Exploration of novel phthalazinone derivatives as potential efflux transporter inhibitors for reversing multidrug resistance and improving the oral absorption of paclitaxel

Wei Shi; Ping Zhang; Feng Zou; Jiaqi Zhou; Ziyu Yin; Zilong Cai; Hesham Ghaleb; Yuxuan Jiang; Wenlong Huang; Yan Liu; Qianqian Qiu; Hai Qian

doi:10.1016/j.ejmech.2022.114231

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. 2022 Apr 5:233:114231. doi: 10.1016/j.ejmech.2022.114231. Epub 2022 Feb 25.

Authors

Wei Shi¹, Ping Zhang¹, Feng Zou¹, Jiaqi Zhou¹, Ziyu Yin¹, Zilong Cai¹, Hesham Ghaleb¹, Yuxuan Jiang¹, Wenlong Huang², Yan Liu³, Qianqian Qiu⁴, Hai Qian⁵

Affiliations

¹ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
² Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
³ School of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China. Electronic address: drliuyan@126.com.
⁴ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: qianqianqiu_cpu@126.com.
⁵ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: qianhai24@163.com.

PMID: 35247755
DOI: 10.1016/j.ejmech.2022.114231

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.

Keywords: BCRP; Efflux transporter; Multidrug resistance; Oral bioavailability; P-gp.

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Humans
Neoplasm Proteins / metabolism
Neoplasms* / drug therapy
Paclitaxel* / pharmacology
Paclitaxel* / therapeutic use

Substances

ATP Binding Cassette Transporter, Subfamily G, Member 2
Neoplasm Proteins
Paclitaxel