RESUMO
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.
RESUMO
In the present study, 5-arylidene rhodanine derivatives 3a-f, N-glucosylation rhodanine 6, S-glucosylation rhodanine 7, N-glucoside rhodanine 8 and S-glucosylation 5-arylidene rhodanines 13a-c were synthesised and screened for cytotoxicity against a panel of cancer cells with investigating the effective molecular target and mechanistic cell death. The anomers were separated by flash column chromatography and their configurations were assigned by NMR spectroscopy. The stable structures of the compounds under study were modelled on a molecular level, and DFT calculations were carried out at the B3LYP/6-31 + G (d,p) level to examine their electronic and geometric features. A good correlation between the quantum chemical descriptors and experimental observations was found. Interestingly, compound 6 induced potent cytotoxicity against MCF-7, HepG2 and A549 cells, with IC50 values of 11.7, 0.21, and 1.7 µM, compared to Dox 7.67, 8.28, and 6.62 µM, respectively. For the molecular target, compound 6 exhibited topoisomerase II inhibition and DNA intercalation with IC50 values of 6.9 and 19.6 µM, respectively compared to Dox (IC50 = 9.65 and 31.27 µM). Additionally, compound 6 treatmnet significantly activated apoptotic cell death in HepG2 cells by 80.7-fold, it induced total apoptosis by 34.73% (23.07% for early apoptosis, 11.66% for late apoptosis) compared to the untreated control group (0.43%) arresting the cell population at the S-phase by 49.6% compared to control 39.15%. Finally, compound 6 upregulated the apoptosis-related genes, while it inhibted the Bcl-2 expression. Hence, glucosylated rhodanines may serve as a promising drug candidates against cancer with promising topoisomerase II and DNA intercalation.
