Mechanisms of cytotoxicity in six classes of ionic liquids: Evaluating cell cycle impact and genotoxic and apoptotic effects.

Ionic liquids (ILs), earlier praised for their eco-friendliness, have emerged as key chemicals in advancing green chemistry, catalysis, solvent development, and more. However, the discovery of their notable toxicity has led to a controversial reputation of ILs and has shifted the research landscape towards understanding their biological impacts. The present study examines the mechanism of cytotoxicity of 32 ILs across six classes, highlighting their effects on the cell cycle of the Jurkat cell line.

New Polyether Macrocycles as Promising Antitumor Agents-Targeted Synthesis and Induction of Mitochondrial Apoptosis.

A series of previously unknown aromatic polyether macrodiolides containing a -1,5-diene moiety in the molecule were synthesized in 47-74% yields. Macrocycle compounds were first obtained by intermolecular esterification of aromatic polyether diols with α,ω-alka-nZ,(n+4)Z-dienedioic acids mediated by -(3-(dimethylamino)propyl)-'-ethylcarbodiimide hydrochloride (EDC·HCl) and 4-(dimethylamino)pyridine (DMAP). For the synthesized compounds, studies of cytotoxicity on tumor (Jurkat, K562, U937), conditionally normal (HEK293) cell lines, and normal fibroblasts were carried out.

Natural Acetogenins, Chatenaytrienins-1, -2, -3 and -4, Mitochondrial Potential Uncouplers and Autophagy Inducers-Promising Anticancer Agents.

The present paper details the complete stereoselective synthesis of four natural acetogenins, chatenaytrienins-1, -2, -3 and -4, previously isolated from the roots of fruit trees of the family Annonaceae ( and ), as an inseparable mixture. The novel organometallic reactions, developed by the authors, of Ti-catalyzed cross-cyclomagnesiation of O-containing and aliphatic allenes using available Grignard reagents were applied at the key stage of synthesis. We have studied the biological activity of the synthesized individual chatenaytrienins-1, -2, -3 and -4 in vitro, including their cytotoxicity in a panel of tumor lines and their ability to induce apoptosis, affect the cell cycle and mitochondria, and activate the main apoptotic signaling pathways in the cell, applying modern approaches of flow cytometry and multiplex analysis with Luminex xMAP technology.

Mono- and binuclear complexes of copper(II) with dimethylaminomethyl derivatives of 2-naphthol and 6-quinolinol: synthesis and in vitro study of antitumor properties.

1-(Dimethylamino)methyl-6-quinolinol scaffold, a structural moiety of the molecule of anticancer drug topotecan, was modified into copper-containing products to study cytotoxic properties. New mononuclear and binuclear Cu(II) complexes with 1-(N,N-dimethylamino)methyl-6-quinolinol were synthesized for the first time. The same way Cu(II) complexes with 1-(dimethylamino)methyl-2-naphtol ligand were synthesized.

Pentacyclic Triterpenoids-Based Ionic Compounds: Synthesis, Study of Structure-Antitumor Activity Relationship, Effects on Mitochondria and Activation of Signaling Pathways of Proliferation, Genome Reparation and Early Apoptosis.

The present research paper details the synthesis of novel ionic compounds based on triterpene acids (betulinic, oleanolic and ursolic), with these acids acting both as anions and connected through a spacer with various nitrogen-containing compounds (pyridine, piperidine, morpholine, pyrrolidine, triethylamine and dimethylethanolamine) and acting as a cation. Based on the latter, a large number of ionic compounds with various counterions (BF-, SbF-, PF-, CHCOO-, CHSO-, -CH(OH)COO- and CHCH(OH)COO-) have been synthesized. We studied the cytotoxicity of the synthesized compounds on the example of various tumor (Jurkat, K562, U937, HL60, A2780) and conditionally normal (HEK293) cell lines.

Synthesis, crystal structure, and in vitro evaluation of the anticancer activity of new Pt (Pd) complexes with 1-[(dimethylamino)methyl]-2-naphthol ligand.

The synthesis of new Pt(II) and Pd(II) complexes with 1-aminomethyl-2-naphtol ligands has been first performed. The adducts of [PtCl4]2- and [PdCl4]2- anions with the 1-aminomethyl-2-naphtol NH cation were synthesized. The structure for four Pt (Pd)-containing compounds was investigated using X-ray diffraction.

Cobalt(I)-Catalyzed [6π + 2π] Cycloaddition of 1,2-Dienes and 1,3-Diynes to -Carbocholesteroxyazepine in the Synthesis of Previously Undescribed Heterofunctional 9-Azabicyclo[4.2.1]nonadi(tri)enes.

Promising heterofunctional ()-9-azabicyclo[4.2.1]nona-2,4-dienes (79-92%) and 9-azabicyclo[4.

Direct Synthesis of Polyaromatic Cyclophanes Containing Bis-Methylene-Interrupted -Double Bonds and Study of Their Antitumor Activity In Vitro.

An original synthetic route was developed for the preparation of previously unknown unsaturated polyaromatic macrolactones containing a 1Z,5Z-diene moiety in 48-71% yields and with >98% stereoselectivity. The method is based on intermolecular cyclocondensation of aromatic dicarboxylic acids with α,ω-alka-nZ,(n+4)Z-dienediols (1,12-dodeca-4Z,8Z-dienediol, 1,14-tetradeca-5Z,9Z-dienediol, 1,18-octadeca-7Z,11Z-dienediol) mediated by -(3-dimethylaminopropyl)-'-ethylcarbodiimide hydrochloride (EDC)/4-dimethylaminopyridine (DMAP). The unsaturated diols were prepared by successive homo-cyclomagnesiation of tetrahydropyran ethers of O-containing 1,2-dienes with EtMgBr in the presence of Mg metal and the CpTiCl catalyst (10 mol.

Synthesis of New Functionally Substituted 9-Azabicyclo[4.2.1]nona-2,4,7-trienes by Cobalt(I)-Catalyzed [6π + 2π]-Cycloaddition of -Carbocholesteroxyazepine to Alkynes.

Catalytic [6π + 2π]-cycloaddition of -carbocholesteroxyazepine with functionally substituted terminal alkynes and 1,4-butynediol was performed for the first time under the action of the Co(acac)(dppe)/Zn/ZnI three-component catalytic system. The reaction gave previously undescribed but promising 9-azabicyclo[4.2.

Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies.

The first Z-stereoselective method was developed for the synthesis of unsaturated acids containing a 1Z,5Z,9Z-triene moiety in 61-64% yields using the new Ti-catalyzed cross-coupling of oxygen-containing and aliphatic 1,2-dienes as the key synthetic step. It was shown for the first time that trienoic acids with non-methylene-interrupted Z-double bonds show moderate cytotoxic activities against tumor cell lines (Jurkat, K562, U937, HL60, HeLa), human embryonic kidney cells (Hek293), normal fibroblasts and human topoisomerase I (hTop1) inhibitory activity in vitro. The synthesized acids efficiently initiate apoptosis of Jurkat tumor cells, with the cell death mechanism being activated by the mitochondrial pathway.

Synthesis and cytotoxic activity of unsaturated macrolides and their hybrid molecules with a C fullerene.

Previously unreported macrodiolides containing a 1Z,5Z-diene fragment in the structure have been synthesized with high yields and stereoselectivity by our research group, using the intermolecular esterification of malonic acid with α,ω-diols containing bis-methylene-separated Z-double bonds, catalyzed by Hf(OTf)4 hafnium triflate. Under Bingel-Hirsch conditions, the synthesized macrodiolides were chemically bonded with a C60 fullerene to produce the corresponding methanofullerenes. The cytotoxic activity of macrodiolides and methanofullerenes in relation to Jurkat, K562, U937, HL60 tumor cell lines and normal fibroblasts was studied.

Synthesis and Anticancer Activity of Hybrid Molecules Based on Lithocholic and (5,9)-Tetradeca-5,9-dienedioic Acids Linked via Mono(di,tri,tetra)ethylene Glycol and α,ω-Diaminoalkane Units.

For the first time, hybrid molecules were synthesized on the basis of lithocholic and (5,9)-1,14-tetradeca-5,9-dienedicarboxylic acids, obtained in two stages using the homo-cyclomagnesiation reaction of 2-(hepta-5,6-diene-1-yloxy)tetrahydro-2H-pyran at the key stage. The resulting hybrid molecules containing 5,9-dienoic acids are of interest as novel synthetic biologically active precursors to create modern drugs for the treatment of human oncological diseases. The synthesized hybrid molecules were found to exhibit extremely high in vitro inhibitory activity against human topoisomerase I, which is 2-4 times higher than that of camptothecin, a known topoisomerase I inhibitor.

Synthesis of Functionally Substituted Bicyclo[4.2.1]nona-2,4-dienes and Bicyclo[4.2.1]nona-2,4,7-trienes by Cobalt(I)-catalyzed [6π + 2π] Cycloaddition of 2-Tropylcyclohexanone.

The [6π + 2π] cycloaddition of 2-tropylcyclohexanone to allenes and alkynes was accomplished for the first time using the three-component catalytic system Co(acac)(dppe)/Zn/ZnI, thus giving previously unknown functionally substituted bicyclo[4.2.1]nona-2,4-dienes and bicyclo[4.

New synthetic analogues of natural 5Z,9Z-dienoic acids: Stereoselective synthesis and study of the anticancer activity.

A stereoselective method was developed for the synthesis of synthetic analogues of natural 5Z,9Z-dienoic acids by esterification of aliphatic and aromatic alcohols and carboxylic acids with (5Z,9Z)-1,14-tetradeca-5,9-dienedioic acid and (5Z,9Z)-1,14-tetradeca-5,9-dienediol, synthesized by Ti-catalyzed homo-cyclomagnesiation of the tetrahydropyran ether of hepta-5,6-dien-1-ol with Grignard reagents. In order to establish the effect of molecular structure on the antitumor activity, the obtained 5Z,9Z-dienoic acids were tested for the inhibitory activity against human topoisomerase I, the cytotoxic activity in vitro against several cancer and normal cell lines (Jurkat, HL-60, K562, U937, fibroblasts), the effect on the cell cycle, and apoptosis-inducing ability using flow cytofluorometry. In addition, the effect of the synthesized acids on the cancer cell production of some phosphorylated and unphosphorylated proteins responsible for proliferation and apoptosis was studied by a new multiplex assay technology, MAGPIX.

Total Synthesis of Natural Lembehyne C and Investigation of Its Cytotoxic Properties.

The first -stereoselective method for the synthesis of the natural marine alkynol lembehyne C, containing a 1,5,9-triene moiety, in 41% yield was developed using the new Ti-catalyzed cross-coupling of oxygenated and aliphatic 1,2-dienes as the key step. It was found for the first time that lembehyne C exhibits moderate cytotoxicity against Jurkat, K562, U937, and HL60 cancer cells and also efficiently induces apoptosis in Jurkat cells, with the cell death mechanism being activated by the mitochondrial pathway. The lembehyne C inhibition of the cell cycle follows the mitotic catastrophe mechanism.

Hybrid molecules based on fullerene C60 and 5Z,9Z-dienoic acids: Synthesis and cytotoxic activity.

The present research project details synthesis of new hybrid methanofullerenes based on acetylene and triazole esters of malonic acid containing 5Z,9Z-dienoic acids and fullerene C under Bingel-Hirsch conditions, including study of the cytotoxic activity with respect to Jurkat, K562, U937 and HL60 tumor cell lines. Hybrid methanofullerenes containing acetylenic fragments, unlike triazole substituents, were found to exhibit higher cytotoxicity, but are characterized by lower selectivity of action in relation to healthy cells.

Synthesis, structure, and antitumor activity of 2,9-disubstituted perhydro 2,3a,7b,9,10a,14b-hexaazadibenzotetracenes.

Catalytic methods for the synthesis of previously unknown 2,9-disubstituted 3b*,7a*,10b*,14a*--14c,14d-perhydro-2,3a,7b,9,10a,14b-hexaazadibenzotetracenes have been developed. The structures were established by 1D (H, C) and 2D (COSY, HSQC, HMBC) NMR spectroscopy, MALDI TOF/TOF mass spectrometry, and X-ray diffraction analysis. Primary screening of the synthesized perhydro hexaazadibenzotetracenes for antitumor activity was carried out.

New 1Z,5Z-diene macrodiolides: Catalytic synthesis, anticancer activity, induction of mitochondrial apoptosis, and effect on the cell cycle.

An original scheme was developed for the synthesis of previously undescribed unsaturated macrodiolides containing a 1Z,5Z-diene moiety in 44-80% yields and with high stereoselectivity (>95%) based on the intermolecular esterification of α,ω-diols with α,ω-alka-nZ,(n + 4)Z-dienedicarboxylic acids (1,12-dodeca-4Z,8Z-dienedicarboxylic acid, 1,14-tetradeca-5Z,9Z-dienedicarboxylic acid, 1,18-octadeca-7Z,11Z-dienedicarboxylic acid) catalyzed by hafnium triflate [Hf(OTf)]. The unsaturated dicarboxylic acids were prepared via homo-cyclomagnesiation of tetrahydropyran ethers of O-containing 1,2-dienes with EtMgBr in the presence of Mg metal and the CpTiCl catalyst (10 mol.%) and the subsequent Jones oxidation of pyran ethers formed after the acid hydrolysis of magnesacyclopentanes.

Synthesis of new ,'-Pd(Pt) complexes based on sulfanyl pyrazoles, and investigation of their anticancer activity.

The synthesis of new ,'-mononuclear bi-ligand Pd(ii) and tri-ligand Pt(ii)complexes bearing sulfanyl(phenyl, benzyl, cyclohexyl, 4-hydroxyphenyl)3,5-dimethyl-1-pyrazole ligands has been carried out. The obtained compounds were studied for apoptosis-inducing activity and effect on the cell cycle for Jurkat, K562, and U937 neoplastic cell cultures and conditionally normal human embryonic kidney HEK293 cells. The cells showed the highest sensitivity to platinum and palladium complexes in comparison with ligands and cisplatin.

Comparative in vitro Studies of the Topoisomerase I Inhibition and Anticancer Activities of Metallated N-Confused Porphyrins and Metallated Porphyrins.

Using the original approach, a series of metallated N-confused porphyrins and metallated porphyrins have been synthesized and characterized. For all the synthesized porphyrins, in vitro studies of cytotoxic activity against K562, U937, HL-60, Jurkat, A549 and HeLa cancer cell lines, the ability to induce apoptosis and effects on the cell cycle as well as the kinetics of proliferative activity of porphyrins and their respective metallated complexes in real time have been developed. The inhibitory activity of metallated porphyrins against human topoisomerase I and the possible mechanism of inhibition have been carried out by modelling using molecular docking.

New 1,3-Diynoic Derivatives of Natural Lembehyne B: Stereoselective Synthesis, Anticancer, and Neuritogenic Activity.

An original method has been developed for the synthesis of 1,3-dyine derivatives of natural lembehyne B in high yields (50-67%) and with high selectivity (>98%). The key stage of the synthesis is new Ti-catalyzed cross-cyclomagnesiation of oxygenated and aliphatic 1,2-dienes induced by Grignard reagents. For studying the effect of the structure on the antitumor and neuritogenic activities, a series of lembehyne B analogues with different distances between the terminal hydroxy group and the 1,3-diyne moiety was prepared and tested for neuritogenic activity on mouse neuroblastoma Neuro 2A cells and for cytotoxicity, induction of apoptosis, and effects on the cell cycle using Jurkat, U937, K562, HeLa, and Hek293 tumor cell lines.

Diversity-oriented synthesis of spirothiazolidinediones and their biological evaluation.

We report a new synthetic approach to assemble spirothiazolidinediones via a [2 + 2 + 2] cyclotrimerization reaction and the derivatives were further functionalized through DA chemistry and click reaction. Using flow cytometry, it was shown for the first time that the new benzyl alcohol derivatives of thiazolidine-2,4-dione generated here are efficient apoptosis inducers in the HeLa, Hek293, U937, Jurkat, and K562 cell lines.

Synthesis of New Cu Complex Based on Natural 5,9-Eicosadienoic Acid: Effective Topoisomerase I Inhibitor and Cytotoxin against the Cisplatin-Resistant Cell Line.

The complex (bipy)Cu(5,9-eicd) was prepared by the reaction of Cu(OAc) with 5,9-eicosadienoic acid and 2,2'-bipyridine in methanol. The new copper complex showed high antitumor activity in vitro toward A2780cis, A2780, Hek293, K562, HL60, Jurkat, and U937 cell lines and efficiently inhibited human topoisomerase I. Using flow cytofluorometry, (bipy)Cu(5,9-eicd) was studied for the effect on the cell cycle and apoptosis-inducing activity in tumor cells.

Synthesis of C Fullerene-Quadricyclane Hybrid Compound and Its Preliminary In Vitro Antitumor Activity in Combination with Cisplatin.

This paper describes the authors' preliminary studies directed toward the possibility of the practical implementation of the idea to design efficient antitumor drugs based on hybrid molecules composed of fullerene C and quadricyclanes. The essence of the proposed idea is that these hybrid molecules are able to cleave DNA owing to the fullerene moiety they contain and to simultaneously thermally affect tumor cells via cleavage of the carbon-carbon bond in quadricyclanes under the action of Pd and Pt ions. As a result, testing of the cytotoxic activity in vitro for a number of fullerene C hybrids with the norbornadiene or quadricyclane moieties against the human T-lymphoblastic leukemia cells (Jurkat cells) in combination of the known cisplatin drug, which was taken as the source of Pt ions, showed a statistically reliable dose-dependent increase in the number of dead cells in each group, which were formed according to the amount of cisplatin added, in comparison with the control, that is, cells treated with cisplatin or quadricyclane fullerene derivatives alone.