Multicomponent Assembly of Bicyclic Aza-peroxides Catalyzed by Samarium Complexes and Their Cytotoxic Activity.

An original strategy toward bridged tetraoxazaspirobicycloalkanes was developed. The synthesis is based on a three-component condensation-cyclization reaction of primary arylamines with 1,1'-peroxybis (1-hydroperoxycycloalkanes) and pentane-1,5-dial catalyzed by Sm(NO3)3·6H2O. The structures and conformations of the products were determined by X-ray diffraction analysis and 1H and 13C NMR spectroscopy. High cytotoxic activity and biological potential toward ferroptosis induction were found for the synthesized bicyclic aza-peroxides.

Synthesis and cytotoxic activity of unsaturated macrolides and their hybrid molecules with a C60 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. Covalent binding of macrodiolides to the C60 fullerene molecule was found to significantly increase the cytotoxic effect (from 5 to 170 times) of the hybrid molecule as compared to the initial macrodiolide. Moreover, the synthesized hybrid molecules initiate apoptosis by uncoupling oxidation and phosphorylation of the mitochondrial membrane of tumor cells.

Direct Synthesis of Polyaromatic Cyclophanes Containing Bis-Methylene-Interrupted Z-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 N-(3-dimethylaminopropyl)-N'-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 Cp2TiCl2 catalyst (10 mol.%) and subsequent treatment with 0.1 equiv. of para-toluenesulfonic acid of pyran ethers formed after the acid hydrolysis of magnesacyclopentanes. The resulting cyclophanes exhibited high cytotoxic activity in vitro against Jurkat, K562, U937, and HL60 cancer lines. Additionally, the synthesized products were studied for their effect on mitochondria, ability to induce apoptosis, and influence on the cell cycle using modern flow cytometry methods.

Natural and synthetic drugs used for the treatment of the dementia.

This review is devoted to comparative pharmacological analysis of synthetic drugs such as memantine and its isomers, as well as tacrine, velnacrine, rivastigmine, and donepezil, with natural alkaloids, terpenoids, and triterpenoid peroxides, which are used to treat dementia, Alzheimer's and Parkinson's diseases, myasthenia gravis and other neurodegenerative diseases. Recently discovered by French scientists from Marseille triterpenoid hydroperoxides demonstrate high activity as potential therapeutic agents for the treatment of dementia. The information presented in this review is of great interest to pharmacologists, medical chemists, physiologists, neurologists and doctors, as well as for the pharmaceutical industry.

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 C60 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.

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

The first Z-stereoselective method for the synthesis of the natural marine alkynol lembehyne C, containing a 1Z,5Z,9Z-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.

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)4]. 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 Cp2TiCl2 catalyst (10 mol.%) and the subsequent Jones oxidation of pyran ethers formed after the acid hydrolysis of magnesacyclopentanes. The thus prepared macrodiolides exhibit high cytotoxic activity in vitro against Jurkat, K562, U937, Hek293 and HeLa cancer cell lines. It was found that induction of the programmed cell death in Jurkat cells by macrodiolides corresponds to the mitochondrial apoptosis pathway. Also, it was shown that the prepared macrodiolides efficiently suppress phosphorylation of Akt and p38 kinases and CREB transcription factor in cancer cells.

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.

First Example of Catalytic Synthesis of Cyclic S-Containing Di- and Triperoxides.

An efficient method for the synthesis of tetraoxathiaspiroalkanes, tetraoxathiocanes, and hexaoxathiadispiroalkanes was developed by reactions of pentaoxacanes, pentaoxaspiroalkanes, and heptaoxadispiroalkanes with hydrogen sulfide in the presence of a catalyst, Sm(NO3)3·6H2O. We found that the synthesized S-containing di- and triperoxides exhibit high cytotoxic activity against Jurkat, K562, U937, and HL60 tumor cultures, and fibroblasts.

The Synthesis of Bicyclo[4.2.1]nona-2,4,7-trienes by [6π + 2π]-Cycloaddition of 1-Substituted 1,3,5-Cycloheptatrienes Catalyzed by Titanium and Cobalt Complexes.

The [6π + 2π]-cycloaddition of alkynes to 1-methyl-, propyl-, benzyl-, and hydroxymethyl-substituted 1,3,5-cycloheptatrienes in the presence of catalytic systems Ti(acac)2Cl2-Et2AlCl and Co(acac)2(dppe)/Zn/ZnI2 was performed for the first time to give practically valuable bicyclo[4.2.1]nona-2,4,7-trienes in high yields (72-88%). The structures of the obtained bicyclic compounds were reliably proved by NMR methods and X-ray diffraction analysis. The newly synthesized bicycles have been investigated for their in vitro cytotoxic activity against Jurkat, K562, U937, and HL60 tumor and normal cell lines and induction of apoptosis.

Comparison of Predictive In Silico Tools on Missense Variants in GJB2, GJB6, and GJB3 Genes Associated with Autosomal Recessive Deafness 1A (DFNB1A).

In silico predictive software allows assessing the effect of amino acid substitutions on the structure or function of a protein without conducting functional studies. The accuracy of in silico pathogenicity prediction tools has not been previously assessed for variants associated with autosomal recessive deafness 1A (DFNB1A). Here, we identify in silico tools with the most accurate clinical significance predictions for missense variants of the GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) connexin genes associated with DFNB1A. To evaluate accuracy of selected in silico tools (SIFT, FATHMM, MutationAssessor, PolyPhen-2, CONDEL, MutationTaster, MutPred, Align GVGD, and PROVEAN), we tested nine missense variants with previously confirmed clinical significance in a large cohort of deaf patients and control groups from the Sakha Republic (Eastern Siberia, Russia): Сх26: p.Val27Ile, p.Met34Thr, p.Val37Ile, p.Leu90Pro, p.Glu114Gly, p.Thr123Asn, and p.Val153Ile; Cx30: p.Glu101Lys; Cx31: p.Ala194Thr. We compared the performance of the in silico tools (accuracy, sensitivity, and specificity) by using the missense variants in GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) genes associated with DFNB1A. The correlation coefficient (r) and coefficient of the area under the Receiver Operating Characteristic (ROC) curve as alternative quality indicators of the tested programs were used. The resulting ROC curves demonstrated that the largest coefficient of the area under the curve was provided by three programs: SIFT (AUC = 0.833, p = 0.046), PROVEAN (AUC = 0.833, p = 0.046), and MutationAssessor (AUC = 0.833, p = 0.002). The most accurate predictions were given by two tested programs: SIFT and PROVEAN (Ac = 89%, Se = 67%, Sp = 100%, r = 0.75, AUC = 0.833). The results of this study may be applicable for analysis of novel missense variants of the GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) connexin genes.

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 and Evaluation of Anticancer Activities of Novel C-28 Guanidine-Functionalized Triterpene Acid Derivatives.

Triterpene acids, namely, 20,29-dihydrobetulinic acid (BA), ursolic acid (UA) and oleanolic acid (OA) were converted into C-28-amino-functionalized triterpenoids 4⁻7, 8a, 15, 18 and 20. These compounds served as precursors for the synthesis of novel guanidine-functionalized triterpene acid derivatives 9b⁻12b, 15c, 18c and 20c. The influence of the guanidine group on the antitumor properties of triterpenoids was investigated. The cytotoxicity was tested on five human tumor cell lines (Jurkat, K562, U937, HEK, and Hela), and compared with the tests on normal human fibroblasts. The antitumor activities of the most tested guanidine derivatives was lower, than that of corresponding amines, but triterpenoids with the guanidine group were less toxic towards human fibroblasts. The introduction of the tris(hydroxymethyl)aminomethane moiety into the molecules of triterpene acids markedly enhanced the cytotoxic activity of the resulting conjugates 15, 15c, 18b,c and 20b,c irrespective of the triterpene skeleton type. The dihydrobetulinic acid amine 15, its guanidinium derivative 15c and guanidinium derivatives of ursolic and oleanolic acids 18c and 20c were selected for extended biological investigations in Jurkat cells, which demonstrated that the antitumor activity of these compounds is mediated by induction of cell cycle arrest at the S-phase and apoptosis.

Cobalt-Catalyzed [6 + 2] Cycloaddition of Alkynes with 1,3,5,7-Cyclooctatetraene as a Key Element in the Direct Construction of Substituted Bicyclo[4.3.1]decanes.

A new, effective catalytic system based on Co(acac)2 has been developed for [6 + 2] cycloaddition of terminal alkynes to 1,3,5,7-cyclooctatetraene to give substituted bicyclo[4.2.2]deca-2,4,7,9-tetraenes in high yields (68-85%). The electrophilic activation of double bonds in the bicyclic products with m-CPBA is an efficient method for the synthesis of substituted bicyclo[4.3.1]deca-2,4,8-triene-7,10-diols, which form the key structural moieties of numerous natural biologically active compounds. The structures of the obtained compounds were reliably proven by modern spectral methods and X-ray diffraction. The mechanism of the discovered rearrangement was studied both using deuterium-labeled bicyclo[4.2.2]deca-2,4,7,9-tetraenes and utilizing quantum chemical calculations. The obtained substituted bicyclo[4.3.1]deca-2,4,8-triene-7,10-diols and their keto derivatives showed high antitumor activity in vitro against Hek293, Jurkat, K562, and A549 tumor cell lines.

The first total synthesis of the marine acetylenic alcohol, lembehyne B - a selective inducer of early apoptosis in leukemia cancer cells.

The communication reports a new stereoselective method for the synthesis of a natural acetylenic alcohol, lembehyne B. The key stage of the process uses new cross-cyclomagnesiation reaction of aliphatic and oxygenated 1,2-dienes with Grignard reagents in the presence of a catalytic amount of Cp2TiCl2. A study of the cytotoxic properties of lembehyne B on tumor cell lines using flow cytometry demonstrated that this is a selective inducer of early apoptosis of the Jurkat, HL-60 and K562 cell cultures and hypodiploid (sub-G1) sub-population inducer in cell cycle studies for all cell lines used.

Short Route to the Total Synthesis of Natural Muricadienin and Investigation of Its Cytotoxic Properties.

An original synthesis of the acetogenin muricadienin, the bioprecursor of solamin, has been developed. The key step in the five-step 41% overall yield synthesis is the catalytic cross-cyclomagnesiation reaction of functionally substituted 1,2-dienes with EtMgBr in the presence of Cp2TiCl2 and magnesium metal. It has been demonstrated for the first time that muricadienin exhibits a moderate in vitro inhibitory activity against topoisomerases I and IIα, key cell cycle enzymes. Using flow cytometry, muricadienin was shown to have high cytotoxicity toward the HEK293 kidney cancer cells (IC50 0.39 µM).

Stereoselective synthesis of 11-phenylundeca-5Z,9Z-dienoic acid and investigation of its human topoisomerase I and IIα inhibitory activity.

(5Z,9Z)-11-Phenylundeca-5,9-dienoic acid was stereoselectively synthesized, based on original cross-cyclomagnesiation of 2-(hepta-5,6-dien-1-yloxy)tetrahydro-2H-pyran and buta-2,3-dien-1-ylbenzene with EtMgBr in the presence of Cp2TiCl2 catalyst giving 2,5-dialkylidenemagnesacyclopentane in 86% yield. The acid hydrolysis of the product and the Jones oxidation of the resulting 2-{[(5Z,9Z)-11-phenylundeca-5,9-dien-1-yl]oxy}tetrahydro-2Н-pyran afforded (5Z,9Z)-11-phenylundeca-5,9-dienoic acid in an overall yield of 75%. A high inhibitory activity of the synthesized acid with respect to human topoisomerase I (hTop1) and II (hTop2α) was determined.

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

A series of previously unknown aromatic polyether macrodiolides containing a cis,cis-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 N-(3-(dimethylamino)propyl)-N'-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. CC50 was determined, and the therapeutic selectivity index of cytotoxic action (SI) in comparison with normal fibroblasts was evaluated. With the involvement of modern methods of flow cytometry for the most promising macrocycles, their effect on mitochondria and the cell cycle was investigated. It was found that a new macrocycle exhibits pronounced apoptosis-inducing activity toward Jurkat cells and can retard cell division by blocking at the G1/S checkpoint. Also, it was shown that the synthesized macrodiolides influence mitochondria due to their high ability to penetrate the mitochondrial membrane.

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. Focusing on five ILs with pronounced cytotoxicity, we uncover their genotoxic effects and their role in inducing apoptosis. Our findings suggest intricate interplay between the extrinsic and intrinsic apoptotic pathways at different time points after exposure to ILs. Moreover, the ILs studied displayed marked genotoxicity, likely stemming from the accumulation of double-strand DNA breaks in the Jurkat cells. This investigation offers a comprehensive view on interactions of ILs with eukaryotic cells, thereby providing new guidelines for developing safer pharmaceutical and industrial applications of these chemicals. The results not only broaden and enhance the previous perceptions but also open new avenues in research, emphasizing the dual potential of ILs in innovation and safety, and marking a significant step towards integrating chemical innovations with biological safety.

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 (A. nutans and A. muricata), 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. It has been shown that chatenaytrienins affect mitochondria by uncoupling the processes of mitochondrial respiration, causing the accumulation of ROS ions, followed by the initiation of apoptosis. The most likely mechanism for the death of cortical neurons from the consumption of tea from the seeds of Annona fruit is long-term chronic hypoxia, which leads to the development of an atypical form of Parkinson's disease that is characteristic of the indigenous inhabitants of Guam and New Caledonia.