Alteration of steric hindrance modulates glutathione resistance and cytotoxicity of three structurally related Ru^II-p-cymene complexes

Abstract

The effect of steric hindrance on reactivity towards biomolecules while designing Ru(II)-η(6)-p-cymene based anticancer agents seems to be an important parameter in improving the activity and inducing resistance against glutathione (GSH) deactivation. Herein we present the structure, hydrolysis, anticancer activity and the effect of steric hindrance on deactivation by glutathione for three complexes, [Ru(II)(η(6)-p-cym)(L1)(Cl)](PF6) (1), [Ru(II)(η(6)-p-cym)(L2)(Cl)](PF6) (2) and [Ru(II)(η(6)-p-cym)(L3)(Cl)](PF6) (3). The ligands L1-L3 are Schiff bases which show increasing substitution in a benzene ring, such that two ortho hydrogens are replaced by -methyl in 2 and by -isopropyl in 3. The cytotoxicity results strongly suggest that controlling the rate of hydrolysis through tuning of steric hindrance may be a feasible pathway to derive GSH resistant anticancer agents. The cellular studies show that all the three complexes show good blood compatibility (haemolysis <3%) and induce cellular death through caspase activation via the mitochondrial pathway. They have anti-angiogenic activity and prevent the healing of treated cells.

Tunable Anticancer Activity of Furoylthiourea‐Based RuII–Arene Complexes and Their Mechanism of Action

“…The structures of C1 – C4 and C6 (Ru– p ‐cymene complexes), and C8 and C14 (Ru–benzene complexes) were determined by single‐crystal XRD analysis. The complexes showed a pseudo‐octahedral geometry around the ruthenium ion with a piano stool form (Figure 4 and Tables S3 and S4 in the Supporting Information) [22–24] . On going from C1 (2.405 Å) to C3 (2.4206 Å), there was a noticeable increase in the Ru−S bond length, owing to the distancing of the phenyl group from the thiocarbonyl (C=S) moiety.…”

“…The complexes showedap seudooctahedral geometry around the ruthenium ion with ap iano stool form (Figure 4a nd Tables S3 and S4 in the Supporting Information). [22][23][24] On going from C1 (2.405 )t oC3 (2.4206 ), there was an oticeable increase in the RuÀSb ond length, owing to the distancing of the phenyl group from the thiocarbonyl( C =S) moiety.T his increase was also observed in the case of C4 (2.4065 ), in which electron-donating ethyl groups are attached at the ortho positions of the terminal phenyl moiety, from which it can be concluded that the RuÀSb ond becomes weaker in such cases. In contrast, the RuÀSb ond was shorter in C6 (2.4025 ), ands till shorter in C14 (2.3875 ) compared with their parent complexes C1 and C8 (2.406 ), respectively,which signifies the strengthening of the bond in the presenceo fe lectron-withdrawing group(s).…”

An Efficient Protocol for the Synthesis of 1, 5‐ disubstituted Tetrazole Derivatives via a TMS‐N3 Based Ugi Reaction and their Anti‐cancer Activity

“…The effect of steric hindrance on reactivity towards anticancer agents seems to be an important parameter in improving the activity. The cytotoxicity results strongly suggest that fruitful selection of groups with minimum steric hindrance and substituents nature with respect to donating and withdrawing effect may be a feasible pathway to derive anticancer agents . The molecules 4a and 4b contains electron donating influence from methyl and flouro groups, while O ‐ and P ‐ substituted groups were not shown major cytotoxicity.…”

Synthesis and Antitumor Activity of New Multifunctional Coumarins

“…In the next step, the aldol condensation reaction was designed to involve the nucleophilic attack of the enol form of MA2 to the protonated aldehyde moiety of the employed acetaldehyde derivatives affording MA3-MA5 products (Amarasekara and Ha, 2018). The aldehyde groups of these products were coupled with the primary amine groups of the utilized toluidine derivatives to generate Schiff-base containing products termed multifunctional coumarin derivatives (MC1-MC9) (Purkait et al, 2016;Al Zoubi et al, 2018;van Schijndel et al, 2019). The design of the synthetic plan, as well as the characterization data, confirmed that the chemical structures represented in Figure 1 could be attributed to the target synthetic products.…”