Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors.

Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the development of new antitumor agents. In this work, we present a series of 41 compounds designed based on the well-known and successful strategy of introducing thienopyridine and pyrimidine as bioisosteres of other heterocycles in active antitumor compounds. Notwithstanding the fact that some of these compounds do not show significant enzymatic inhibition, others, in contrast, feature substantially improved enzymatic and antiproliferative inhibition values. This is also confirmed by docking analysis, whereby compounds with longer linkers and thienopyrimidine cationic head have been identified as the most compelling. Among the best compounds is Ff-35, which inhibits the growth of different tumor cells at submicromolar concentrations. Moreover, Ff-35 is more potent in inhibiting CKα1 than other previous biscationic derivatives. Treatment of A549, Hela, and MDA-MB-231 cells with Ff-35 results in their arrest at the G1 phase of the cell cycle. Furthermore, the compound induces cellular apoptosis in a concentration-dependent manner. Altogether, these findings indicate that Ff-35 is a promising new chemotherapeutic agent with encouraging preclinical potential.

New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity.

In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds that are capable of inhibiting Plasmodium falciparum Choline Kinase and therefore to reduce choline uptake, which is essential for the development of the parasite. Of the 41 bioisosteric compounds reported herein, none showed any influence of the linker on the antimalarial and enzyme inhibitory activity, whereas an effect of the type of cationic heads used could be observed. SARs determined that the thienopyrimidine substituted in 4 by a pyrrolidine is the best scaffold, independently of the chosen linker. The decrease in lipophilicity seems to improve the antimalarial activity but to cause an opposite effect on the inhibition of the enzyme. While potent compounds with similar good inhibitory values have been related to the proposed mechanism of action, some of them still show discrepancies and further studies are needed to determine their specific molecular target.

Synthesis of γ-Oxo-α-amino Acids via Radical Acylation with Carboxylic Acids.

Herein we present a highly efficient, light-mediated, deoxygenative protocol to access γ-oxo-α-amino acid derivatives. This radical methodology employs photoredox catalysis, in combination with triphenylphosphine, to generate acyl radicals from readily available (hetero)aromatic and vinylic carboxylic acids. This approach allows for the straightforward synthesis of γ-oxo-α-amino acids bearing a wide range of functional groups (e.g., Cl, CN, furan, thiophene, Bpin) in synthetically useful yields (∼60% average yield). To further highlight the utility of the methodology, several deprotection and derivatization reactions were carried out.

Radical-Based Synthesis and Modification of Amino Acids.

Amino acids (AAs) are key structural motifs with widespread applications in organic synthesis, biochemistry, and material sciences. Recently, with the development of milder and more versatile radical-based procedures, the use of strategies relying on radical chemistry for the synthesis and modification of AAs has gained increased attention, as they allow rapid access to libraries of novel unnatural AAs containing a wide range of structural motifs. In this Minireview, we provide a broad overview of the advancements made in this field during the last decade, focusing on methods for the de novo synthesis of α-, ß-, and γ-AAs, as well as for the selective derivatisation of canonical and non-canonical α-AAs.

Light-Mediated Formal Radical Deoxyfluorination of Tertiary Alcohols through Selective Single-Electron Oxidation with TEDA2+.

The synthesis of tertiary alkyl fluorides through a formal radical deoxyfluorination process is described herein. This light-mediated, catalyst-free methodology is fast and broadly applicable allowing for the preparation of C-F bonds from (hetero)benzylic, propargylic, and non-activated tertiary alcohol derivatives. Preliminary mechanistic studies support that the key step of the reaction is the single-electron oxidation of cesium oxalates-which are readily available from the corresponding tertiary alcohols-with in situ generated TEDA2+. (TEDA: N-(chloromethyl)triethylenediamine), a radical cation derived from Selectfluor®.