Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships

Abstract

Inspired by the well-established clinical evidence about the interplay between apoptotic TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) mechanism and reactive oxygen species (ROS)-mediated oxidative stress, a set of novel ONC201 hybrids containing the impiridone core and one or two differently positioned ferrocenylalkyl groups were synthesised in our present work. These two types of residues have been implicated in the aforementioned mechanisms associated with cytotoxic activity. A straightforward, primary amine-based synthetic approach was used allowing the introduction of a variety of N-substituents into the two opposite regions of the heterocyclic skeleton. Reference model compounds with benzyl and halogenated benzyl groups were also synthesised and tested. The in vitro assays of the novel impiridones on five malignant cell lines disclosed characteristic structure-activity relationship (SAR) featuring significant substituent-dependent activity and cell-selectivity. A possible contribution of ROS-mechanism to the cytotoxicity of the novel metallocenes was suggested by density functional theory (DFT)studies on simplified models. Accordingly, unlike the mono-ferrocenylalkyl-substituted products, the compounds containing two ferrocenylalkyl substituents in the opposite regions of the impiridone core display a much more pronounced long-term cytotoxic effect against A-2058 cell line than do the organic impiridones including ONC201 and ONC212. Furthermore, the prepared bis-metallocene derivatives also present substantial activity against COLO-205- and EBC-1 cell lines.

Novel Polycondensed Partly Saturated β-Carbolines Including Ferrocene Derivatives: Synthesis, DFT-Supported Structural Analysis, Mechanism of Some Diastereoselective Transformations and a Preliminary Study of their In Vitro Antiproliferative Effects

“…Prompted by the aforementioned highly promising precedents, in the frame of our ongoing research aimed at identification of novel leads including ferrocene hybrids [22][23][24][25][26][27][28][29] we envisaged atryptamine-and tryptophan-based synthesis, detailed structural analysis and preliminary in vitro evaluation of 6-aryl-substituted 5,6,8,9,14,14b-hexahydroindolo [2 ,3 :3,4]pyrido [1,2-c]quinazolines (I), 5,5b,17,18-tetrahydroindolo [2 ,3 :3,4]pyrido [1,2-c]isoindolo[2,1-a]quinazolin-11(15bH)-ones (II), and (S p )-2-formyl-1-ferrocenecarboxylate-derived 5,5b, 11,14b,16,17-hexahydroindolo [2 ,3 :3,4]pyrido [1,2-c]ferroceno[c]pyrrolo[1,2-a]quinazoline-11(14bH)-ones (III), featuring alkaloid-like frameworks with diverse stereostructures (Figure 1).…”

“…Prompted by the aforementioned highly promising precedents, in the frame of our ongoing research aimed at identification of novel leads including ferrocene hybrids [22][23][24][25][26][27][28][29] we envisaged atryptamine-and tryptophan-based synthesis, detailed structural analysis and preliminary in vitro evaluation of 6-aryl-substituted 5,6,8,9,14,14b-hexahydroindolo[2',3':3,4]pyrido [1,2-c]quinazolines (I), 5,5b,17,18-tetrahydroindolo [2',3':3,4]pyrido [1,2-c]isoindolo[2,1-a]quinazolin-11(15bH)-ones (II), and (Sp)-2-formyl-1-ferrocenecarboxylate-derived 5,5b, 11,14b,16,17- A straightforward retrosynthetic analysis of pentacycles type I set up an obvious synthetic pathway starting with a Pictet-Spengler (PS) annelation involving tryptophan-based precursors and Molecules 2020, 25, 1599 3 of 25 2-nitrobenzaldehyde followed by nitro group reduction and subsequent aldehyde-mediated cyclisation of the resulting 2-aminophenyl-substituted β-carboline framework to construct the targeted pentacyclic products (Scheme 1). Accordingly, tryptamine (1) was first converted into the nitrophenyl derivative 3 by an efficient PS protocol using an acetic acid/boric acid system at reflux temperature to promote the reaction [30] which practically went to completion within 4 h and allowed the isolation of the product as a racemic mixture in 85% yield.…”

Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer

“…The protocol for the alamarBlue-assay was similar to the method which was published earlier [ 26 ], with some minor modifications. Briefly, the cell seeding occurred on 96-well cell culture plates (Sarstedt AG, Nümbrecht, Germany) at 10 4 cells/well concentration.…”

Synthesis, Structure and In Vitro Cytotoxic Activity of Novel Cinchona—Chalcone Hybrids with 1,4-Disubstituted- and 1,5-Disubstituted 1,2,3-Triazole Linkers

“…The steps of our impedimetric experiment proceeded in the same way as what was indicated in [22]. In brief, after gaining a constant CI value during the background measurement, the PANC-1 cells (1.5 × 10 4 cells/well) were added to the so-called E-plate, and their adhesion/spreading was monitored for 24 h in order to settle the plateau phase of cell culture.…”