Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction

8-hydroxyquinoline (oxine) is a widely known and frequently used chelating agent, and the pharmacological effects of the core molecule and its derivatives have been studied since the 19th century. There are several synthetic methods to modify this core. The Mannich reaction is one of the most easily implementable examples, which requires mild reaction conditions and simple chemical reagents. The three components of the Mannich reaction are a primary or secondary amine, an aldehyde and a compound having a hydrogen with pronounced activity. In the modified Mannich reaction, naphthol or a nitrogen-containing naphthol analogue (e.g., 8-hydroxyquinoline) is utilised as the active hydrogen provider compound, thus affording the formation of aminoalkylated products. The amine component can be ammonia and primary or secondary amines. The aldehyde component is highly variable, including aliphatic and aromatic aldehydes. Based on the pharmacological relevance of aminomethylated 8-hydroxyquinolines, this review summarises their syntheses via the modified Mannich reaction starting from 8-hydroxyquinoline, formaldehyde and various amines

Fine-Tuned Reactivity of N-Containing Naphthol Analogues

6-Hydroxyquinoline and 3-hydroxyisoquinoline as N-containing naphthol analogues were tested in modified Mannich reactions (mMr’s). In the case of 6-hydroxyquinoline, the outcomes of the attempted Mannich reactions were strongly influenced by the amine components. Aminoalkylation of this substrate with reagents 1-naphthaldehyde and N-benzylmethylamine led to the isolation of a diol regarded as a stabilised water adduct of an ortho-quinone methide (o-QM), of which formation can be ascribed to the presence of a hydroxide ion in a relatively higher concentration generated by the bulky and basic amine component with decreased nucleophilicity. The classical Mannich base was isolated as a single product when the amine component was replaced for morpholine, featuring nucleophilicity rather than basic character under the applied reaction conditions. Starting from the isomer substrate 3-hydroxyisoquinoline, independently on the nucleophile (methanol or morpholine) besides the formation of the classical Mannich base, the nucleophilic attack at position one of the heterocyclic substrate was also observed. The DFT analysis of the acceptor molecular orbitals of the potential electrophilic components and the thermodynamics of the assumed-possible transformations demonstrated that this regioselective addition is a feasible process on the investigated heterocyclic skeleton. DFT modelling studies also suggest that besides the steric bulk, the orbital-controlled electronic properties of the aryl group, originating from the aldehyde components, have a strong influence on the ratios and the NMR-monitored interconversions of the C-1-substituted 3-hydroxyisoquinolines and the classical Mannich bases formed in multistep reaction sequences. On the basis of the DFT analysis of the thermodynamics of alternative pathways, a reaction mechanism was proposed for the rationalization of these characteristic substrate-controlled interconversions

Synthesis of 4-Hydroxyquinolines as Potential Cytotoxic Agents

The synthesis of alkyl 2-(4-hydroxyquinolin-2-yl) acetates and 1-phenyl-4-(phenylamino)pyridine-2,6(1H,3H)-dione was optimised. Starting from 4-hydroxyquinolines (4HQs), aminomethylation was carried out via the modified Mannich reaction (mMr) applying formaldehyde and piperidine, but a second paraformaldehyde molecule was incorporated into the Mannich product. The reaction also afforded the formation of bisquinoline derivatives. A new 1H-azeto [1,2-a]quinoline derivative was synthesised in two different ways; namely starting from the aminomethylated product or from the ester-hydrolysed 4HQ. When the aldehyde component was replaced with aromatic aldehydes, Knoevenagel condensation took place affording the formation of the corresponding benzylidene derivatives, with the concomitant generation of bisquinolines. The reactivity of salicylaldehyde and hydroxynaphthaldehydes was tested; under these conditions, partially saturated lactones were formed through spontaneous ring closure. The activity of the derivatives was assessed using doxorubicin-sensitive and -resistant colon adenocarcinoma cell lines and normal human fibroblasts. Some derivatives possessed selective toxicity towards resistant cancer cells compared to doxorubicin-sensitive cancer cells and normal fibroblasts. Cytotoxic activity of the benzylidene derivatives and the corresponding Hammett–Brown substituent were correlated

A 2-naftol nitrogén-tartalmú analógjainak transzformációi: The transformation of nitrogen-containing analogues of 2-naphthol

The Mannich reaction can be used to form C–C bond that takes place between three reactants under relatively mild reaction conditions. The modified Mannich reaction (mMR) involves an aldehyde, an amine and an electron rich aromatic compound (for instance 1- or 2-naphthol), and results an aminoalkyl derivative. During our work, we have examined 6-hydroxyquinoline (6HQ) and 3-hydroxyisoquinoline (3HIQ) as nitrogen-containing 2-naphthol analogues. When the aminoalkylation of these electron rich aromatic substances was tested, the 5-substituted derivative was synthesised in case of 6HQ; but in contrast, 3HIQ showed an unexpected reactivity. Two main product types were identified, from which the first one is the classical aminoalkyled derivative, and the other is a 4-benzylidene-1-morpholino-lactam derivative. The ratio of the formed products was examined systematically, when the effect of aldehyde component on product selectivity was tested, regarding the length of the reaction time. Kivonat A Mannich reakció egy C–C kötés kialakítására alkalmas eljárás, amely három reaktáns között játszódik le viszonylag enyhe reakciókörülmények között. A módosított Mannich reakció (mMR) egy aldehid, egy amin és egy elektrondús aromás vegyület (mint például 1- vagy 2-naftol) részvételével játszódik le, egy aminoalkil származékot eredményezve. Munkánk során a 6-hidroxikinolint (6HQ) és a 3-hidroxiizokinolint (3HIQ), mint nitrogén-tartalmú 2-naftol analógokat vizsgáltuk. Ezen elektrondús aromás vegyületek aminoalkilezése során a 6HQ esetén előállítottuk az 5-szubszituált származékot, viszont a 3HIQ alkalmazásakor eltérő reaktivitást tapasztaltunk. Két fő terméktípust azonosítottunk, amelyek közül az egyik a klasszikus aminoalkil vegyület, míg a másik egy 4-benzilidén-1-morfolino-laktám származék. Szisztematikusan vizsgáltuk a két termék képződési arányát, mely során teszteltük az aldehidkomponens hatását a termékszelektivitásra, illetve reakcióidő hosszának szerepét. &nbsp

An 8-hydroxyquinoline–proline hybrid with multidrug resistance reversal activity and the solution chemistry of its half-sandwich organometallic Ru and Rh complexes

Herein the design and synthesis of a new 8-hydroxyquinoline derivative, (S)-5-chloro-7-((proline-1-yl)methyl)8-hydroxyquinoline (HQCl-Pro), with good water solubility and multidrug resistance reversal activity are reported. In this work the proton dissociation processes of HQCl-Pro and its complex formation with [Rh(η5-C5Me5)(H2O)3]2+, [Ru(η6-p-cymene)(H2O)3]2+and [Ru(η6-toluene)(H2O)3]2+were investigated by the combined use of pH-potentiometry, UV-visible spectrometry and1H NMR spectroscopy. Our results revealed the prominent solution stability of the complexes in all cases. The lipophilicity of the complexes increased with the chloride ion concentration, and the complexes showed moderate log Dvalues (−0.8 to +0.4) at pH 7.4 at all tested Cl−concentrations. The formation of mixed hydroxido complexes from the aqua complexes was characterized by relatively high pKavalues (8.45-9.62 in chloride-free medium). Complexation processes are much slower with the Ru(η6-arene) triaqua cations than with [Rh(η5-C5Me5)(H2O)3]2+. Both the pKavalues and H2O/Cl−exchange constants of the Ru-complexes are lower by 0.5-1.0 orders of magnitude than those of the Rh analogue. Arene loss (p-cymene and toluene) and oxidation were found in the case of Ru-complexes when an excess of HQCl-Pro and aromatic (N,N) bidentate ligands was added. The cytotoxicity and antiproliferative effect of HQCl-Pro and its complexes were assayedin vitro. In contrast to the structurally familiar 8-hydroxyquinoline, HQCl-Pro and its Rh(η5-C5Me5) complex were somewhat more effective against drug resistant Colo 320 adenocarcinoma human cells compared to the drug sensitive Colo 205 cells. The Ru- and Rh-complexes showed a similar metal uptake level after 4 h, while a longer incubation time resulted in higher cellular Rh concentration

Anticancer 8-hydroxyquinoline-amino acid hybrids and their half-sandwich Ru and Rh complexes : solution chemistry and interaction with biomolecules

Development of novel chemotherapeutic agents aims to obtain more effective and selective compounds. Platinum(II)-containing chemotherapeutics have been widely used for decades in cancer therapy against solid tumors due to their effectiveness; although, their use is accompanied by drawbacks such the serious side-effects and resistance [1]. To overcome these problems, efforts have been made to find better alternatives such as the complexes of other platinum metals. 8-hydroxyquinolines and their metal complexes are widely investigated due to their anticancer properties [2,3]; however, they often have limited water solubility. In this work two novel water-soluble 8-hydroxyquinoline-D-amino acid hybrids, [(R)-1-((5-chloro-8- hydroxyquinolin-7-yl)methyl)pyrrolidine-2-carboxylic acid (8HQCl-D-Pro) and its homologue 8HQCl-D-hPro (Chart 1), and their [Ru(η6 -p-cymene)(H2O)3] 2+ and [Rh(η5 -C5Me5)(H2O)3] 2+ complexes were developed