Design, Synthesis, Computational Investigations, and Antitumor Evaluation of N-Rhodanine Glycosides Derivatives as Potent DNA Intercalation and Topo II Inhibition against Cancer Cells

Ahmed I Khodair; Fatimah M Alzahrani; Mohamed K Awad; Siham A Al-Issa; Ghaferah H Al-Hazmi; Mohamed S Nafie

doi:10.1021/acsomega.3c00641

Design, Synthesis, Computational Investigations, and Antitumor Evaluation of N-Rhodanine Glycosides Derivatives as Potent DNA Intercalation and Topo II Inhibition against Cancer Cells

ACS Omega. 2023 Mar 28;8(14):13300-13314. doi: 10.1021/acsomega.3c00641. eCollection 2023 Apr 11.

Authors

Ahmed I Khodair¹, Fatimah M Alzahrani², Mohamed K Awad³, Siham A Al-Issa², Ghaferah H Al-Hazmi², Mohamed S Nafie⁴

Affiliations

¹ Chemistry Department, Faculty of Science, Kafrelsheikh University, 33516 Kafrelsheikh, Egypt.
² Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia.
³ Theoretical Applied Chemistry Unit (TACU), Chemistry Department, Faculty of Science, Tanta University, 6632110 Tanta, Egypt.
⁴ Chemistry Department (Biochemistry program), Faculty of Science, Suez Canal University, 41522 Ismailia, Egypt.

Abstract

Nitrogen and sulfur glycosylation was carried out via the reaction of rhodanine (1) with α-acetobromoglucose 3 under basic conditions. Deacetylation of the protected nitrogen nucleoside 4 was performed with CH₃ONa in CH₃OH without cleavage of the rhodanine ring to afford the deprotected nitrogen nucleoside 6. Further, deacetylation of the protected sulfur nucleoside 5 was performed with CH₃ONa in CH₃OH with the cleavage of the rhodanine ring to give the hydrolysis product 7. The protected nitrogen nucleosides 11a-f were produced by condensing the protected nitrogen nucleoside 4 with the aromatic aldehydes 10a-f in C₂H₅OH while using morpholine as a secondary amine catalyst. Deacetylation of the protected nitrogen nucleosides 11a-f was performed with NaOCH₃/CH₃OH without cleavage of the rhodanine ring to afford the deprotected nitrogen nucleosides 12a-f. NMR spectroscopy was used to designate the anomers' configurations. To examine the electrical and geometric properties derived from the stable structure of the examined compounds, molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were carried out. The quantum chemical descriptors and experimental findings showed a strong connection. The IC₅₀ values for most compounds were very encouraging when evaluated against MCF-7, HepG2, and A549 cancer cells. Interestingly, IC₅₀ values for 11a, 12b, and 12f were much lower than those for Doxorubicin (7.67, 8.28, 6.62 μM): (3.7, 8.2, 9.8 μM), (3.1, 13.7, 21.8 μM), and (7.17, 2.2, 4.5 μM), respectively. Against Topo II inhibition and DNA intercalation, when compared to Dox (IC₅₀ = 9.65 and 31.27 μM), compound 12f showed IC₅₀ values of 7.3 and 18.2 μM, respectively. In addition, compound 12f induced a 65.6-fold increase in the rate of apoptotic cell death in HepG2 cells, with the cell cycle being arrested in the G2/M phase as a result. Additionally, it upregulated the apoptosis-mediated genes of P53, Bax, and caspase-3,8,9 by 9.53, 8.9, 4.16, 1.13, and 8.4-fold change, while it downregulated the Bcl-2 expression by 0.13-fold. Therefore, glucosylated Rhodanines may be useful as potential therapeutic candidates against cancer because of their topoisomerase II and DNA intercalation activity.