Next Article in Journal
A Trisbenzimidazole Phosphoramidite Building Block Enables High-Yielding Syntheses of RNA-Cleaving Oligonucleotide Conjugates
Previous Article in Journal
Improved Detection of Molecular Markers of Atherosclerotic Plaques Using Sub-Millimeter PET Imaging
Open AccessArticle

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

1
Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan 98167-43463, Iran
2
Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz 71348-53734, Iran
3
Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz 71468-64685, Iran
4
Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(8), 1839; https://doi.org/10.3390/molecules25081839
Received: 9 February 2020 / Revised: 28 March 2020 / Accepted: 31 March 2020 / Published: 16 April 2020
(This article belongs to the Section Medicinal Chemistry)
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. View Full-Text
Keywords: anticancer drug resistance; efflux pumps; antiproliferative agents; drug design; 1,4-dihydropyridine anticancer drug resistance; efflux pumps; antiproliferative agents; drug design; 1,4-dihydropyridine
Show Figures

Figure 1

MDPI and ACS Style

Shahraki, O.; Khoshneviszadeh, M.; Dehghani, M.; Mohabbati, M.; Tavakkoli, M.; Saso, L.; Edraki, N.; Firuzi, O. 5-Oxo-hexahydroquinoline Derivatives and Their Tetrahydroquinoline Counterparts as Multidrug Resistance Reversal Agents. Molecules 2020, 25, 1839.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop