Divergent Reactivity of Triaryldivinyl Ketones: Competing 4π and Putative 6π Electrocyclization Pathways.

This work describes an acid-promoted cyclization of triaryldivinyl ketones containing a thiophene moiety in the α-position. Two cyclization pathways are accessible: one a 4π-Nazarov cyclization and the other we propose to proceed through a 6π electrocyclic mechanism. The relative proportion of products from these divergent pathways is affected by reaction conditions and steric bulk in the substrate. We present experimental and computational evidence that when using HCl in dioxane, the 4π-conrotatory electrocyclization is more favorable, whereas GaCl3 in methylene chloride shifts the chemoselectivity toward a putative 6π-disrotatory electrocyclization. DFT calculations suggest that a complex interplay between kinetic and thermodynamic factors is implicated in the chemodivergent behavior.

Photostability and Antiproliferative Activity of Furan Analogues of Combretastatin A-4.

Cancer is one of the most serious health problems that usually require heavy medical treatment. It is important to ensure that no additional burden is placed on patients due to the modes of administration and/or poor quality of pharmaceuticals. In this regard, understanding, quantifying, and improving the photostability (resistance to UV light or sunlight) of drugs is among the important elements that can improve the patient's quality of life. In this work, the photochemical properties of a wide range of furanone analogues of combretastatin A-4 and their antiproliferative activity against A-431 epidermoid carcinoma cells were studied in a search for compounds with improved photostability and antiproliferative activity. It was found that the incorporation of an arylidene moiety led to a significant improvement in photostability, while the antiproliferative activity strongly depends on the nature of the aryl residue in the arylidene moiety. The high photostability of arylidenes was achieved due to the delocalization of the central double bond of the 1,3,5-hexatriene system, which limited the 6π-electrocyclization. The best results in terms of antiproliferative activity were obtained for thiophene arylidene (IC50 = 0.6 µM) and 3,4-diarylfuran (IC50 = 0.047 µM). The obtained results address the lack of data available now in scientific literature on the photodegradation of combretastatin A-4 analogues and should be taken into account in studies of the side effects of pharmaceuticals based on them.

Photoinduced Skeletal Rearrangement of Diarylethenes: Photorelease of Lewis Acid and Synthetic Applications.

The skeletal photorearrangement including 6π-electrocyclization induced by UV light of ortho-halogen-substituted diarylethenes has been studied. It has been found that the reaction pathways leading to bi- or tricyclic frameworks depend on the kind of halogen substituent and solvent. Photocyclization with halogen abstraction leads to bicyclic fused aromatics, while the tricyclic frameworks are formed due to the tandem 6π-electrocyclization/sigmatropic shift reaction. THF is preferred as the solvent in the former process and chloroform in the latter reaction. It was found for the first time that, owing to the ability of this series of diarylethenes to undergo skeletal photorearrangement with the release of the bromide cation, they can be used both as brominating agents and as Lewis acids for catalyzing electrophilic reactions.

Photocyclization of Diarylethenes: The Effect of Electron and Proton Acceptors as Additives.

The effect of electron and proton acceptors on the photocyclization of diarylethenes has been studied. Without any additives, the deprotonation reaction is predominant, although other processes, including the sigmatropic shift, are not excluded. A deuterium exchange experiment has shown that a strong base (DABCO) facilitates the deprotonation reaction, thereby limiting the sigmatropic shift. In the presence of an oxidizing agent or additional sources of radicals (O2, I2, TEMPO), the processes of deprotonation and rearrangement (H-shift) are practically not observed, and the reaction proceeds along a radical pathway with the formation of phenanthrene or its heterocyclic analogue.

Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells.

The acid-catalyzed cyclization of benzylidenes based on 16-dehydropregnenolone acetate (16-DPA) was studied. It was found that these compounds readily undergo regioselective interrupted Nazarov cyclization with trapping chloride ion and an efficient method of the synthesis of d-annulated pentacyclic steroids based on this reaction was proposed. The structures of the synthesized pentacyclic steroids were determined by NMR and X-ray diffraction. It was found that the reaction affords a single diastereomer, but the latter can crystallize as two conformers depending on the structure. Antiproliferative activity of synthesized compounds was evaluated against two breast cancer cell lines: MCF-7 and MDA-MB-231. All tested compounds showed relatively high antiproliferative activity. The synthetic potential of the protocol developed was illustrated by the gram-scale experiment.

Mechanism of photochromic transformations and photodegradation of an asymmetrical 2,3-diarylcyclopentenone.

A mechanistic study of the photochromic properties and photodegradation processes of an asymmetrical diarylcyclopentenone bearing thiophene and benzothiophene units using stationary photolysis, nanosecond laser flash photolysis and time-resolved luminescence was performed. It was found that the light-induced reversible isomerization of (3-(2,5-dimethyltiophen-3-il)-2-(2-methyl-1-benzylthiophen-3-il)cyclopent-2-en-1-one, compound 1) from open to closed form is a common photochromic transformation inherent to diarylethenes, while the photodegradation process proceeds in two ways. The first is a formal 1,2-dyotropic rearrangement, proceeding without the participation of oxygen. The second is the oxygen-dependent mechanism involving the excitation of the open form 1A into the triplet state, quenching of the latter by dissolved oxygen, and oxidation of the initial compound by singlet oxygen.

Reversible Shifting of a Chemical Equilibrium by Light: The Case of Keto-Enol Tautomerism of a ß-Ketoester.

Manipulating the equilibrium between a ketone and an enol by light opens up ample opportunities in material chemistry and photopharmacology. By incorporating ß-ketoester into the ethene bridge of a photoactive diarylethene, we achieved reversible light-induced tautomerization to give thermally stable enol. In a pristine state, the tautomeric equilibrium is almost completely shifted toward the ketone. Photocyclization of diarylethene results in a new equilibrium containing a significant fraction of the enol tautomer.

Photochromic diarylethene ligands featuring 2-(imidazol-2-yl)pyridine coordination site and their iron(II) complexes.

A new family of photochromic diarylethene-based ligands bearing a 2-(imidazol-2-yl)pyridine coordination unit has been developed. Four members of the new family have been synthesized. The photoactive ligands feature non-aromatic ethene bridges (cyclopentene, cyclopentenone, and cyclohexenone), as well as closely spaced photoactive and metal coordination sites aiming a strong impact of photocyclization on the electronic structure of the coordinated metal ion. The ligands with cyclopentenone and cyclohexenone bridges show good cycloreversion quantum yields of 0.20-0.32. The thermal stability of closed-ring isomers reveals half-lives of up to 20 days in solution at room temperature. The ligands were used to explore coordination chemistry with iron(II) targeting photoswitchable spin-crossover complexes. Unexpectedly, dinuclear and tetranuclear iron(II) complexes were obtained, which were thoroughly characterized by X-ray crystallography, magnetic measurements, and Mössbauer spectroscopy. The formation of multinuclear complexes is facilitated by two coordination sites of the diarylethene, acting as a bridging ligand. The bridging nature of the diarylethene in the complexes prevents photocyclization.

Photoswitching off the Antiproliferative Activity of Combretastatin A-4 Analogues.

The photostability and antiproliferative activity of combretastatin A-4 (CA-4) analogues against human epidermoid carcinoma cells A-431 were studied. For the first time, it was shown that UV or sunlight irradiation of furanone analogues of CA-4 results in a photorearrangement giving products with relatively low antiproliferative activity. The observed ability of this series CA-4 to the photodegradation can be used for the design of a new class of drug candidates with high selectivity to cancer cells.

Synthesis and evaluation of the antiproliferative activity of benzylidenes of 16-dehydroprogesterone series.

Novel benzylidenes (chalcones) of the 16-dehydroprogesterone series have been characterized and their antitumor activity against two breast cancer cell lines was evaluated. Benzylidenes exhibit significant antiproliferative effect on cells and inhibit cell growth in hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines. Compound 3d exhibits the highest activity against two breast cancer cell lines, with the IC50 value of about 2 µM. Compounds 3e,m,n display considerable selectivity for hormone-dependent breast cancer cells, with the IC50 value lower than 6 µM. Moreover, these steroidal benzylidenes regulate ERα signaling and reveal p53-independent mechanism of pro-apoptotic action in MCF-7 cells. The new class of antitumor compounds holds promise as the basis for the design of agents for cancer therapy.

Triaryl-Substituted Divinyl Ketones Cyclization: Nazarov Reaction versus Friedel-Crafts Electrophilic Substitution.

The acid-catalyzed cyclization of a wide range of triaryl-substituted divinyl ketones has been studied. It was found that the reaction pathway strongly depends on the nature of the aryl substituent at the α-position to the carbonyl group. An electron-rich aromatic substituent promotes the reaction to proceed through the intramolecular Friedel-Crafts electrophilic substitution giving dihydronaphthalene derivatives. In contrast, the presence of an electron-deficient substituent is favorable for the Nazarov 4π-conrotatory cyclization yielding triaryl-substituted cyclopentenones. The electrophilic substitution reaction was applied to thiophene and thiazole derivatives.