Flavoenzyme-mediated reduction reactions and antitumor activity of nitrogen-containing tetracyclic ortho-quinone compounds and their nitrated derivatives

Authors

  • Milda Peciukaityte-Alksne Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, Vilnius, LT-10257, Lithuania
  • Jonas Šarlauskas Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, Vilnius, LT-10257, Lithuania
  • Lina Miseviciene Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, Vilnius, LT-10257, Lithuania
  • Audrone Maroziene Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, Vilnius, LT-10257, Lithuania
  • Narimantas Cenas Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, Vilnius, LT-10257, Lithuania
  • Kastis Krikštopaitis Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, Vilnius, LT-10257, Lithuania
  • Zita Staniulyte Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, Vilnius, LT-10257, Lithuania
  • Žilvinas Anusevicius Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, Vilnius, LT-10257, Lithuania

DOI:

https://doi.org/10.17179/excli2017-273

Keywords:

heterocycle quinones, ortho-quinones, enzymatic reactivity, antitumor activity, apoptosis, DFT computation

Abstract

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 activities of the compounds on tumor cell lines followed the concentration-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 cytotoxic effects. Tumor cells quantified by AO/EB staining showed that the cell death induced by the compounds occurs primarily through apoptosis.

Downloads

Published

2017-05-11

How to Cite

Peciukaityte-Alksne, M., Šarlauskas, J., Miseviciene, L., Maroziene, A., Cenas, N., Krikštopaitis, K., … Anusevicius, Žilvinas. (2017). Flavoenzyme-mediated reduction reactions and antitumor activity of nitrogen-containing tetracyclic ortho-quinone compounds and their nitrated derivatives. EXCLI Journal, 16, 663–678. https://doi.org/10.17179/excli2017-273

Issue

Vol. 16 (2017)

Section

Original articles

License

Authors who publish in this journal agree to the following terms:

  • The authors keep the copyright and grant the journal the right of first publication under the terms of the Creative Commons Attribution license, CC BY 4.0. This licencse permits unrestricted use, distribution and reproduction in any medium, provided that the original work is properly cited.
  • The use of general descriptive names, trade names, trademarks, and so forth in this publication, even if not specifically identified, does not imply that these names are not protected by the relevant laws and regulations.
  • Because the advice and information in this journal are believed to be true and accurate at the time of publication, neither the authors, the editors, nor the publisher accept any legal responsibility for any errors or omissions presented in the publication. The publisher makes no guarantee, express or implied, with respect to the material contained herein.
  • The authors can enter into additional contracts for the non-exclusive distribution of the journal's published version by citing the initial publication in this journal (e.g. publishing in an institutional repository or in a book).

Most read articles by the same author(s)