Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Dec;35(1):831-839.
doi: 10.1080/14756366.2020.1743281.

Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity

Sara T Al-Rashood  1 , Ahmed R Hamed  2   3 , Ghada S Hassan  4 , Hamad M Alkahtani  1 , Abdulrahman A Almehizia  1 , Amal Alharbi  1 , Mohammad M Al-Sanea  5 , Wagdy M Eldehna  6
Affiliations

Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity

Sara T Al-Rashood et al. J Enzyme Inhib Med Chem. 2020 Dec.

Abstract

In the current medical era, spirooxindole motif stands out as a privileged heterospirocyclic scaffold that represents the core for a wide range of bioactive naturally isolated products (such as Strychnofoline and spirotryprostatins A and B) and synthetic compounds. Interestingly, no much attention has been paid to develop spirooxindole derivatives with dual antioxidant and anticancer activities. In this context, a series of spirooxindoles 6a-p was examined for their anticancer effect towards HepG2 hepatocellular carcinoma and PC-3 prostate cancer cell lines. Spirooxindole 6a was found to be an efficient anti-proliferative agent towards both HepG2 and PC-3 cells (IC50 = 6.9 and 11.8 µM, respectively). Afterwards, spirooxindole 6a was assessed for its apoptosis induction potential in HepG2 cells, where its pro-apoptotic impact was approved via the significant elevation in the Bax/Bcl-2 ratio and the expression levels of caspase-3.

Keywords: Anti-proliferative; antioxidants; apoptosis; spiroxindoles; synthesis.

PubMed Disclaimer

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Chemical structure of some naturally isolated anticancer spirooxindoles, and the synthetic spirooxindoles 6a–p.
Scheme 1.
Scheme 1.
Synthesis of target compounds 6a–p; Reagents and conditions: (i) CH3CN, DMF, NaH, benzene, reflux 4 h; (ii) Ethanol, phenylhydrazine, reflux 1 h; (iii) HOAc/H2O (1:1 v/v), heating at 120 °C, 8–11 h.
Figure 2.
Figure 2.
Morphological changes following 48 h exposure of HepG2 cells to indicated concentrations of 6a, 6e and 6i. Signs of toxicity indicated with arrows represent cell rounding, shrinkage and/or loss of monolayer integrity. Total magnification = 300.
Figure 3.
Figure 3.
Effect of spirooxindole 6a on the phases of cell cycle of HepG2 cells.
Figure 4.
Figure 4.
Effect of spirooxindole 6a on the percentage of annexin V-FITC-positive staining in HepG2 cells. The experiments were done in triplicates. The four quadrants identified as: LL: viable; LR: early apoptotic; UR: late apoptotic; UL: necrotic.
Figure 5.
Figure 5.
(A) Predicted Boiled-Egg plot from swissADME online web tool for spirooxindole 6a; (B) Bioavailability radar chart for spirooxindole 6a; The pink area represents the range of the optimal property values for oral bioavailability and the red line is spirooxindole 6a predicted properties.
See this image and copyright information in PMC

References

    1. (a) de Torre MP, Cavero RY, Calvo MI, Vizmanos JL, A simple and a reliable method to quantify antioxidant activity in vivo. Antioxidants 2019;8:142. - PMC - PubMed
    2. (b) Kundu T, Bhattacharjee B, Hazra S, et al. Synthesis and biological assessment of pyrrolobenzoxazine scaffold as a potent antioxidant. J Med Chem 2019;62:6315–29. - PubMed
    1. Habrant D, Poigny S, Ségur-Derai M, et al. Evaluation of antioxidant properties of monoaromatic derivatives of pulvinic acids. J Med Chem 2009;52:2454–64. - PubMed
    1. (a) Yanovsky I, Finkin-Groner E, Zaikin A, et al. Carbamate derivatives of indolines as cholinesterase inhibitors and antioxidants for the treatment of Alzheimer’s disease. J Med Chem 2012;55:10700–15. - PubMed
    2. (b) Zhang C, Zhou Q, Wu XN, et al. Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer’s disease. J Enzym Inhib Med Chem 2019;34:260–70. - PMC - PubMed
    1. Hassan SZ, Gheita TA, Kenawy SA, et al. Oxidative stress in systemic lupus erythematosus and rheumatoid arthritis patients: relationship to disease manifestations and activity. Int J Rheum Dis 2011;14:325–31. - PubMed
    1. Segovia J, Perez-Severiano F.. Oxidative damage in Huntington’s disease. Methods Mol Biol 2004;277:321–34. - PubMed

MeSH terms