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Modification of C-seco taxoids through ring tethering and substituent replacement leading to effective agents against tumor drug resistance mediated by βIII-Tubulin and P-glycoprotein (P-gp) overexpressions.

AutorTang, Yong; Rodríguez-Salarichs, Javier; Estévez Gallego, J.; Balaguer, Francisco de Asís; Redondo-Horcajo, Mariano ; Lucena-Agell, Daniel; Barasoain, Isabel ; Díaz, José Fernando ; Fang, Wei-shuo S.
Palabras claveTaxoids
Drug resistance
Fecha de publicación3-jun-2017
CitaciónEur J Med Chem. 137:488-503 (2017)
ResumenIn 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 βIII-tubulin overexpression. Based on the structure of C-seco taxoid 1 m (IDN5390) which was believed to more selectively interact with βIII-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.
Descripción53 p.-6 fig.-3 tab.-1 graf. Tang, Yong et al.
Versión del editorhttp://dx.doi.org/10.1016/j.ejmech.2017.06.001
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