Synthesis and biological evaluation of carbamates derived from aminocombretastatin A-4 as vascular disrupting agents
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Otros documentos de la autoría: Conesa Milián, Laura; Falomir, Eva; Murga, Juan; Carda, Miguel; Meyen, Eef; Liekens, Sandra; Marco, J. Alberto
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Título
Synthesis and biological evaluation of carbamates derived from aminocombretastatin A-4 as vascular disrupting agentsAutoría
Fecha de publicación
2018-03-10Editor
ElsevierCita bibliográfica
CONESA MILIÁN, Laura; FALOMIR VENTURA, Eva; MURGA CLAUSELL, Juan; CARDA, Miguel; MEYEN, Eef; LIEKENS, Sandra; MARCO, J. Alberto. (2018). Synthesis and biological evaluation of carbamates derived from aminocombretastatin A-4 as vascular disrupting agents. European Journal of Medicinal Chemistry v. 147, p. 183-193Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
https://www.sciencedirect.com/science/article/pii/S0223523418300710?via%3DihubVersión
info:eu-repo/semantics/submittedVersionPalabras clave / Materias
Resumen
A series of t wenty-six carbamates derived from aminocombretastatin A- 4 (AmCA-4 ) were syn thesized
and evaluated for their capacity to affect cell proliferation, tubulin polymerization, mitotic cell arrest,
micr ... [+]
A series of t wenty-six carbamates derived from aminocombretastatin A- 4 (AmCA-4 ) were syn thesized
and evaluated for their capacity to affect cell proliferation, tubulin polymerization, mitotic cell arrest,
microtubule network organization, apoptos is and endothelial tubular structures in vitro. The anti-
pro liferative activity of the synthetic carbamates was measured on several human tumor cell lines
(i.e. HT-29, MCF-7, HeLa, A-549, MDA-MB-231, H L-60) as well as on the endothelial cell line HMEC-1
and the non-tumor cell line H EK-293. The compounds showed anti-proliferative activity in the
nanomolar range thereby exceeding by far the activity of combretastatin A-4 (CA-4 ) and, in some cases,
the activity of AmCA-4. The most active compounds proved to be the carbamates bearing chloro,
bromo or methoxy groups in the meta position of the phenyl ring. Moreover, all carbamates inhibited
in vitro tubulin polymerization, in a similar manne r to that of CA-4 and Am CA-4 by interacting with
the colchicine binding site in tubulin. The synthetic carbamates proved as active as AmCA-4 in causing
mitotic arrest, as asses sed in A549 human lung cancer cells, and disruption of the microtubule ce llular
network. Some selected carbamates induced apoptosis at concentrations as low as 10 nM, being more
active than AmCA-4. Final ly, these selected carbamates displayed a vascular disrupting activity on
endothelial cells in a dose-dependent manner. In conclusion, our data indicate that carbamates derived
from aminocombretastatin A-4 represent interesting lead compounds for the design of vascular dis-
rupting agents [-]
Publicado en
European Journal of Medicinal Chemistry (2018), v. 147Proyecto de investigación
This research has been funded by 1) the Ministerio de Economía y Competitividad (project CTQ2014-52949-P), 2) by the Universitat Jaume I (project PI-1B2015-75) and 3) by the Conselleria d’Educació, Investigació, Cultura i Sport de la Generalitat Valenciana (project PROMETEO 2013/027); 4) Spanish Ministry of Educa-tion, Culture and Sport for a FPU fellowship (FPU14/00878)Derechos de acceso
http://rightsstatements.org/vocab/CNE/1.0/
info:eu-repo/semantics/openAccess
info:eu-repo/semantics/openAccess
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