RESUMO
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.
Assuntos
Álcoois/farmacologia , Alcinos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Álcoois Graxos/farmacologia , Álcoois/síntese química , Álcoois/química , Alcinos/síntese química , Alcinos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Álcoois Graxos/síntese química , Álcoois Graxos/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
(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-2Ð-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.
Assuntos
DNA Topoisomerases Tipo I/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Simulação por Computador , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Ácidos Graxos Insaturados/química , Regulação Enzimológica da Expressão Gênica , Humanos , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Inibidores da Topoisomerase I/químicaRESUMO
(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 the Cp2TiCl2 catalyst giving 2,5-dialkylydenemagnesacyclopentane in 86% yield. The acid hydrolysis of the product and Jones oxidation of the resulting 2-{[(5Z,9Z)-11-phenylundeca-5,9-dien-1-yl]oxy}tetrahydro-2Ð-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 detected. Resorting to the data of molecular docking, a mechanism of inhibition was proposed.
Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Desenho de Fármacos , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/farmacologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Sítios de Ligação , Domínio Catalítico , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Ácidos Graxos Insaturados/metabolismo , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/metabolismo , Inibidores da Topoisomerase II/metabolismoRESUMO
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.
Assuntos
DNA Topoisomerases Tipo I/química , Esteroides , Inibidores da Topoisomerase I , Humanos , Esteroides/síntese química , Esteroides/química , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/químicaRESUMO
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.