Regina A. Tuktarova

Catalytic cyclometallation in steroid chemistry III: Synthesis of steroidal derivatives of 5Z,9Z-dienoic acid and investigation of its human topoisomerase I inhibitory activity

Two approaches to stereoselective synthesis of steroid 5Z,9Z-dienoic acids were developed, the first one being based on the cross-cyclomagnesiation of 2-(hepta-5,6-dien-1-yloxy)tetrahydro-2H-pyran and 1,2-diene cholesterol derivatives on treatment with EtMgBr catalyzed by Cp2TiCl2, while the other involving the synthesis of esters of hydroxy steroids with (5Z,9Z)-tetradeca-5,9-dienedioic acid, prepared in two steps using homo-cyclomagnesiation of 2-(hepta-5,6-dien-1-yloxy)tetrahydro-2H-pyran as the key step. High inhibitory activity of the synthesized acids against human topoisomerase I (hTop1) was found.

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).

Novel Hybrid Molecules on the Basis of Steroids and (5Z,9Z)-Tetradeca-5,9-dienoic Acid: Synthesis, Anti-Cancer Studies and Human Topoisomerase I Inhibitory Activity

Novel steroid derivatives of 5Z,9Z-dienoic acids were prepared by the DCC/DMAP-catalyzed esterification of (5Z,9Z)-tetradeca-5,9-dienoic acid with hydroxy steroids. High cytotoxicity towards the HEK293, Jurkat, K562 cancer cell lines and human topoisomerase I (hTop1) inhibitory activity in vitro were found for the synthesized acids. A probable mechanism of topoisomerase I inhibition was hypothesized on the basis of in silico studies resorting to docking.

Synthesis and transformations of metallacycles. 45. Cross-cyclomagnesiation of 1,2-dienes in the synthesis of 5Z,9Z-dienoic acids, efficient inhibitors of human topoisomerase I

An original method for the synthesis of natural and synthetic 5Z,9Z-dienoic acids with high selectivity (>98%) and ~50% yields was elaborated. The method is based on a new Cp2TiCl2catalyzed cross-cyclomagnesiation reaction of terminal aliphatic and O-containing 1,2-dienes using Grignard reagents. The synthesized acids exhibited in vitro high inhibiting activity against human topoisomerase I.

Synthesis and transformations of metallacycles 42. Cp2ZrCl2-Catalyzed cycloalumination of 3-methylidenespiro[cyclobutane-1,3′-(5′α)-cholestane] with Et3Al

A Cp2ZrCl2-catalyzed cycloalumination of 3-methylidenespiro[cyclobutane-1,3′-(5′α)-cholestane] with Et3Al gives 3-ethyl-3-aluminadispiro[cyclopentane-1,1′-cyclobutane-3′,3″-(5″α)-cholestane] in 84% yield.

Diels-Alder Reactions of Alumina- and Magnesacyclopentadienes

Abstract[4π + 2π]-Cycloaddition of substituted alumina-and magnesacyclopenta-2,4-dienes with such dienophiles as maleic anhydride, N-methylmaleimide, 1,4-benzoquinone, and 1,4-naphthoquinone resulted in the formation of the corresponding fused alumina-and magnesanorbornenes whose hydrolysis gave isobenzofuran, isoindole, naphthalene, and anthracene derivatives in high yields.

Synthesis and transformations of metallacycles 44. Cycloalumination of methylenecyclobutane terpene derivatives with Et3Al catalyzed by Cp2ZrCl2

Cycloalumination of methylenecyclobutane terpene derivatives (d(+)-camphor, (+)-camphene, β-pinene, and l(–)-menthol) with Et3Al catalyzed by Cp2ZrCl2 produced novel spirofused organoaluminum compounds in high yields. The synthesized compounds were in situ transformed into the corresponding spiro tetrahydroselenophenes and spiro phospholanes.

Catalytic cyclometallation in steroid chemistry V: Synthesis of hybrid molecules based on steroid oximes and (5Z,9Z)-tetradeca-5,9-dienedioic acid as potential anticancer agents

Graphical abstract Figure. No Caption available. HighlightsSynthesis of steroid containing 5Z,9Z‐dienoic acids have been developed.New molecules are efficient apoptosis inducers in cancer cells.The structures of all novel compounds were confirmed by NMR measurements. ABSTRACT Synthetic analogues of natural 5Z,9Z‐dienoic acids ‐ hybrid molecules based on the oximes of cholesterol, pregnenolone, and androsterone with 1,14‐tetradeca‐5Z,9Z‐dienedicarboxylic acid ‐ were synthesized for the first time and studied for antitumor activity in vitro. The acid was prepared using catalytic cyclomagnesiation of O‐containing 1,2‐dienes with Grignard reagent in the presence of Cp2TiCl2 as the key step. Using flow cytometry, it was shown for the first time that the new molecules are efficient apoptosis inducers in the HeLa, Hek293, U937, Jurkat, and K562.

Catalytic cyclometallation in steroid chemistry VI: Targeted synthesis of hybrid molecules based on steroids and tetradeca-5Z,9Z-diene-1,14-dicarboxylic acid and study of their antitumor activity

Graphical abstract Figure. No Caption available. HighlightsSynthesis of steroid containing 5Z,9Z‐dienoic acids have been developed.New molecules are efficient apoptosis inducers in cancer cells.The structures of all novel compounds were confirmed by NMR measurements. ABSTRACT Hybrid molecules based on a number of steroids (cholesterol, pregnenolone, androsterone) and 1,14‐tetradeca‐5Z,9Z‐dienedicarboxylic acid linked via mono‐ and diethylene glycol spacers were synthesized for the first time and studied for antitumor activity in vitro. The acid was prepared using catalytic cyclomagnesiation of oxygenated 1,2‐dienes with Grignard reagent in the presence of Cp2TiCl2 as the key synthetic step. Using flow cytometry, the new molecules were shown for the first time to be efficient apoptosis inducers in the HeLa, Hek293, U937, Jurkat, and K562 cell cultures and to have dose‐dependent effect on the S and G2 phases of the cell cycle.

Catalytic cyclometallation in steroid chemistry IV: Efficient method for the synthesis of tetrahydrothiophene, tetrahydroselenophen and cyclopentanone derivatives of (5α)-cholestane

Catalytic cycloalumination of (3β,5α)-3-vinylcholestane and (3α,5α)-3-allylcholestane with Et3Al catalyzed by Cp2ZrCl2 was performed for the first time to give previously unknown aluminacyclopentanes in ∼90% yield; these products were converted in situ to carbo- and heterocyclic (5α)-cholestane derivatives.