ABSTRACT
A set of novel selenohydantoins were synthesized via a convenient and versatile approach involving the reaction of isoselenocyanates with various amines. We also revealed an unexpected ZâE isomerization of pyridin-2-yl-substituted selenohydantoins in the presence of Cu(2+) cations. The detailed mechanism of this transformation was suggested on the basis of quantum-chemical calculations, and the key role of Cu(2+) was elucidated. The obtained compounds were subsequently evaluated against a panel of different cancer cell lines. As a result, several molecules were identified as promising micromolar hits with good selectivity index. Instead of analogous thiohydantoins, which have been synthesized previously, selenohydantoins demonstrated a relatively high antioxidant activity comparable (or greater) to the reference molecule, Ebselen, a clinically approved drug candidate. The most active compounds have been selected for further biological trials.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antioxidants/chemical synthesis , Hydantoins/chemical synthesis , Organoselenium Compounds/chemical synthesis , Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Azoles/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Copper/chemistry , Cyanates/chemistry , Drug Screening Assays, Antitumor , Glutathione Peroxidase/antagonists & inhibitors , Glutathione Peroxidase/chemistry , Humans , Hydantoins/pharmacology , Inhibitory Concentration 50 , Isoindoles , Organoselenium Compounds/pharmacology , Pyridines/chemistry , Quantum Theory , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A rapid new approach to produce biologically relevant bisindoles, namely indolyltetrahydrocarbazoles and indolo[3,2-b]carbazoles, has been developed, based on the Ga(OTf)3 -catalyzed [3+3] cyclodimerization of indole-derived donor-acceptor cyclopropanes. Chemoselectivity of the process depends on the location of the three-membered ring at the indole core.
ABSTRACT
(3 + 2)-Annulation of donor-acceptor cyclopropanes to alkynes induced by both Lewis and Brønsted acids has been developed. The reaction provides a rapid approach to functionalized indenes displaying intense visible emission (λmax = 430 nm, Φ = 0.28-0.34).
Subject(s)
Alkynes/chemistry , Cyclopropanes/chemistry , Lewis Acids/chemistry , Catalysis , Indenes/chemistry , Molecular Structure , StereoisomerismABSTRACT
A novel Lewis acid-catalyzed domino (3+2)-cyclodimerization of 2-arylcyclopropane-1,1-diesters and related stepwise cross-reaction of two different cyclopropanes were developed. These processes provide efficient and highly stereoselective access to polyoxygenated indanes and cyclopentannulated heteroarene derivatives, which display significant cytotoxicity against several lines of cancer cells (IC50 of 10(-6)-10(-5) M) while being non-toxic for normal cells.
Subject(s)
Hydrocarbons/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Dimerization , Humans , Hydrocarbons/pharmacology , Lewis Acids/chemistry , StereoisomerismABSTRACT
Quo vadis? The Lewis acid catalyzed reaction of (hetero)aryl-derived donor-acceptor cyclopropanes with alkenes can be selectively directed along a [3+2] annulation pathway (see scheme). This new process provides convenient and efficient access to indanes and other cyclopentannulated (hetero)arenes, among which polyoxygenated 1-arylindanes exhibit significant cytotoxicity against several cancer cell lines with an IC50 of 10(-6)-10(-5) M.
