Exploration of novel phthalazinone derivatives as potential efflux transporter inhibitors for reversing multidrug resistance and improving the oral absorption of paclitaxel.
Eur J Med Chem
; 233: 114231, 2022 Apr 05.
Article
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| MEDLINE
| ID: mdl-35247755
ABSTRACT
Chemotherapy is an important means of cancer treatment. However, overexpression of efflux transporters (including but not limited to P-gp and BCRP) can lead to resistance to cancer chemotherapy. Multiple-target inhibitors of efflux transporter can be overcome the resistance and improve the oral bioavailability of chemotherapy drugs. Therefore, we designed and synthesized a series of phthalazinone ring derivatives (1-20) with different aromatic heterocycles substituents on the amide bond for dual inhibition of P-gp and BCRP. Most target compounds significantly increased the accumulation of P-gp substrates in the chemo-resistant cancer cell lines by inhibiting the efflux of transporters. Compound 19 in particular showed stronger MDR reversal compared to Gefitinib and Verapamil, and comparable to that of the BCRP inhibitor Ko143. In addition, compound 19 improved intestinal absorption of paclitaxel (PTX) and enhanced the bioavailability of the orally administered drug in vivo.
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Bases de datos:
MEDLINE
Asunto principal:
Paclitaxel
/
Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2022
Tipo del documento:
Article