Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP

Autores
Garcia, Lia C.; Gandolfi Donadío, Lucía; Mann, Ella; Kolusheva, Sofiya; Kedei, Noemi; Lewin, Nancy E.; Hill, Collin S.; Kelsey, Jessica S.; Yang, Jing; Esch, Timothy E.; Santos, Marina; Peach, Megan L.; Kelley, James A.; Blumberg, Peter M.; Jelinek, Raz; Marquez, Victor E.; Comin, Maria Julieta
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2–5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined.
Fil: Garcia, Lia C.. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Gandolfi Donadío, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Mann, Ella. Ben Gurion University of The Negev; Israel
Fil: Kolusheva, Sofiya. Ben Gurion University of The Negev; Israel
Fil: Kedei, Noemi. National Cancer Institute. Bethesda; Estados Unidos
Fil: Lewin, Nancy E.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Hill, Collin S.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Kelsey, Jessica S.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Yang, Jing. National Cancer Institute. Bethesda; Estados Unidos
Fil: Esch, Timothy E.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Santos, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Peach, Megan L.. National Institutes of Health; Estados Unidos
Fil: Kelley, James A.. National Institutes of Health; Estados Unidos
Fil: Blumberg, Peter M.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Jelinek, Raz. Ben Gurion University of The Negev; Israel
Fil: Marquez, Victor E.. National Institutes of Health; Estados Unidos
Fil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina
Materia
Indolo-Lactones
C1 Domain
Rasgrp
Cancer
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:11336/35694

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oai_identifier_str oai:ri.conicet.gov.ar:11336/35694
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRPGarcia, Lia C.Gandolfi Donadío, LucíaMann, EllaKolusheva, SofiyaKedei, NoemiLewin, Nancy E.Hill, Collin S.Kelsey, Jessica S.Yang, JingEsch, Timothy E.Santos, MarinaPeach, Megan L.Kelley, James A.Blumberg, Peter M.Jelinek, RazMarquez, Victor E.Comin, Maria JulietaIndolo-LactonesC1 DomainRasgrpCancerhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2–5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined.Fil: Garcia, Lia C.. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Gandolfi Donadío, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Mann, Ella. Ben Gurion University of The Negev; IsraelFil: Kolusheva, Sofiya. Ben Gurion University of The Negev; IsraelFil: Kedei, Noemi. National Cancer Institute. Bethesda; Estados UnidosFil: Lewin, Nancy E.. National Cancer Institute. Bethesda; Estados UnidosFil: Hill, Collin S.. National Cancer Institute. Bethesda; Estados UnidosFil: Kelsey, Jessica S.. National Cancer Institute. Bethesda; Estados UnidosFil: Yang, Jing. National Cancer Institute. Bethesda; Estados UnidosFil: Esch, Timothy E.. National Cancer Institute. Bethesda; Estados UnidosFil: Santos, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Peach, Megan L.. National Institutes of Health; Estados UnidosFil: Kelley, James A.. National Institutes of Health; Estados UnidosFil: Blumberg, Peter M.. National Cancer Institute. Bethesda; Estados UnidosFil: Jelinek, Raz. Ben Gurion University of The Negev; IsraelFil: Marquez, Victor E.. National Institutes of Health; Estados UnidosFil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaPergamon-Elsevier Science Ltd.2014-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/35694Garcia, Lia C.; Gandolfi Donadío, Lucía; Mann, Ella; Kolusheva, Sofiya; Kedei, Noemi; et al.; Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP; Pergamon-Elsevier Science Ltd.; Bioorganic & Medicinal Chemistry; 22; 12; 6-2014; 3123-31400968-0896CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.bmc.2014.04.024info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0968089614002788info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:48:54Zoai:ri.conicet.gov.ar:11336/35694instacron: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:34982025-09-03 09:48:54.595CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP
title Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP
spellingShingle Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP
Garcia, Lia C.
Indolo-Lactones
C1 Domain
Rasgrp
Cancer
title_short Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP
title_full Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP
title_fullStr Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP
title_full_unstemmed Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP
title_sort Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP
dc.creator.none.fl_str_mv Garcia, Lia C.
Gandolfi Donadío, Lucía
Mann, Ella
Kolusheva, Sofiya
Kedei, Noemi
Lewin, Nancy E.
Hill, Collin S.
Kelsey, Jessica S.
Yang, Jing
Esch, Timothy E.
Santos, Marina
Peach, Megan L.
Kelley, James A.
Blumberg, Peter M.
Jelinek, Raz
Marquez, Victor E.
Comin, Maria Julieta
author Garcia, Lia C.
author_facet Garcia, Lia C.
Gandolfi Donadío, Lucía
Mann, Ella
Kolusheva, Sofiya
Kedei, Noemi
Lewin, Nancy E.
Hill, Collin S.
Kelsey, Jessica S.
Yang, Jing
Esch, Timothy E.
Santos, Marina
Peach, Megan L.
Kelley, James A.
Blumberg, Peter M.
Jelinek, Raz
Marquez, Victor E.
Comin, Maria Julieta
author_role author
author2 Gandolfi Donadío, Lucía
Mann, Ella
Kolusheva, Sofiya
Kedei, Noemi
Lewin, Nancy E.
Hill, Collin S.
Kelsey, Jessica S.
Yang, Jing
Esch, Timothy E.
Santos, Marina
Peach, Megan L.
Kelley, James A.
Blumberg, Peter M.
Jelinek, Raz
Marquez, Victor E.
Comin, Maria Julieta
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Indolo-Lactones
C1 Domain
Rasgrp
Cancer
topic Indolo-Lactones
C1 Domain
Rasgrp
Cancer
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2–5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined.
Fil: Garcia, Lia C.. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Gandolfi Donadío, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Mann, Ella. Ben Gurion University of The Negev; Israel
Fil: Kolusheva, Sofiya. Ben Gurion University of The Negev; Israel
Fil: Kedei, Noemi. National Cancer Institute. Bethesda; Estados Unidos
Fil: Lewin, Nancy E.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Hill, Collin S.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Kelsey, Jessica S.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Yang, Jing. National Cancer Institute. Bethesda; Estados Unidos
Fil: Esch, Timothy E.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Santos, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Peach, Megan L.. National Institutes of Health; Estados Unidos
Fil: Kelley, James A.. National Institutes of Health; Estados Unidos
Fil: Blumberg, Peter M.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Jelinek, Raz. Ben Gurion University of The Negev; Israel
Fil: Marquez, Victor E.. National Institutes of Health; Estados Unidos
Fil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina
description The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2–5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined.
publishDate 2014
dc.date.none.fl_str_mv 2014-06
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/11336/35694
Garcia, Lia C.; Gandolfi Donadío, Lucía; Mann, Ella; Kolusheva, Sofiya; Kedei, Noemi; et al.; Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP; Pergamon-Elsevier Science Ltd.; Bioorganic & Medicinal Chemistry; 22; 12; 6-2014; 3123-3140
0968-0896
CONICET Digital
CONICET
url http://hdl.handle.net/11336/35694
identifier_str_mv Garcia, Lia C.; Gandolfi Donadío, Lucía; Mann, Ella; Kolusheva, Sofiya; Kedei, Noemi; et al.; Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP; Pergamon-Elsevier Science Ltd.; Bioorganic & Medicinal Chemistry; 22; 12; 6-2014; 3123-3140
0968-0896
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bmc.2014.04.024
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0968089614002788
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
application/pdf
dc.publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd.
publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd.
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
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