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15 pages, 2217 KiB

Open AccessArticle

Fluorinated Analogues of Lepidilines A and C: Synthesis and Screening of Their Anticancer and Antiviral Activity

by Grzegorz Mlostoń, Mateusz Kowalczyk, Małgorzata Celeda, Marcin Jasiński, Marta Denel-Bobrowska and Agnieszka B. Olejniczak

Molecules 2022, 27(11), 3524; https://doi.org/10.3390/molecules27113524 - 30 May 2022

Cited by 10 | Viewed by 2478

Abstract

Starting with fluorinated benzylamines, a series of 2-unsubstituted imidazole N-oxides was prepared and subsequently deoxygenated in order to prepare the corresponding imidazoles. The latter were treated with benzyl halides yielding imidazolium salts, which are considered fluorinated analogues of naturally occurring imidazolium alkaloids known as lepidilines A and C. A second series of oxa-lepidiline analogues was obtained by O-benzylation of the initially synthetized imidazole N-oxides. Both series of imidazolium salts were tested as anticancer and antiviral agents. The obtained results demonstrated that the introduction of a fluorine atom, fluoroalkyl or fluoroalkoxy substituents (F, CF₃ or OCF₃) amplifies cytotoxic properties, whereas the cytotoxicity of some fluorinated lepidilines is promising in the context of drug discovery. All studied compounds revealed a lack of antiviral activity against the investigated viruses in the nontoxic concentrations. Full article

(This article belongs to the Special Issue Biosynthesis and Biological Activities of Natural Products)

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16 pages, 1122 KiB

Open AccessArticle

Synthesis, Selected Transformations, and Biological Activity of Alkoxy Analogues of Lepidilines A and C

by Grzegorz Mlostoń, Małgorzata Celeda, Wiktor Poper, Mateusz Kowalczyk, Katarzyna Gach-Janczak, Anna Janecka and Marcin Jasiński

Materials 2020, 13(18), 4190; https://doi.org/10.3390/ma13184190 - 21 Sep 2020

Cited by 7 | Viewed by 3239

Abstract

Condensation of diacetyl monooxime with formaldimines derived from alkoxyamines in glacial acetic acid at room temperature leads to corresponding 2-unsubstituted imidazole N-oxides bearing an alkoxy substituent at the N(1) atom of the imidazole ring. Subsequent O-benzylation afforded, depending on the type of alkylating agent, either symmetric or nonsymmetric alkoxyimidazolium salts considered as structural analogues of naturally occurring imidazole alkaloids, lepidilines A and C. Some of the obtained salts were tested as precursors of nucleophilic heterocyclic carbenes (NHCs), which in situ reacted with elemental sulfur to give the corresponding N-alkoxyimidazole-2-thiones. The cytotoxic activity of selected 4,5-dimethylimidazolium salts bearing either two benzyloxy or benzyloxy and 1-adamantyloxy groups at N(1) and N(3) atoms was evaluated against HL-60 and MCF-7 cell lines using the MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay. Notably, in two cases of alkoxyimidazolium salts, no effect of the counterion exchange (Br⁻ → PF₆⁻) on the biological activity was observed. Full article

(This article belongs to the Special Issue Research of Organic Molecules and Materials for Biological Application)

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17 pages, 5186 KiB

Open AccessFeature PaperArticle

Novel Anticancer NHC*-Gold(I) Complexes Inspired by Lepidiline A

by Danielle Curran, Helge Müller-Bunz, Sofia I. Bär, Rainer Schobert, Xiangming Zhu and Matthias Tacke

Molecules 2020, 25(15), 3474; https://doi.org/10.3390/molecules25153474 - 30 Jul 2020

Cited by 18 | Viewed by 4126

Abstract

N-Heterocyclic carbene gold(I) complexes derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*) represent a promising class of anticancer drugs. Complexes of the type NHC*-Au-L (L = Br⁻, I⁻, C≡C-R) and [NHC*-Au-L]⁺ (L = NHC*, PPh₃) have been synthesised. The X-ray crystal structures of all gold(I) complexes are presented; aurophilic interactions were observed in five of the complexes. The anticancer activity was assessed via MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-based proliferation assays against the human colon carcinoma cell line HCT-116^wt and the multidrug-resistant human breast carcinoma cell line MCF-7^topo. Most complexes showed good cytotoxicity with IC₅₀ values in the low micromolar range, while excellent sub-micromolar activity was observed for 2c, 3a and 3b. Generally, the activity of the ligands studied was as follows: carbene > phosphine > alkyne > halide, with an exception for the highly active iodido derivative 2c. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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11 pages, 3154 KiB

Open AccessArticle

The Natural Product Lepidiline A as an N-Heterocyclic Carbene Ligand Precursor in Complexes of the Type [Ir(cod)(NHC)PPh₃)]X: Synthesis, Characterisation, and Application in Hydrogen Isotope Exchange Catalysis

by Alison R. Cochrane, Alan R. Kennedy, William J. Kerr, David M. Lindsay, Marc Reid and Tell Tuttle

Catalysts 2020, 10(2), 161; https://doi.org/10.3390/catal10020161 - 1 Feb 2020

Cited by 7 | Viewed by 4262

Abstract

A range of iridium(I) complexes of the type [Ir(cod)(NHC)PPh₃)]X are reported, where the N-heterocyclic carbene (NHC) is derived from the naturally-occurring imidaozlium salt, Lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride). A range of complexes were prepared, with a number of NHC ligands and counter-ions, and various steric and electronic parameters of these complexes were evaluated. The activity of the [Ir(cod)(NHC)PPh₃)]X complexes in hydrogen isotope exchange reactions was then studied, and compared to established iridium(I) complexes. Full article

(This article belongs to the Special Issue N‐Heterocyclic Carbenes and Their Complexes in Catalysis)

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17 pages, 2497 KiB

Open AccessFeature PaperArticle

Synthesis and Cytotoxicity Studies of Novel NHC*-Gold(I) Complexes Derived from Lepidiline A

by Danielle Curran, Oyinlola Dada, Helge Müller-Bunz, Matthias Rothemund, Goar Sánchez-Sanz, Rainer Schobert, Xiangming Zhu and Matthias Tacke

Molecules 2018, 23(8), 2031; https://doi.org/10.3390/molecules23082031 - 14 Aug 2018

Cited by 25 | Viewed by 6241

Abstract

Ten novel N-heterocyclic carbene gold(I) complexes derived from lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride) are reported here with full characterisation and biological testing. (1,3-Dibenzyl-4,5-diphenylimidazol-2-ylidene)gold(I) chloride (NHC*-AuCl) (1) was modified by substituting the chloride for the following: cyanide (2), dithiocarbamates (3–5), p-mercaptobenzoate derivatives (12–14) and N-acetyl-l-cysteine derivatives (15–17). All complexes were synthesised in good yields of 57–78%. Complexes 2, 12, 13, and 14 were further characterised by X-ray crystallography. Initial evaluation of the biological activity was conducted on all ten complexes against the multidrug resistant MCF-7^topo breast cancer, HCT-116^wt, and p53 knockout mutant HCT-116^−/− colon carcinoma cell lines. Across the three cell lines tested, mainly single-digit micromolar IC₅₀ values were observed. Nanomolar activity was exhibited on the MCF-7^topo cell line with 3 displaying an IC₅₀ of 0.28 μM ± 0.03 μM. Complexes incorporating a Au–S bond resulted in higher cytotoxic activity when compared to complexes 1 and 2. Theoretical calculations, carried out at the MN15/6–311++G(2df,p) computational level, show that NHC* is the more favourable ligand for Au(I)-Cl when compared to PPh₃. Full article

(This article belongs to the Special Issue Metal Complexes of Biological Ligands)

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