Design, synthesis and biological evaluation of N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide derivatives as novel P-glycoprotein inhibitors reversing multidrug resistance

Qianqian Qiu; Jiaqi Zhou; Wei Shi; Mutta Kairuki; Wenglong Huang; Hai Qian

doi:10.1016/j.bioorg.2019.01.039

Design, synthesis and biological evaluation of N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide derivatives as novel P-glycoprotein inhibitors reversing multidrug resistance

Bioorg Chem. 2019 May:86:166-175. doi: 10.1016/j.bioorg.2019.01.039. Epub 2019 Jan 22.

Authors

Qianqian Qiu¹, Jiaqi Zhou², Wei Shi², Mutta Kairuki², Wenglong Huang³, Hai Qian⁴

Affiliations

¹ School of Pharmacy, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, Yancheng Teachers' University, Yancheng 224007, PR China.
² Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
³ 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: [email protected].
⁴ 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: [email protected].

PMID: 30710850
DOI: 10.1016/j.bioorg.2019.01.039

Abstract

The overexpression of P-glycoprotein plays an important role in the process of multidrug resistance (MDR). P-gp inhibitors are one of the effective strategies to reverse tumor MDR. Novel P-gp inhibitors with phthalazinone scaffolds were designed, synthesized and evaluated. Compound 26 was found to be the most promising for further study. Compound 26 possessed high potency (EC₅₀ = 46.2 ± 3.5 nM) and low cytotoxicity.26 possessed high MDR reversal activity towards doxorubicin-resistant K56/A02 cells. Reversal fold (RF) value reach to 44.26. 26 also increased accumulation of doxorubicin (DOX or ADM) or other MDR-related anticancer drugs with different structures. In conclusion, compound 26 deserves more research for its good features as P-gp inhibitor.

Keywords: Doxorubicin; Multidrug resistance; P-glycoprotein inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Antibiotics, Antineoplastic / chemical synthesis
Antibiotics, Antineoplastic / chemistry
Antibiotics, Antineoplastic / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Doxorubicin / chemical synthesis
Doxorubicin / chemistry
Doxorubicin / pharmacology*
Drug Design*
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
Humans
Isoquinolines / chemical synthesis
Isoquinolines / chemistry
Isoquinolines / pharmacology*
K562 Cells
Molecular Structure
Phthalazines / chemical synthesis
Phthalazines / chemistry
Phthalazines / pharmacology*
Structure-Activity Relationship

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antibiotics, Antineoplastic
Isoquinolines
Phthalazines
Doxorubicin