Discovery of Di(het)arylmethane and Dibenzoxanthene Derivatives as Potential Anticancer Agents.

A family of bifunctional dihetarylmethanes and dibenzoxanthenes is assembled via a reaction of acetals containing a 2-chloroacetamide moiety with phenols and related oxygen-containing heterocycles. These compounds demonstrated selective antitumor activity associated with the induction of cell apoptosis and inhibition of the process of glycolysis. In particular, bis(heteroaryl)methane containing two 4-hydroxy-6-methyl-2H-pyran-2-one moieties combine excellent in vitro antitumor efficacy with an IC50 of 1.7 µM in HuTu-80 human duodenal adenocarcinoma models with a high selectivity index of 73. Overall, this work highlights the therapeutic potential of dimeric compounds assembled from functionalized acetals and builds a starting point for the development of a new family of anticancer agents.

Hypervalent Sulfur Derivatives as Sulfenylating Reagents: Visible-Light-Mediated Direct Thiolation of Activated C(sp2)-H Bonds with Dihalosulfuranes.

In contrast to hypervalent iodine compounds, the chemistry of their sulfur analogues has been considerably less explored. Herein, we report the direct C-H bond thiolation of electron-rich heterocycles, arenes, and 1,3-dicarbonyls by dichlorosulfuranes under mild conditions. Mechanistic studies and density functional theory calculations suggest the radical chain mechanism of the disclosed transformation. The key to success is attributed to a strikingly low S-Cl bond dissociation energy, which enables the generation of radical species upon exposure to daylight.

One-Step Synthesis of Functionalized Pyrazolo[3,4-b]pyridines via Ring Opening of the Pyrrolinium Ion.

Herein, we report a highly regioselective one-pot synthesis of pyrazolo[3,4-b]pyridines via the reaction of 3-arylidene-1-pyrrolines with aminopyrazoles. The reaction proceeds through the sequential nucleophilic addition/electrophilic substitution/C-N bond cleavage and provides easy access to pyrazolo[3,4-b]pyridine derivatives featuring a primary amino group. Moreover, the reaction can be terminated at the electrophilic substitution stage, thus providing convenient entry to the hardly accessible pyrazolopyrrolopyridine scaffold.

"Stereoelectronic Deprotection of Nitrogen": Recovering Nucleophilicity with a Conformational Change.

Ureas are often thought of as "double amides" due to the obvious structural similarity of these functional groups. The main structural feature of an amide is its planarity, which is responsible for the conjugation between the nitrogen atom and carbonyl moiety and the decrease of amide nucleophilicity. Consequently, since amides are poor nucleophiles, ureas are often thought of as poor nucleophiles as well. Herein, we demonstrate that ureas can be distinctly different from amides. These differences can be amplified by rotation around one of the ureas' C-N bonds, which switches off the amide resonance and recovers the nucleophilicity of one of the nitrogen atoms. This conformational change can be further facilitated by the judicious introduction of steric bulk to disfavor the planar conformation. This change in reactivity is an example of "stereoelectronic deprotection," a concept when the desired reactivity of a functional group is produced by a conformational change rather than a chemical modification. This concept may be used complementarily to the traditional protecting groups. We also demonstrate both the viability and the utility of this concept by the synthesis of unusual 2-oxoimidazolium salts possessing quaternary nitrogen atoms at the urea moiety.

One-Pot Synthesis of Novel Functionalized Fused Pyridine Derivatives via Consecutive Pyrrolidine Ring-Closure/Ring-Opening/Formal Aza-Diels-Alder Reactions.

In this article, we report a highly regioselective method for the synthesis of new fused pyridine derivatives─2,3-disubstituted quinolines and 1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one derivatives. The method is based on the reaction of 1,1-diethoxybutane derivatives with aromatic and heterocyclic nucleophiles. The isolated compounds are similar to the products formed as a result of the Debner-Miller reaction. However, we have shown that the interaction of 1,1-diethoxybutane derivatives with (hetero)aromatic amines proceeds according to a mechanism different from that of the Doebner-Miller reaction. The proposed method is distinguished by the possibility of obtaining a wide range of substituted quinolines and 1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one derivatives in one step, the absence of the need to use expensive metal-containing catalysts, and a high product yield.

Enamine-mediated Mannich reaction of cyclic N,O-acetals and amido acetals: the multigram synthesis of pyrrolidine alkaloid precursors.

The cooperative L-proline/Brønsted acid/base promoted reaction of 2-ethoxypyrrolidines or N-substituted 4,4-diethoxybutan-1-amines with methyl(alkyl/aryl)ketones for the synthesis of 2-(acylmethylene)pyrrolidine derivatives is reported. The key features of the developed protocol are gram-scale synthesis of the target compounds, easily available starting materials, operational simplicity and usage of non-expensive reagents.

Synthesis and Biological Evaluation of Taurine-Derived Diarylmethane and Dibenzoxanthene Derivatives as Possible Cytotoxic and Antimicrobial Agents.

The series of novel taurine-derived diarylmethanes and dibenzoxanthenes was synthesized starting from simple commercially available precursors via modular three-stage approach. All the newly synthesized compounds were screened for in vitro antibacterial and antifungal activity, as well as cytotoxicity towards normal and cancer cell lines. Some of the synthesized compounds exhibited 2-4-fold higher activity against S. aureus, E. faecalis and B. cereus compared with Chloramphenicol. In contrast to Chloramphenicol, the tested compounds also showed bactericidal, rather than bacteriostatic effect, which makes them promising candidates for further studies.

The Highly Regioselective Synthesis of Novel Imidazolidin-2-Ones via the Intramolecular Cyclization/Electrophilic Substitution of Urea Derivatives and the Evaluation of Their Anticancer Activity.

A series of novel 4-(het)arylimidazoldin-2-ones were obtained by the acid-catalyzed reaction of (2,2-diethoxyethyl)ureas with aromatic and heterocyclic C-nucleophiles. The proposed approach to substituted imidazolidinones benefits from excellent regioselectivity, readily available starting materials and a simple procedure. The regioselectivity of the reaction was rationalized by quantum chemistry calculations and control experiments. The anti-cancer activity of the obtained compounds was tested in vitro.

Synthesis of Novel 2-(Het)arylpyrrolidine Derivatives and Evaluation of Their Anticancer and Anti-Biofilm Activity.

A library of novel 2-(het)arylpyrrolidine-1-carboxamides were obtained via a modular approach based on the intramolecular cyclization/Mannich-type reaction of N-(4,4-diethoxybutyl)ureas. Their anti-cancer activities both in vitro and in vivo were tested. The in vitro activity of some compounds towards M-Hela tumor cell lines was twice that of the reference drug tamoxifen, whereas cytotoxicity towards normal Chang liver cell did not exceed the tamoxifen toxicity. In vivo studies showed that the number of surviving animals on day 60 of observation was up to 83% and increased life span (ILS) was up to 447%. Additionally, some pyrrolidine-1-carboxamides possessing a benzofuroxan moiety obtained were found to effectively suppress bacterial biofilm growth. Thus, these compounds are promising candidates for further development both as anti-cancer and anti-bacterial agents.

Synthesis and Evaluation of Water-Soluble 2-Aryl-1-Sulfonylpyrrolidine Derivatives as Bacterial Biofilm Formation Inhibitors.

The approach to the novel 1-[(2-aminoethyl)sulfonyl]-2-arylpyrrolidines via unique intramolecular cyclization/aza-Michael reactions of N-(4,4-diethoxybutyl)ethenesulfonamide have been developed, which benefits from high yields of target compounds, mild reaction conditions, usage of inexpensive and low-toxic reagents, and allows for wide variability in both amine and aryl moieties. Biotesting with whole-cell luminescent bacterial biosensors responding to DNA damage showed that all tested compounds are not genotoxic. Tested compounds differently affect the formation of biofilms by Vibrio aquamarinus DSM 26054. Some of the tested compounds were found to suppress the bacterial biofilms growth and thus are promising candidates for further studies.