title: Naphtho[1',2':4,5]imidazo[1,2-a]pyridine-5,6-diones: Synthesis, enzymatic reduction and cytotoxic activity.
abstract: Naphtho[1',2':4,5]imidazo[1,2-a]pyridine-5,6-diones (NPDOs), a new type of N-heterocycle-fused o-quinones, have been synthesized. They have been found to be efficient electron-accepting substrates of NADPH-dependent single-electron-transferring P-450R and two-electron transferring NQO1, generating reactive oxygen species (ROS) with a concomitant decrease in NADPH, which is consistent with redox-cycling. The reactivity of NPDOs toward P-450R (in terms of kcat/Km) varied in the range of 10(6)-10(7)M(-1)s(-1), while their reduction by NQO1 proceeded much faster, approaching the diffusion control limit (kcat/Km∼10(8)-10(9)M(-1)s(-1)). NPDOs exhibited relatively high cytotoxic activity against human lung carcinoma (A-549) and breast tumor (MCF-7) cell lines (LC50=0.1-8.3μM), while promyelocytic leukemia cells (HL-60) were less sensitive to NPDOs (LC50⩾10μM). 3-Nitro-substituted NPDO (11) revealed the highest potency against both A-549 and MCF-7 cell lines, with LC50 of 0.12±0.03μM and 0.28±0.08μM, respectively. Dicoumarol partly suppressed the activity of the compounds against A-594 and MCF-7 cell lines, suggesting that their cytotoxic action might be partially influenced by NQO1-mediated bioreductive activation.
authors.affiliation: Institute of Biochemistry of Vilnius University, Mokslininku 12, LT-08662 Vilnius, Lithuania. Electronic address: jonas.sarlauskas@bchi.vu.lt.
authors.forename: Jonas
authors.initials: J
authors.lastname: Šarlauskas
authors.affiliation: Institute of Biochemistry of Vilnius University, Mokslininku 12, LT-08662 Vilnius, Lithuania.
authors.forename: Milda
authors.initials: M
authors.lastname: Pečiukaitytė-Alksnė
authors.affiliation: Institute of Biochemistry of Vilnius University, Mokslininku 12, LT-08662 Vilnius, Lithuania.
authors.forename: Lina
authors.initials: L
authors.lastname: Misevičienė
authors.affiliation: Institute of Biochemistry of Vilnius University, Mokslininku 12, LT-08662 Vilnius, Lithuania.
authors.forename: Audronė
authors.initials: A
authors.lastname: Marozienė
authors.affiliation: Institute of Biochemistry of Vilnius University, Mokslininku 12, LT-08662 Vilnius, Lithuania.
authors.forename: Evelina
authors.initials: E
authors.lastname: Polmickaitė
authors.affiliation: Institute of Biochemistry of Vilnius University, Mokslininku 12, LT-08662 Vilnius, Lithuania.
authors.forename: Zita
authors.initials: Z
authors.lastname: Staniulytė
authors.affiliation: Institute of Biochemistry of Vilnius University, Mokslininku 12, LT-08662 Vilnius, Lithuania.
authors.forename: Narimantas
authors.initials: N
authors.lastname: Čėnas
authors.affiliation: Institute of Biochemistry of Vilnius University, Mokslininku 12, LT-08662 Vilnius, Lithuania. Electronic address: zilvinas.anusevicius@bchi.vu.lt.
authors.forename: Žilvinas
authors.initials: Ž
authors.lastname: Anusevičius
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D001728:Dicumarol / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019779:Salmonella enterica / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D009285:Naphthoquinones; D011725:Pyridines; D001728:Dicumarol; D003577:Cytochrome P-450 Enzyme System
keywords: Antibacterial activity; Antitumor activity; Bioreductive activation; Cytochrome P-450 reductase (P-450R); DFT calculation; Enzymatic reactivity; Quinone reductase (NQO1); Quinones