Alteration of Anticancer and Protein-Binding Properties of Gold(I) Alkynyl by Phenolic Schiff Bases Moieties

Abstract
A set of five gold complexes with the general formula Au(PR3)(C≡C-C6H4-4-R′) (R = PPh3, R′ = –CHO (1), R = PCy3, R′ = –CHO (2), R = PPh3, R′ = –N=CH-C6H4-2-OH (3), R = PPh3, R′ = –N=CH-C6H4-4-OH (4), R = PCy3, R′ = –N=CH-C6H4-2-OH (5)) were synthesized and characterized by elemental analysis, 1H-NMR spectroscopy, 31P-NMR spectroscopy, and mass spectrometry. The structures of complexes 2 and 5 were determined by X-ray crystallography. The effects of the structural modifications on the protein binding affinities and anticancer activities of the five gold complexes were assessed. Fluorescence quenching experiments to assess binding to human serum albumin (HSA) revealed that the Schiff base complexes (3, 4, and 5) had binding constants that were superior to their parent aldehyde complexes and highlighted the position of the hydroxy group because complex 4 (4-hydroxy) had a binding constant 6400 times higher than complex 3 (2-hydroxy). The anticancer activities of the complexes against the OVCAR-3 (ovarian carcinoma) and HOP-62 (non-small-cell lung) cancer cell lines showed that the Schiff bases (3–5) were more cytotoxic than the aldehyde-containing complexes (1 and 2). Notably, compound 4 had cytotoxic activity comparable to that of cisplatin against OVCAR-3, demonstrating the significance of the para position for the hydroxy group. Molecular docking studies against the enzyme thioredoxin reductase (TrxR) and human serum albumin were conducted, with docking scores in good agreement with the experimental data. The current study highlights how small structural modifications can alter physiochemical and anticancer properties. Moreover, this simple design strategy using the aldehyde group can generate extensive opportunities to explore new gold(I)-based anticancer drugs via condensation, cyclization, or nucleophilic addition reactions of the aldehyde.

Citation
Babgi, B. A., Alsayari, J., Alenezi, H. M., Abdellatif, M. H., Eltayeb, N. E., Emwas, A.-H. M., … Hussien, M. A. (2021). Alteration of Anticancer and Protein-Binding Properties of Gold(I) Alkynyl by Phenolic Schiff Bases Moieties. Pharmaceutics, 13(4), 461. doi:10.3390/pharmaceutics13040461

Acknowledgements
M.H.A. is very thankful for Taif University researcher support; project number: TURSP/91, Taif University, Taif, Saudi Arabia. M.J. would like to express his thanks to KAUST for financial and technical support. H.M.A. and B.A.B. would like to express their thanks to KACST for financially supporting this work.
Hana M. Alenezi would like to thank King Fahd Medical Research Centre (KFMRC) at KAU for allowing the use of their facilities. Mariusz Jaremko and Abdul-Hamid M. Emwas would like to thank the King Abdullah University of Science and Technology (KAUST) for the financial support. Magda H. Abdellatif is very thankful for Taif University researcher support; project number: TURSP/91, Taif University, Taif, Saudi Arabia.

Publisher
MDPI AG

Journal
Pharmaceutics

DOI
10.3390/pharmaceutics13040461

PubMed ID
33805337

Additional Links
https://www.mdpi.com/1999-4923/13/4/461

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