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.

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. The structures of mono- and binuclear Cu(II) complexes with 1-aminomethyl-2-naphtol were confirmed by X-ray diffraction. The obtained compounds were examined for in vitro cytotoxic activity against Jurkat, K562, U937, MDA-MB-231, MCF7, T47D, and HEK293 cells. The induction of apoptosis and the effect of novel Cu complexes on the cell cycle were investigated. The cells showed a higher sensitivity to mononuclear Cu(II) complex with 1-(N,N-dimethylamino)methyl-6-quinolinolligand. All synthesized Cu(II) complexes had higher antitumor activity than the drugs topotecan, camptothecin, and platinum containing cisplatin.

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. The obtained compounds were examined for in vitro cytotoxic activity against Jurkat and K562 human leukemia cells, lymphoma U937cells, A2780 and the cisplatin-resistant A2780cis lines of human ovarian cancer, and normal fibroblasts. Study of induction of apoptosis and the effect of new palladium and platinum complexes on the cell cycle was carried out. The cells showed a higher sensitivity to Pt(II) compounds than to Pd(II) ones. All the synthesized metal complexes show much more antitumor activity compared with a platinum-containing cisplatin drug.

Metal-free multicomponent synthesis of novel macrocyclic tetrathiadienes with cyano and amino groups.

The first synthesis of 5,12-diamino-7,14-bis(aryl)-1,4,8,11-tetrathiacyclotetradeca-5,12-diene-6,13-dicarbonitriles was performed as a multicomponent macroheterocyclization of malononitrile, aryl aldehydes, and 1,2-ethanedithiol in the presence of a catalytic amount of triethylamine in ethanol. The structures of the obtained macroheterocycles were confirmed by spectral methods, X-ray diffraction, and MALDI TOF mass spectrometry.

Twist-chair conformation of the tetraoxepane ring remains unchanged in tetraoxaspirododecane diamines.

A detailed structural analysis has been performed for N,N'-bis(4-chlorophenyl)-7,8,11,12-tetraoxaspiro[5.6]dodecane-9,10-diamine, C20H22Cl2N2O4, (I), N,N'-bis(2-fluorophenyl)-7,8,11,12-tetraoxaspiro[5.6]dodecane-9,10-diamine, C20H22F2N2O4, (II), and N,N'-bis(4-fluorophenyl)-7,8,11,12-tetraoxaspiro[5.6]dodecane-9,10-diamine, C20H22F2N2O4, (III). The seven-membered ring with two peroxide groups adopts a twist-chair conformation in all three compounds. The lengths of the C-N and O-O bonds are slightly shorter than the average statistical values found in the literature for azepanes and 1,2,4,5-tetraoxepanes. The geometry analysis of compounds (I)-(III), the topological analysis of the electron density at the (3, -1) bond critical points within Bader's quantum theory of `Atoms in molecules' (QTAIM) and NBO (natural bond orbital) analysis at the B3LYP/6-31G(d,2p) level of theory showed that there are nO→σ*(C-O), nN→σ*(C-O) and nO→σ*(C-N) stereoelectronic effects. The molecules of compounds (I) and (III) are packed in the crystals as zigzag chains due to strong N-H...O and C-H...O hydrogen-bond interactions, whereas the molecules of compound (II) form chains in the crystals bound by N-H...O, C-H...π and C-H...O contacts. All these data show that halogen atoms and their positions have a minimal effect on the geometric parameters, stereoelectronic effects and crystal packing of compounds (I)-(III), so that the twist-chair conformation of the tetraoxepane ring remains unchanged.

How the oxazole fragment influences the conformation of the tetraoxazocane ring in a cyclohexanespiro-3'-(1,2,4,5,7-tetraoxazocane): single-crystal X-ray and theoretical study.

Single crystals of (2S,5R)-2-isopropyl-5-methyl-7-(5-methylisoxazol-3-yl)cyclohexanespiro-3'-(1,2,4,5,7-tetraoxazocane), C16H26N2O5, have been studied via X-ray diffraction. The tetraoxazocane ring adopts a boat-chair conformation in the crystalline state, which is due to intramolecular interactions. Conformational analysis of the tetraoxazocane fragment performed at the B3LYP/6-31G(d,2p) level of theory showed that there are three minima on the potential energy surface, one of which corresponds to the conformation realized in the solid state, but not to a global minimum. Analysis of the geometry and the topological parameters of the electron density at the (3,-1) bond critical points (BCPs), and the charge transfer in the tetraoxazocane ring indicated that there are stereoelectronic effects in the O-C-O and N-C-O fragments. There is a two-cross hyperconjugation in the N-C-O fragment between the lone electron pair of the N atom (lpN) and the antibonding orbital of a C-O bond (σ*C-O) and vice versa between lpO and σ*C-N. The oxazole substituent has a considerable effect on the geometry and the topological parameters of the electron density at the (3,-1) BCPs of the tetraoxazocane ring. The crystal structure is stabilized via intermolecular C-H...N and C-H...O hydrogen bonds, which is unambiguously confirmed with PIXEL calculations, a quantum theory of atoms in molecules (QTAIM) topological analysis of the electron density at the (3,-1) BCPs and a Hirshfeld analysis of the electrostatic potential. The molecules form zigzag chains in the crystal due to intermolecular C-H...N interactions being electrostatic in origin. The molecules are further stacked due to C-H...O hydrogen bonds. The dispersion component in the total stabilization energy of the crystal lattice is 68.09%.

First Example of Catalytic Synthesis of Difurazanohexahydrohexaazapyrenes and in Vitro Study of Their Antitumor Activity.

Catalytic method for synthesis of hexahydrohexaazapyrenes bearing two annelated furazan moieties has been successfully developed. Structures of synthesized hexahydrodioxadecaazadicyclopenta[e,l]pyrenes have been determined on the basis of NMR data using 2D techniques, MALDI TOF/TOF mass spectrometry, and X-ray analysis. Primary screening of hexahydrodioxadecaazadicyclopenta[e,l]pyrenes for cytotoxic activity against the K562, Jurkat, U937, and HeLa tumor cell lines has been performed. Studies on the induction of apoptosis and the effect of the synthesized compounds on the cell cycle have been successfully implemented. The synthesized compounds have been found to induce apoptosis of cancer cells in the K562, Jurkat, U937, and HeLa lines.

New synthesis of tetraoxaspirododecane-diamines and tetraoxazaspirobicycloalkanes.

An efficient method for the synthesis of new spiro-tetraoxadodecanediamines and tetraoxazaspirobicycloalkanes has been developed by reactions of primary arylamines with gem-dihydroperoxides and α,ω-dialdehydes (glyoxal, pentanedial) catalyzed by lanthanide catalysts. A potential pathway for formation of tetraoxaspirododecane-diamines and tetraoxazospirobicycloalkanes has been proposed that involves generation of intermediate tetraoxaspiroalkanediols under the reaction conditions. The structures of the crystalline products have been confirmed by XRD. It was shown that the synthesized tetraoxazaspirobicycloalkanes exhibit high cytotoxic activity against Jurkat, K562, and U937 tumor cultures and Fibroblasts.

Stereospecific 7α-alkylation of 20-hydroxyecdysone in a lithium-ammonia solution.

The reaction of 20-hydroxyecdysone with methyl or ethyl iodide or allyl bromide in a lithium-ammonia solution results in stereospecific 7α-alkylation to give 7α-methyl-, 7α-ethyl-, and 7α-allyl-14-deoxy-Δ(8(14))-20-hydroxyecdysones, respectively. By catalytic hydrogenation (Pd-C/MeOH), the 7α-allyl derivative was converted to 7α-n-propyl-14-deoxy-Δ(8(14))-20-hydroxyecdysone.