Design and synthesis of new spirooxindole candidates and their selenium nanoparticles as potential dual Topo I/II inhibitors, DNA intercalators, and apoptotic inducers

Abstract

A new wave of dual Topo I/II inhibitors was designed and synthesised via the hybridisation of spirooxindoles and pyrimidines. In situ selenium nanoparticles (SeNPs) for some derivatives were synthesised. The targets and the SeNP derivatives were examined for their cytotoxicity towards five cancer cell lines. The inhibitory potencies of the best members against Topo I and Topo II were also assayed besides their DNA intercalation abilities. Compound 7d NPs exhibited the best inhibition against Topo I and Topo II enzymes with IC 50 of 0.042 and 1.172 μM, respectively. The ability of compound 7d NPs to arrest the cell cycle and induce apoptosis was investigated. It arrested the cell cycle in the A549 cell at the S phase and prompted apoptosis by 41.02% vs. 23.81% in the control. In silico studies were then performed to study the possible binding interactions between the designed members and the target proteins.

Repurposed organoselenium tethered amidic acids as apoptosis inducers in melanoma cancer via P53, BAX, caspases-3, 6, 8, 9, BCL-2, MMP2, and MMP9 modulations

“…Dox is generally used as a positive control and widespread chemotherapeutic drug owing to its multiple modes of action (e.g., topoisomerase II inhibition and intercalation into DNA). 55,56 Intriguingly, among the investigated OSe compounds, 8 manifested the best mean GI% (64.60%) in comparison to Dox which displayed a GI% of 70.22%. Moreover, low GI% values were attained by the investigated OSe compounds against the utilized normal cell lines assuring their safety and selectivity to cancer cells.…”

Design and synthesis of novel chloropyridazine hybrids as promising anticancer agents acting by apoptosis induction and PARP-1 inhibition through a molecular hybridization strategy

“…The PARP-1 inhibitory potential of the novel 4-chloropyridazinoxyphenyl hybrids ( 3a–h , 4a–e , and 5 ) was investigated using the drug design docking approach. 56,57 All members were transferred from ChemDraw to the working window to be prepared through partial charge optimization and energy minimization steps. 58 The Protein Data Bank website was used to download the target PARP-1 receptor (PDB ID: ) which was prepared by correcting the missed parts, adding the 3D hydrogens, and minimizing its energy.…”

Investigating the effect of polymerase inhibitors on cellular proliferation: Computational studies, cytotoxicity, CDK1 inhibitory potential, and LC‐MS/MS cancer cell entrapment assays

“…All compounds were ranked according to their affinities towards the target receptors and the best ones were selected for further investigation. On the other side, validation processes were carried out for the cocrystal inhibitors within their binding pockets, and acceptable values were obtained (RMSD < 2) (Al-Karmalawy et al, 2023;El-Kalyoubi et al, 2023).…”