Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines

Autores
Bermejo, Almudena; Andreu, Inmaculada; Suvire, Fernando Daniel; Léonce, Stephane; Caignard, Daniel H.; Renard, Pierre; Pierré, Alain; Enriz, Ricardo Daniel; Cortes, Diego; Cabedo, Nuria
Año de publicación
2002
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in vitro against the leukemia L 1210 cell line to evaluate their ability to perturb the cell cycle by arresting cells in the G1 phase. 1-Benzoylimines, 1-phenylimines, and 1-alkylimines were synthesized. The most powerful cytotoxic derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were obtained from amides I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in acetonitrile. SAR studies let us to identify the essential structural features for cytotoxic activity. The most bioactive compounds (with IC50 < 5μM) were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19), and they are characterized by the following: (i) An α-ketoimine moiety is necessary for potent antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40, are less active). (ii) An hydrophobic, benzyloxy, alkyloxy, or allyloxy group at the C-6 position seems to be relevant for cytotoxicity. (iii) Regarding the influence of the benzoylic moiety, both the unsubstituted (13, 8, 9, 11, 1, and 6) and the 3′-monosubstituted (22, 21, 20, and 19) compounds were more potent than compounds with other substitutions.
Fil: Bermejo, Almudena. Universidad de Valencia; España
Fil: Andreu, Inmaculada. Universidad de Valencia; España
Fil: Suvire, Fernando Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina
Fil: Léonce, Stephane. Laboratoire Servier; Francia
Fil: Caignard, Daniel H.. Laboratoire Servier; Francia
Fil: Renard, Pierre. Laboratoire Servier; Francia
Fil: Pierré, Alain. Laboratoire Servier; Francia
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina
Fil: Cortes, Diego. Universidad de Valencia; España
Fil: Cabedo, Nuria. Universidad de Valencia; España
Materia
Benzoyldihydroisoquinolines
SAR
Inhibitors of G1 phase of the cell cycle
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/136293
Acceder
id CONICETDig_dfdeb9709e03d64668121fc2d164afed
oai_identifier_str oai:ri.conicet.gov.ar:11336/136293
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolinesBermejo, AlmudenaAndreu, InmaculadaSuvire, Fernando DanielLéonce, StephaneCaignard, Daniel H.Renard, PierrePierré, AlainEnriz, Ricardo DanielCortes, DiegoCabedo, NuriaBenzoyldihydroisoquinolinesSARInhibitors of G1 phase of the cell cyclehttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in vitro against the leukemia L 1210 cell line to evaluate their ability to perturb the cell cycle by arresting cells in the G1 phase. 1-Benzoylimines, 1-phenylimines, and 1-alkylimines were synthesized. The most powerful cytotoxic derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were obtained from amides I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in acetonitrile. SAR studies let us to identify the essential structural features for cytotoxic activity. The most bioactive compounds (with IC50 < 5μM) were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19), and they are characterized by the following: (i) An α-ketoimine moiety is necessary for potent antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40, are less active). (ii) An hydrophobic, benzyloxy, alkyloxy, or allyloxy group at the C-6 position seems to be relevant for cytotoxicity. (iii) Regarding the influence of the benzoylic moiety, both the unsubstituted (13, 8, 9, 11, 1, and 6) and the 3′-monosubstituted (22, 21, 20, and 19) compounds were more potent than compounds with other substitutions.Fil: Bermejo, Almudena. Universidad de Valencia; EspañaFil: Andreu, Inmaculada. Universidad de Valencia; EspañaFil: Suvire, Fernando Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; ArgentinaFil: Léonce, Stephane. Laboratoire Servier; FranciaFil: Caignard, Daniel H.. Laboratoire Servier; FranciaFil: Renard, Pierre. Laboratoire Servier; FranciaFil: Pierré, Alain. Laboratoire Servier; FranciaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; ArgentinaFil: Cortes, Diego. Universidad de Valencia; EspañaFil: Cabedo, Nuria. Universidad de Valencia; EspañaAmerican Chemical Society2002-09-15info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/136293Bermejo, Almudena; Andreu, Inmaculada; Suvire, Fernando Daniel; Léonce, Stephane; Caignard, Daniel H.; et al.; Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines; American Chemical Society; Journal of Medicinal Chemistry; 45; 23; 15-9-2002; 5058-50680022-26231520-4804CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/jm020831a#info:eu-repo/semantics/altIdentifier/doi/10.1021/jm020831ainfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-05-27T14:32:11Zoai:ri.conicet.gov.ar:11336/136293instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-05-27 14:32:11.72CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines
title Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines
spellingShingle Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines
Bermejo, Almudena
Benzoyldihydroisoquinolines
SAR
Inhibitors of G1 phase of the cell cycle
title_short Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines
title_full Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines
title_fullStr Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines
title_full_unstemmed Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines
title_sort Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines
dc.creator.none.fl_str_mv Bermejo, Almudena
Andreu, Inmaculada
Suvire, Fernando Daniel
Léonce, Stephane
Caignard, Daniel H.
Renard, Pierre
Pierré, Alain
Enriz, Ricardo Daniel
Cortes, Diego
Cabedo, Nuria
author Bermejo, Almudena
author_facet Bermejo, Almudena
Andreu, Inmaculada
Suvire, Fernando Daniel
Léonce, Stephane
Caignard, Daniel H.
Renard, Pierre
Pierré, Alain
Enriz, Ricardo Daniel
Cortes, Diego
Cabedo, Nuria
author_role author
author2 Andreu, Inmaculada
Suvire, Fernando Daniel
Léonce, Stephane
Caignard, Daniel H.
Renard, Pierre
Pierré, Alain
Enriz, Ricardo Daniel
Cortes, Diego
Cabedo, Nuria
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Benzoyldihydroisoquinolines
SAR
Inhibitors of G1 phase of the cell cycle
topic Benzoyldihydroisoquinolines
SAR
Inhibitors of G1 phase of the cell cycle
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in vitro against the leukemia L 1210 cell line to evaluate their ability to perturb the cell cycle by arresting cells in the G1 phase. 1-Benzoylimines, 1-phenylimines, and 1-alkylimines were synthesized. The most powerful cytotoxic derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were obtained from amides I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in acetonitrile. SAR studies let us to identify the essential structural features for cytotoxic activity. The most bioactive compounds (with IC50 < 5μM) were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19), and they are characterized by the following: (i) An α-ketoimine moiety is necessary for potent antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40, are less active). (ii) An hydrophobic, benzyloxy, alkyloxy, or allyloxy group at the C-6 position seems to be relevant for cytotoxicity. (iii) Regarding the influence of the benzoylic moiety, both the unsubstituted (13, 8, 9, 11, 1, and 6) and the 3′-monosubstituted (22, 21, 20, and 19) compounds were more potent than compounds with other substitutions.
Fil: Bermejo, Almudena. Universidad de Valencia; España
Fil: Andreu, Inmaculada. Universidad de Valencia; España
Fil: Suvire, Fernando Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina
Fil: Léonce, Stephane. Laboratoire Servier; Francia
Fil: Caignard, Daniel H.. Laboratoire Servier; Francia
Fil: Renard, Pierre. Laboratoire Servier; Francia
Fil: Pierré, Alain. Laboratoire Servier; Francia
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina
Fil: Cortes, Diego. Universidad de Valencia; España
Fil: Cabedo, Nuria. Universidad de Valencia; España
description A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in vitro against the leukemia L 1210 cell line to evaluate their ability to perturb the cell cycle by arresting cells in the G1 phase. 1-Benzoylimines, 1-phenylimines, and 1-alkylimines were synthesized. The most powerful cytotoxic derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were obtained from amides I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in acetonitrile. SAR studies let us to identify the essential structural features for cytotoxic activity. The most bioactive compounds (with IC50 < 5μM) were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19), and they are characterized by the following: (i) An α-ketoimine moiety is necessary for potent antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40, are less active). (ii) An hydrophobic, benzyloxy, alkyloxy, or allyloxy group at the C-6 position seems to be relevant for cytotoxicity. (iii) Regarding the influence of the benzoylic moiety, both the unsubstituted (13, 8, 9, 11, 1, and 6) and the 3′-monosubstituted (22, 21, 20, and 19) compounds were more potent than compounds with other substitutions.
publishDate 2002
dc.date.none.fl_str_mv 2002-09-15
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/136293
Bermejo, Almudena; Andreu, Inmaculada; Suvire, Fernando Daniel; Léonce, Stephane; Caignard, Daniel H.; et al.; Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines; American Chemical Society; Journal of Medicinal Chemistry; 45; 23; 15-9-2002; 5058-5068
0022-2623
1520-4804
CONICET Digital
CONICET
url http://hdl.handle.net/11336/136293
identifier_str_mv Bermejo, Almudena; Andreu, Inmaculada; Suvire, Fernando Daniel; Léonce, Stephane; Caignard, Daniel H.; et al.; Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines; American Chemical Society; Journal of Medicinal Chemistry; 45; 23; 15-9-2002; 5058-5068
0022-2623
1520-4804
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/jm020831a#
info:eu-repo/semantics/altIdentifier/doi/10.1021/jm020831a
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1866373065055666176
score 13.130638

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