ABSTRACT
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.
Subject(s)
Alcohols/pharmacology , Alkynes/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Fatty Alcohols/pharmacology , Alcohols/chemical synthesis , Alcohols/chemistry , Alkynes/chemical synthesis , Alkynes/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Fatty Alcohols/chemical synthesis , Fatty Alcohols/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
DNA Topoisomerases, Type I/chemistry , Steroids , Topoisomerase I Inhibitors , Humans , Steroids/chemical synthesis , Steroids/chemistry , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/chemistryABSTRACT
(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.
Subject(s)
DNA-Binding Proteins/antagonists & inhibitors , Drug Design , Fatty Acids, Unsaturated/chemical synthesis , Fatty Acids, Unsaturated/pharmacology , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Antigens, Neoplasm/chemistry , Antigens, Neoplasm/metabolism , Binding Sites , Catalytic Domain , DNA Topoisomerases, Type I/chemistry , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Fatty Acids, Unsaturated/metabolism , Humans , Molecular Docking Simulation , Protein Binding , Protein Conformation , Structure-Activity Relationship , Topoisomerase I Inhibitors/metabolism , Topoisomerase II Inhibitors/metabolismABSTRACT
(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.
Subject(s)
DNA Topoisomerases, Type I/metabolism , DNA-Binding Proteins/antagonists & inhibitors , Fatty Acids, Unsaturated/chemical synthesis , Fatty Acids, Unsaturated/pharmacology , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Antigens, Neoplasm/genetics , Antigens, Neoplasm/metabolism , Computer Simulation , DNA Topoisomerases, Type II/genetics , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Fatty Acids, Unsaturated/chemistry , Gene Expression Regulation, Enzymologic , Humans , Models, Chemical , Models, Molecular , Molecular Structure , Topoisomerase I Inhibitors/chemistryABSTRACT
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.
