards was prepared, some of which were selectively toxic to the ER-positive breast cancer cell line MCF-7, as compared with the ER(-) negative line MDA-MB231. The ability both to bind to DNA and to interact significantly with the ER were essential to achieve selective lethality toward ER(+) cells. Compounds forming DNA adducts without the ability to bind receptor showed similar toxicities in the two cell lines. Several models could explain the selective toxicity of the mustard-phenylindole compounds toward ER(+) cells. The favored model suggests that a mustard-DNA adduct is shielded by the ER from DNA repair enzymes and hence cells possessing an abundance of the ER selectively retain the adduct and are killed.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Croy, R G" sort="Croy, R G" uniqKey="Croy R" first="R G" last="Croy">R G Croy</name><name sortKey="Essigmann, J M" sort="Essigmann, J M" uniqKey="Essigmann J" first="J M" last="Essigmann">J M Essigmann</name><name sortKey="Paige, L A" sort="Paige, L A" uniqKey="Paige L" first="L A" last="Paige">L A Paige</name><name sortKey="Solomon, M S" sort="Solomon, M S" uniqKey="Solomon M" first="M S" last="Solomon">M S Solomon</name><name sortKey="Tadayoni Rebek, B M" sort="Tadayoni Rebek, B M" uniqKey="Tadayoni Rebek B" first="B M" last="Tadayoni-Rebek">B M Tadayoni-Rebek</name><name sortKey="Yarema, K J" sort="Yarema, K J" uniqKey="Yarema K" first="K J" last="Yarema">K J Yarema</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Rink, S M" sort="Rink, S M" uniqKey="Rink S" first="S M" last="Rink">S M Rink</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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