New Water-Soluble Copper(II) Complexes with Morpholine–Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

Ohui, Kateryna; Afanasenko, Eleonora; Bacher, Felix; Ting, Rachel Lim Xue; Zafar, Ayesha; Blanco-Cabra, Núria; Torrents, Eduard; Dömötör, Orsolya; May, Nóra V.; Darvasiová, Denisa; Enyedy, Éva A.; Popović‐Bijelić, Ana; Reynisson, Jóhannes; Rapta, Peter; Babak, Maria V.; Pastorin, Giorgia; Arion, Vladimir B.

doi:10.1021/acs.jmedchem.8b01031

Cited by 111 publications

(115 citation statements)

References 85 publications

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“…The solution behaviour of Cu(II) complexes with triapine and other pyridine-2 carboxaldehyde thiosemicarbazones has been reported in our recent works [ 19 , 21 , 47 , 48 ], revealing the predominant formation of [CuL] + complexes in a wide pH range, including the physiological pH, where L is the deprotonated monoanionic ligand. The stability of this type of complex with the (N pyridine ,N,S − ) donor set is so high that its decomposition is negligible even at low micromolar concentrations.…”

Section: Resultsmentioning

confidence: 76%

“…TSCs are known to efficiently chelate first-row transition metals, 3-AP, and its analogues were coordinated to endogenous metals, such as Cu and Fe [ 17 , 18 , 19 , 20 ]. TSC coordination to essential metals often decreases overall toxicity of the drug molecules [ 21 ] and increases their anticancer activity, due to the synergistic action of TSCs and the metal centre [ 19 , 20 , 21 ]. In general, numerous Cu(II) complexes of thiosemicarbazones were characterised by superior anticancer activity when compared to that of the free ligands [ 22 , 23 , 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells

et al. 2020

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Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives HL1 and HL2 were prepared by condensation reactions of 2-pyridinamidrazone and S-methylisothiosemicarbazidium chloride with 3-N-(tert-butyloxycarbonyl) amino-pyridine-2-carboxaldehyde, followed by a Boc-deprotection procedure. Subsequent reaction of HL1 and HL2 with CuCl2·2H2O in 1:1 molar ratio in methanol produced the complexes [CuII(HL1)Cl2]·H2O (1·H2O) and [CuII(HL2)Cl2] (2). The reaction of HL2 with Fe(NO3)3∙9H2O in 2:1 molar ratio in the presence of triethylamine afforded the complex [FeIII(L2)2]NO3∙0.75H2O (3∙0.75H2O), in which the isothiosemicarbazone acts as a tridentate monoanionic ligand. The crystal structures of HL1, HL2 and metal complexes 1 and 2 were determined by single crystal X-ray diffraction. The UV-Vis and EPR spectroelectrochemical measurements revealed that complexes 1 and 2 underwent irreversible reduction of Cu(II) with subsequent ligand release, while 3 showed an almost reversible electrochemical reduction in dimethyl sulfoxide (DMSO). Aqueous solution behaviour of HL1 and 1, as well as of HL2 and its complex 2, was monitored as well. Complexes 1−3 were tested against ovarian carcinoma cells, as well as noncancerous embryonic kidney cells, in comparison to respective free ligands, triapine and cisplatin. While the free ligands HL1 and HL2 were devoid of antiproliferative activity, their respective metal complexes showed remarkable antiproliferative activity in a micromolar concentration range. The activity was not related to the inhibition of ribonucleotide reductase (RNR) R2 protein, but rather to cancer cell homeostasis disturbance—leading to the disruption of cancer cell signalling.

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Section: Resultsmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells

et al. 2020

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“…Small molecules that can sequester Fe from the dinuclear metal center and/or scavenge the tyrosyl radical inhibit R2 activity, thereby preventing de novo DNA synthesis in cancer cells and bacteria. In an international academic collaboration, Ohui et al created a series of Triapine derivatives, all with N‐substituted morpholine attached to the 2‐formylpyridine (iso) thiosemicarbazones (TSCs), motivated by the enhanced solubility contributed by this moiety ( 57 ; Figure ).…”

Section: Pharmacological Activity Of Morpholine Derivatives On Varioumentioning

confidence: 99%

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

171

114

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Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active‐site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug‐like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.

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“…The incorporation of morpholine as a substituent leads to either Gram‐positive or broad spectrum antimicrobial molecules. These effects are related to morpholine‐containing derivatives’ interaction with topoisomerases, peptidyl transferase, ribonucleotide reductase, even to the ability to act as intercalating agents …”

Section: Introductionmentioning

confidence: 99%

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

2020

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Morpholine is a frequently used heterocycle in medicinal chemistry and a privileged structural component of bioactive molecules. This is mainly due to its contribution to a plethora of biological activities as well as to an improved pharmacokinetic profile of such bioactive molecules. The synthesis of morpholines is a subject of much study due to their biological and pharmacological importance, with the last such review being published in 2013. Here, an overview of the main approaches toward morpholine synthesis or functionalization is presented, emphasizing on novel work which has not been reviewed so far. This review is an update on synthetic strategies leading to easily accessible libraries of bioactives which are of interest for drug discovery projects.

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New Water-Soluble Copper(II) Complexes with Morpholine–Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

Cited by 111 publications

References 85 publications

Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells

Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

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