Title Flavoenzyme-mediated reduction reactions and antitumor activity of nitrogen-containing tetracyclic ortho-quinone compounds and their nitrated derivatives /
Authors Pečiukaitytė-Alksnė, Milda ; Šarlauskas, Jonas ; Misevičienė, Lina ; Marozienė, Audronė ; Čėnas, Narimantas ; Krikštopaitis, Kastis ; Staniulytė, Zita ; Anusevičius, Žilvinas
DOI 10.17179/excli2017-273
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Is Part of EXCLI journal.. Dortmund : Leibniz Research Centre for Working Environment and Human Factors. 2017, Vol. 16, p. 663-678.. ISSN 1611-2156
Keywords [eng] heterocycle quinones ; ortho-quinones ; enzymatic reactivity ; antitumor activity ; apoptosis ; DFT computation
Abstract [eng] Nitrogen-based tetracyclic ortho-quinones (naphtho[1'2':4.5]imidazo[1,2-a]pyridine-5,6-diones, NPDOs) and their nitro-substituted derivatives (nitro-(P)NPDOs) were obtained by condensation of substituted 2,3-dichloro-1,4-naphthoquinones with 2-amino-pyridine and -pyrimidine and nitration at an elevated temperature. The structural features of the compounds as well as their global and regional electrophilic potency were characterized by means of DFT computation. The compounds were highly reactive substrates of single- and two-electron (hydride) - transferring P-450R (CPR; EC 1.6.2.4) and NQO-1 (DTD; EC 1.6.99.2), respectively, concomitantly producing reactive oxygen species. Their catalytic efficiency defined in terms of the apparent second-order rate constant (kcat/KM (Q) ) values in P-450R- and NQO-1-mediated reactions varied in the range of 3-6 × 107 M-1 s-1 and 1.6-7.4 × 108 M-1 s-1, respectively. The cytotoxic activ ities of the compounds on tumor cell lines followed the concentra-tion-dependent manner exhibiting relatively high cytotoxic potency against breast cancer MCF-7, with CL50 values of 0.08-2.02 μM L-1 and lower potency against lung cancer A-549 (CL50 = 0.28-7.66 μM L-1). 3-nitro-pyrimidino-NPDO quinone was the most active compound against MCF-7 with CL50 of 0.08 ± 0.01 μM L-1 (0.02 μg mL -1)) which was followed by 3-nitro-NPDO with CL50 of 0.12 ± 0.03 μM L-1 (0.035 μg mL-1)) and 0.28 ± 0.08 μM L-1(0.08 μg mL-1) on A-549 and MCF-7 cells, respectively, while 1- and 4-nitro-quinoidals produced the least cyto-toxic effects. Tumor cells quantified by AO/EB staining showed that the cell death induced by the compounds occurs primarily through apoptosis.
Published Dortmund : Leibniz Research Centre for Working Environment and Human Factors
Type Journal article
Language English
Publication date 2017