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

Abstract

By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine- and quinidine-derived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted- and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines (PANC-1, COLO-205, A2058 and EBC-1). In most cases, the cyclization reactions were accompanied by the transition-metal-catalyzed epimerization of the C9-stereogenic centre in the cinchona fragment. The results of the in vitro assays disclosed that all the prepared hybrids exhibit marked cytotoxicity in concentrations of low micromolar range, while the C9-epimerized model comprising quinidine- and (E)-1-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl) fragments, connected by 1,5-disubstituted 1,2,3-triazole linker, and can be regarded as the most potent lead of which activity is probably associated with a limited conformational space allowing for the adoption of a relatively rigid well-defined conformation identified by DFT modelling. The mechanism of action of this hybrid along with that of a model with markedly decreased activity were approached by comparative cell-cycle analyses in PANC-1 cells. These studies disclosed that the hybrid of enhanced antiproliferative activity exerts significantly more extensive inhibitory effects in subG1, S and G2/M phases than does the less cytotoxic counterpart.

Antitumor Effect of a Novel Spiro-Acridine Compound is Associated with Up-Regulation of Th1-Type Responses and Antiangiogenic Action

“…On cell cycle analysis, AMTAC-17 induced an increase in the sub-G1 peak to 41.48% (p < 0.05), associated with a decrease in the G0/G1 phase to 31.30% (p < 0.05), when compared to a control group (26.16 and 43.98%, respectively) ( Figure 2). Literature have shown that the increase in the sub-G1 peak is indicative of the apoptosis process [14,15]. In addition, previous studies suggested that acridine derivatives could induce cell cycle arrest and apoptosis [16].…”

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.…”

Recent Progress in Catalytic Synthesis of 1,2,3-Triazoles

“…The obtained substrates have been evaluated against HepG-2 and HT-29 cells in vitro, displaying a significant cytostatic activity. Successively, a synthetic route has been proposed by Jernei et al [73] for the preparation of similar cinchona-chalcone hybrids that were revealed to possess an interesting cytostatic activity against PANC-1 cells. Other efficient syntheses have been proposed in the last years for the preparation of numerous substrates possessing notable biological activities against specific biological targets (i.e., Chagas disease, A549, SW480, etc.)…”