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

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.
Wei Shi 1,  Ping Zhang 1,  Feng Zou 1,  Jiaqi Zhou 1,  Ziyu Yin 1,  Zilong Cai 1,  Hesham Ghaleb 1,  Yuxuan Jiang 1,  Wenlong Huang 2,  Yan Liu 3,  Qianqian Qiu 4,  Hai Qian 5
Affiliations

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.

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