2024-03-29T10:43:49Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1376912022-10-27T10:49:10Zcom_10261_86com_10261_1col_10261_339
DIGITAL.CSIC
author
Jantsch, Andrea
author
Nieto, Lidia
author
Gertsch, Jürg
author
Rodríguez-Salarichs, Javier
author
Matesanz, Ruth
author
Jiménez-Barbero, Jesús
author
Díaz, José Fernando
author
Canales, Ángeles
author
Altmann, Karl-Heinz
funder
ETH Zurich
funder
Ministerio de Economía y Competitividad (España)
funder
Comunidad de Madrid
2016-10-04T12:09:49Z
2016-10-04T12:09:49Z
2016-08-03
Molecules 21:1010 (2016)
1420-3049
http://hdl.handle.net/10261/137691
10.3390/molecules21081010
1420-3049
http://dx.doi.org/10.13039/501100003329http://dx.doi.org/10.13039/100012818
27527129
12-Aza-epothilones (azathilones) incorporating quinoline side chains and bearing
different N12-substituents have been synthesized via highly efficient RCM-based macrocyclizations.Quinoline-based azathilones with the side chain N-atom in the meta-position to the C15 atom in the macrocycle are highly potent inhibitors of cancer cell growth in vitro. In contrast, shifting the quinoline nitrogen to the position para to C15 leads to a ca. 1000-fold loss in potency. Likewise,the desaturation of the C9-C10 bond in the macrocycle to an E double bond produces a substantial reduction in antiproliferative activity. This is in stark contrast to the effect exerted by the same
modification in the natural epothilone macrocycle. The conformation of a representative azathilone bound to / -tubulin heterodimers was determined based on TR-NOE measurements and a model for the posture of the compound in its binding site on -tubulin was deduced through a combination of STD measurements and CORCEMA-ST calculations. The tubulin-bound, bioactive conformation of azathilones was found to be overall similar to that of epothilones A and B.
eng
openAccess
Anticancer
Azathilones
Conformation
Drug discovery
Epothilones
Natural product
SAR
STD
Synthesis
Tubulin
Synthesis, biological profiling and determination of the tubulin-bound conformation of 12-Aza-epothilones (azathilones)
artículo
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URL
https://digital.csic.es/bitstream/10261/137691/1/molecules-2016.pdf
File
MD5
581daf3555b048d278bc2f2e8ad4dcf6
2299130
application/pdf
molecules-2016.pdf