title: Alkynyloxy derivatives of 5,8-quinolinedione: Synthesis, in vitro cytotoxicity studies and computational molecular modeling with NAD(P)H:Quinone oxidoreductase 1.
abstract: The natural 7-amino-5,8-quinolinodione antibiotics were the substrate for the NQO1 protein. The structure-activity relationship showed that the 5,8-quinolinedione moiety was responsible for the interaction with the enzyme. In our research, we presented the synthesis, cytotoxic activity and theoretical study of a 5,8-quinolinedione compound as a potential inhibitor of the NQO1 enzyme. Mono and disubstituted alkynyloxy derivatives of the 5,8-quinolinedione were synthesized and characterized by1H,13C NMR, IR and HR-MS spectra. Newly synthesized derivatives were also tested for their biological activity in vitro against the human cancer cell lines. They showed high cytotoxic activity depending on the type of substituent and the employed tumor cell lines. Moreover, two breast cancer cell lines, MDA-MB-231 and MCF-7, were chosen for analysis as they are characterized by different NQO1 protein levels. It was found that cytotoxic activities of all studied compounds increased against the cell line with a higher NQO1 protein level. The molecular docking was used to examine the probable interaction between the molecules of alkynyloxy derivatives and human NAD[P]H-quinone oxidoreductase (NQO1) protein. The computational studies showed that the 5,8-quinolinedione moiety of all docked compounds was located deeply in the hydrophobic matrix of the active site near the side chains of aromatic residues in positions Trp 105, Phe 178, Tyr 126 and Tyr 128. In every case, introduction of aromatic moieties into the 5,8-quinolinedione molecule led to an increase in the binding affinity in relation to the 6,7-dichloro-5,8-quinolinedione.
authors.affiliation: Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland. Electronic address: mkadela@sum.edu.pl.
authors.forename: Monika
authors.initials: M
authors.lastname: Kadela-Tomanek
authors.affiliation: University of Silesia, Institute of Physics, Department of Solid State Physics, 4 Uniwersytecka Str., 40-007 Katowice, Poland; Silesian Center for Education and Interdisciplinary Research, University of Silesia, 41-500 Chorzów, 75 Pułku Piechoty 1 Str., Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Jastrzębska
authors.affiliation: Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Physical Pharmacy, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Pawełczak
authors.affiliation: Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Bębenek
authors.affiliation: Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland.
authors.forename: Elwira
authors.initials: E
authors.lastname: Chrobak
authors.affiliation: Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Cell Biology, 8 Jedności Str., 41-200 Sosnowiec, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Latocha
authors.affiliation: University of Silesia, Institute of Physics, Department of Solid State Physics, 4 Uniwersytecka Str., 40-007 Katowice, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Książek
authors.affiliation: University of Silesia, Institute of Physics, Department of Physics of Crystals, 4 Uniwersytecka Str., 40-007 Katowice, Poland.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kusz
authors.affiliation: Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland.
authors.forename: Stanisław
authors.initials: S
authors.lastname: Boryczka
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C493127:6,7-dichloro-5,8-quinolinedione; D000970:Antineoplastic Agents; D011804:Quinolines; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: 5,8-quinolinedione; Crystal structure; Cytotoxic activity; Molecular docking; NAD[P]H-quinone oxidoreductase