Dependence of anti-proliferative activity on chirality and redox potentials (Eh) of new ferrocene derivatives: Synthesis, crystallographic, photophysical and in-silico study

Abstract

Chiral α-iodoamides (S)-IA-1, (R)-IA-2, (S)-IA-3 and (R)-IA-4 were synthesized and characterized prior to use in the synthesis of four chiral ferrocenyl secondary amines viz. (S)-2-(ferrocenylmethylamino)-N-(1-phenylethyl)acetamide, (S)-FA-5, (R)-2-(ferrocenyl methylamino)-N-(1-phenylethyl)acetamide, (R)-FA-6, (S)-2-(ferrocenylmethylamino)-N-(1-(naphthalen-1-yl)ethyl)acetamide, (S)-FA-7 and (R)-2-(ferrocenylmethylamino)-N-(1-(naphthalen-1-yl)ethyl)acetamide, (R)-FA-8. The purity and composition of the compounds were ascertained by elemental, 1H, 13C NMR, FTIR, UV–visible emission spectral and X-ray diffraction methods. The formation of diverse supramolecular assemblies sustained by several NH…O, CH…O and CH…I intermolecular hydrogen bonding interactions was confirmed by single crystal X-ray diffraction (SCXRD). The impact of Eh and chirality on the anti-proliferative activity of these compounds has been explored. Notably, R-enantiomers are found to be superior to S-enantiomers in the studied MCF 7, IMR 32, HepG2 and L132 cell lines of human origin. In instance, (R)-FA-6 has demonstrated superior activity than cisplatin against MCF 7 (IC 50: 31.38±0.24 μM) and HepG2 (IC 50: 18.78±0.14 μM). Further research, including electrochemical, DFT calculations and a docking analysis, was performed to rationalize and confirm the results. © 2023 Elsevier B.V.