Modification of C-seco taxoids through ring tethering and substituent replacement leading to effective agents against tumor drug resistance mediated by ßIII-Tubulin and P-glycoprotein (P-gp) overexpressions.
Eur J Med Chem
; 137: 488-503, 2017 Sep 08.
Article
en En
| MEDLINE
| ID: mdl-28624703
ABSTRACT
In our efforts to improve the efficacy of taxane-based microtubule (MT) stabilizing agents against tumor drug resistance mediated by multiple mechanisms, two clinically relevant factors were focused i.e., P-glycoprotein and ßIII-tubulin overexpression. Based on the structure of C-seco taxoid 1 m (IDN5390) which was believed to more selectively interact with ßIII-tubulin than paclitaxel, we prepared a series of C-seco taxoids bearing various 7,9-O-linkages and/or different substituents at C2 and C3' positions. Some of them exhibited much more potent binding affinity to MTs and cytotoxicity than their C-seco parent compounds in drug resistant cells with both mechanisms. SAR analysis indicated that C2 modifications significantly enhanced MT binding but brought ambiguous influence to cytotoxicity whereas 7,9-linkage and C3' modifications enhance cytotoxicity more efficiently than improve MT binding. These observations illustrate a better translation of molecular binding effect to cellular activity by C ring closure and C3' modification than C2 modification in C-seco taxoids.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Tubulina (Proteína)
/
Resistencia a Antineoplásicos
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Subfamilia B de Transportador de Casetes de Unión a ATP
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Taxoides
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Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2017
Tipo del documento:
Article
País de afiliación:
China