Synthesis, structure and in vitro cytostatic activity of ferrocene—Cinchona hybrids

Abstract

Exploring copper(I)-and ruthenium(II)-catalyzed azide-alkyne cycloadditions and a Sonogashira protocol, novel cytostatic ferrocene-cinchona hybrids were synthetized displaying significant in vitro activity on HEPG-2 and HT-29 cells. Preliminary SAR studies disclosed that compounds incorporating linkers with 1,2,3-triazole and chalchone residues can be considered as promising lead structures. According to the best of our knowledge this is the first report on the incorporation of ferrocene nucleus in the reputed cinchona family via triazole and chalcone linkers with established pharmaceutical profile.

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

“…195 Ferrocene-substituted chalcones have been connected to cinchona alkaloids using both CuAAC and RuAAC as reported by Csámpai and co-workers. 196 The ruthenium-catalyzed cyclization of …”

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.…”

Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling

“…Through a variety of molecular mechanisms, as discussed in recent reviews, chalcones have significant potential to cause cytotoxic effects against cancer cell lines [25][26][27]. In this context, we previously prepared antiproliferative hybrids comprising ferrocenyl-substituted chalcone and cinchona residues connected with triazole linkers, which were found to display marked cytotoxic activity against human liver cancer (HepG2) and human colon cancer (HT-29) cell lines [28]. Significantly, two representatives of these hybrids were found to act as pro-oxidants sensitizing three multidrug-resistant (MDR) human cancer cell lines and their sensitive counterparts (non-small cell lung carcinoma NCI-H460/R/NCI-H460, colorectal carcinoma DLD1-TxR/DLD1, and glioblastoma U87-TxR/U87) to paclitaxel [29].…”