Aleksey A. Makarov

The facile synthesis of the 5Z,9Z-dienoic acids and their topoisomerase I inhibitory activity

An original, effective approach to the synthesis of natural and synthetic 5Z,9Z-dienoic acids in high yields (61-67%) and with high selectivity (>98%) was developed. The approach is based on the use of the new intermolecular catalytic cross cyclomagnesiation of terminal aliphatic and oxygenated 1,2-dienes upon treatment with Grignard reagents in the presence of the Cp2TiCl2 catalyst. High activity of (5Z,9Z)-5,9-eicosadienoic acid as a human topoisomerase I inhibitor at concentrations above 0.1 μM was elucidated.

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.

Synthesis and transformations of metallacycles 41. Cyclomagnesiation of O-containing 1,2-dienes with Grignard reagents in the presence of Cp2TiCl2

A Cp2TiCl2-catalyzed intermolecular homocyclomagnesiation of O-containing 1,2-dienes and cross-cyclomagnesiation of O-containing 1,2-dienes with aliphatic 1,2-dienes of cyclic and acyclic structure have been accomplished using Grignard reagents, which led to mono- and bicyclic organomagnesium compounds in 61–94% yields.

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.

Cyclomagnesation of Cycloalkynes with the Use of RMgR' Catalyzed by Zirconium Complexes

The intermolecular cyclomagnesation of cycloalkynes and joint cyclomagnesation of cycloalkynes and disubstituted acetylenes was carried out by treating with RMgR′ (R, R′ = Et, Bu, Hlg) in the presence of Cp2ZrCl2 as a catalyst. As a result new unsaturated bi-and tricyclic organomagnesium compounds were obtained in high yields.

Cyclomagnesiation of nitrogen-containing 1,2-dienes with grignard compounds catalyzed by Cp2TiCl2

Cyclomagnesiation of nitrogen-containing 1,2-dienes with Grignard compounds in the presence of activated magnesium and Cp2TiCl2 as catalyst afforded 2,5-bis(aminoalkylidene)magnesacyclopentanes in high yield.

Cyclomagnesation of cyclonona-1,2-diene with EtMgR catalyzed by Cp2ZrCl2

Catalytic cyclomagnesation of cyclonona-1,2-diene with EtMgR (R = Et, Hlg) in the presence of catalyst Cp2ZrCl2 (5 mol%) was performed obtaining according to the reaction conditions either 10-magnesabicyclo-[7.3.01.9]dodec-8-ene or 3-ethylcyclonon-1-enyl-2-magnesiumethyl with a high regio-(>96%) and chemoselectivity (>75%).

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 39. Zr-Catalyzed cyclomagnesiation of N-containing allenes

Catalytic cyclomagnesiation of N-containing 1,2-dienes with Et2Mg in the presence of the Zr-based complexes affords 2-(aminoalkylidene)magnesacyclopentanes in 68–84% yields.

Short and efficient synthetic route to lembehyne B possessing neuritogenic activity

The nerve growth factor (NGF) is a protein of the neurotrophin family, which is responsible for the survival, development, and function of neurons [1, 2]. Investigation of the structure and physiological activity of neurotrophins is considered to form the basis for the design of modern medicinal agents for the treatment of human neurodegenerative diseases [3, 4]. Unfortunately, because of a large size (130 kDa) and high hydrophilicity, these proteins are incapable of permeating the hematoencephalic barrier (HEB), which essentially restricts their application for the treatment of socially significant neurodegenerative disorders (Alzheimer’s and Parkinson’s diseases, Huntington’s chorea, etc.). Search for low-molecular-weight lipophilic compounds readily permeating through the HEB and favoring neuronal cell differentiation and development of methods for the preparation of such compounds possessing neuritogenic activity are topical problems of medicinal chemistry [5–8]. It has recently been found that natural unsaturated acetylenic alcohols (lembehynes) occurring in micro amounts in Indonesian marine fungi Haliclona sp. show a considerable neuritogenic activity toward pheochromocytoma (PC12) and neuroblastoma Neuro2A cells [9–11]. Both R and S isomers of lembehyne B turned out to be biologically active [11, 12]. However, difficult accessibility and the lack of efficient methods of synthesis of natural lembehynes strongly restrains detailed study of their biological activity and design on their base of modern agents for the treatment of neurodegenerative diseases. Analysis of the structure of lembehynes and known approaches to their total syntheses showed that the most complex and multistep stage is stereoselective ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 12, pp. 1844–1846.