Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction.

The scope and limitations of the Nicholas-type cyclization for the synthesis of 10-membered benzothiophene-fused heterocyclic enediynes with different functionalities were investigated. Although the Nicholas cyclization through oxygen could be carried out in the presence of an ester group, the final oxaenediyne was unstable under storage. Among the N-type Nicholas reactions, cyclization via an arenesulfonamide functional group followed by mild Co-deprotection was found to be the most promising, yielding 10-membered azaendiynes in high overall yields. By contrast, the Nicholas cyclization through the acylated nitrogen atom did not give the desired 10-membered cycle. It resulted in the formation of a pyrroline ring, whereas cyclization via an alkylated amino group resulted in a poor yield of the target 10-membered enediyne. The acylated 4-aminobenzenesulfonamide nucleophilic group was found to be the most convenient for the synthesis of functionalized 10-membered enediynes bearing a clickable function, such as a terminal triple bond. All the synthesized cyclic enediynes exhibited moderate activity against lung carcinoma NCI-H460 cells and had a minimal effect on lung epithelial-like WI-26 VA4 cells and are therefore promising compounds in the search for novel antitumor agents that can be converted into conjugates with tumor-targeting ligands.

4-Azidocinnoline-Cinnoline-4-amine Pair as a New Fluorogenic and Fluorochromic Environment-Sensitive Probe.

A new type of fluorogenic and fluorochromic probe based on the reduction of weakly fluorescent 4-azido-6-(4-cyanophenyl)cinnoline to the corresponding fluorescent cinnoline-4-amine was developed. We found that the fluorescence of 6-(4-cyanophenyl)cinnoline-4-amine is strongly affected by the nature of the solvent. The fluorogenic effect for the amine was detected in polar solvents with the strongest fluorescence increase in water. The environment-sensitive fluorogenic properties of cinnoline-4-amine in water were explained as a combination of two types of fluorescence mechanisms: aggregation-induced emission (AIE) and excited state intermolecular proton transfer (ESPT). The suitability of an azide-amine pair as a fluorogenic probe was tested using a HepG2 hepatic cancer cell line with detection by fluorescent microscopy, flow cytometry, and HPLC analysis of cells lysates. The results obtained confirm the possibility of the transformation of the azide to amine in cells and the potential applicability of the discovered fluorogenic and fluorochromic probe for different analytical and biological applications in aqueous medium.

Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization.

To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothiophene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas-type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.

Ring-Closing Metathesis of Co2(CO)6-Alkyne Complexes for the Synthesis of 11-Membered Dienediynes: Overcoming Thermodynamic Barriers.

The feasibility of ring-closing metathesis (RCM) as a synthetic entry to 10- and 11-membered dienediynes fused to a benzothiophene core was explored by experimental and theoretical investigations. An established sequence of iodocyclization of o-(buta-1,3-diynyl)thioanisoles followed by Sonogashira coupling to form diethynylbenzothiophenes was used to synthesize terminal benzothiophene-fused enediyne diolefins as substrates for RCM. Encountering an unexpected lack of reactivity of these substrates under standard RCM conditions, we applied DFT calculations to reveal that the underlying cause was a positive change in Gibbs free energy. The change in Gibbs free energy was also found to be positive for RCM of indole- and benzannulated terminal diolefins when affording smaller than 12-membered rings. We found that modification of the enediyne-diolefin substrate as the Co2(CO)6-alkyne complex allowed the target benzothiophene-fused 11-membered dienediyne to be obtained via RCM; the alkyne complexation strategy therefore provides one valid technique for overcoming challenges to macrocyclization of this kind.

A novel synthesis of benzo[b]selenophenes via regioselective intramolecular transformation of 4-(3-nitroaryl)-1,2,3-selenadiazoles.

Base-promoted transformation of 4-(3-nitroaryl)-1,2,3-selenadiazoles via intermediate formation of eneselenolates followed by 5-exo-trig cyclization is reported. The regiochemistry of the intramolecular cyclization is condition-dependent. In the presence of an oxidant, the oxidative nucleophilic substitution of the hydrogen (ONSH, S(N)Ar(H)) pathway, by oxidative aromatization of the rapidly formed σ(H)-adduct, takes place. In the absence of oxidant, the reaction proceeds via intermediate formation of the σ(Cl)-adduct, following nucleophilic aromatic substitution of the halogen (S(N)Ar(Cl)) pathway.