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7500170 
Journal Article 
Exploring the size adaptability of the B ring binding zone of the colchicine site of tubulin with para-nitrogen substituted isocombretastatins 
Jiménez, C; Ellahioui, Y; Álvarez, R; Aramburu, L; Riesco, A; González, M; Vicente, A; Dahdouh, A; Ibn Mansour, A; Jiménez, C; Martín, D; Sarmiento, RG; Medarde, M; Caballero, E; Peláez, R 
2015 
Yes 
European Journal of Medicinal Chemistry
ISSN: 0223-5234
EISSN: 1768-3254 
100 
210-222 
English 
26092446 
WOS:000358097200021 
We have synthesized and assayed dimethylaminophenyl, pyrrolidin-1-ylphenyl and carbazole containing phenstatins and isocombretastatins as analogues of the highly potent indoleisocombretastatins with extended or reduced ring sizes. This is an attempt to explore beyond the structural constraints of the X-ray crystal structures the zone of the colchicine site where the tropolone ring of colchicine binds to tubulin (zone 1). The isocombretastatins display up to 30 fold increased water solubility when compared with combretastatin A-4, potent inhibition of tubulin polymerization, and nanomolar cytotoxicities against several human cancer cell lines irrespective of the size of the B ring. On the other hand, substitutions ortho to the nitrogen cause an important reduction in potency. We have also shown that representative compounds inhibit autophagy. These results show that zone 1 can adapt to systems of different size as far as they stay in a common plane, but does not tolerate substituents protruding above or below it. These results can help in the understanding of the binding modes of structures with similar systems and in the design of new colchicine site ligands.