5-Oxo-hexahydroquinoline Derivatives and Their Tetrahydroquinoline Counterparts as Multidrug Resistance Reversal Agents.

Omolbanin Shahraki,Marjan Tavakkoli,Mehdi Khoshneviszadeh,Luciano Saso,Mojtaba Dehghani,Omidreza Firuzi,Maryam Mohabbati,Najmeh Edraki

doi:10.3390/molecules25081839

Abstract

Cancer is a leading cause of death worldwide. Multidrug resistance (MDR) is a main reason of chemotherapy failure in many patients and is often related to overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1). Agents that are capable of modulation of the activity of these transporters might be effective in overcoming MDR. In this study, a new set of 1,4,5,6,7,8-hexahydro 5-oxo quinoline-3-carboxamide derivatives bearing 4-methylthiazole moiety and their tetrahydroquinoline counterparts were synthesized. MDR reversal activity of these 16 newly synthesized derivatives was tested in P-gp overexpressing MES-SA-DX5 human uterine sarcoma cells by flow cytometric determination of Rhodamine123 efflux. The effect of the most potent compounds in induction of apoptosis and alterations of cell cycle was examined in these cells by a flow cytometric method. Inherent cytotoxicity of the synthesized compounds was evaluated against MCF-7, A-549 and K562 cancer cell lines, as well as MES-SA-DX5 and their parental non-resistant MES-SA and also HEK-293 non-cancerous cells by MTT assay. Compounds A1 and A2 with 5-oxo-hexahydroquinoline structure bearing 2,4-dichlorophenyl and 4-bromophenyl moieties, respectively, and their tetrahydroquinoline counterparts B1 and B2 significantly blocked P-gp efflux, induced apoptosis and showed the highest cytotoxicities against MES-SA-DX5 cells. However, only A2 and B2 compounds were relatively selective against cancer and MDR cells as compared to non-resistant and non-cancerous cells. These findings demonstrate that 5-oxo-hexahydroquinoline and 5-oxo-tetrahydroquinoline derivatives represent promising agents with therapeutic potential in drug resistant cancers.

Highlights

Cancer is a major cause of death and disability worldwide and despite considerable diagnostic and therapeutic advancements in recent years, it is still the cause of more than 8 million deaths in the worldMolecules 2020, 25, 1839; doi:10.3390/molecules25081839 www.mdpi.com/journal/moleculesMolecules 2020, 25, 1839 every year [1]
Different mechanisms are involved in MDR: Very often it is caused by the overexpression of P-glycoprotein (P-gp), named multidrug resistance protein-1 (MDR1), which is encoded by ATP-binding cassette (ABC) subfamily B member 1 (ABCB1) gene [4]
Compound 1-((2-methylthiazol-4-yl) amino) pentane-2,4-dione was synthesized by the reaction of the commercially available 2-methylthiazol-4-amine with

Summary

Introduction

Cancer is a major cause of death and disability worldwide and despite considerable diagnostic and therapeutic advancements in recent years, it is still the cause of more than 8 million deaths in the worldMolecules 2020, 25, 1839; doi:10.3390/molecules25081839 www.mdpi.com/journal/moleculesMolecules 2020, 25, 1839 every year [1]. The resistance of malignant tumor cells to multiple structurally and mechanistically unrelated classes of anticancer agents is recognized as multidrug resistance (MDR). This phenomenon very often occurs in advanced cancer cases and is a major cause of failure of therapies [2,3]. P-gp has been one of the first members of ABC transporters to be studied [5]. It functions as an efflux pump extruding several substrate molecules and plays an important physiological role in cleaning cells from xenobiotics and maintaining the integrity of blood-brain barrier [6]. Overexpression of P-gp in cancer cells leads to reduced accumulation of cytotoxic drugs and even targeted therapeutics resulting in resistance against these agents [3,7]

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Conclusion