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Título
New indolesulfonamide derivatives targeting the colchicine site of tubulin: synthesis, anti-tumour activity, structure–activity relationships, and molecular modelling
Autor(es)
Materia
Design
Synthesis
Indolesulfonamides
antimitotic
colchicine-site
structure–activity relationships
total polar surface area
Fecha de publicación
2021-12
Resumen
Searching for improved indolesulfonamides with higher polarities, 45 new analogues with modifications on the sulfonamide nitrogen, the methoxyaniline, and/or the indole 3-position were synthesised. They show submicromolar to nanomolar antiproliferative IC50 values against four human tumour cell lines and they are not P-glycoprotein substrates as their potencies against HeLa cells did not improve upon cotreatment with multidrug resistance (MDR) inhibitors. The compounds inhibit tubulin polymerisation in vitro and in cells, thus causing a mitotic arrest followed by apoptosis as shown by cell cycle distribution studies. Molecular modelling studies indicate binding at the colchicine site. Methylated sulfonamides were more potent than those with large and polar substitutions. Amide, formyl, or nitrile groups at the indole 3-position provided drug-like properties for reduced toxicity, with Polar Surface Areas (PSA) above a desirable 75 Å2. Nitriles 15 and 16 are potent polar analogues and represent an interesting class of new antimitotics.
URI
ISSN
1475-6366
DOI
10.1080/14756366.2021.1975277
Versión del editor
Colecciones
- DSEAA. Artículos [11]
Ficheros en el ítem
Tamaño:
3.961Mb
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Descripción:
2021_JEnzInhMedChem_2025_NewIndolesulonamides_VicenteBlazquez_et_al