Electrochemical Iodine-Mediated Oxidation of Enamino-Esters to 2H-Azirine-2-Carboxylates Supported by Design of Experiments

An electrochemical iodine-mediated transformation of enamino-esters for the synthesis of 2H-azirine-2-carboxylates is presented. In addition, a thermic conversion of azirines to 4-carboxy-oxazoles in quantitative yield without purification was described. Both classes 2H-azirines-2-carboxylates and the 4-carboxy-oxazoles are substructures in natural products and therefore are of considerable interest for synthetic and pharmaceutical chemists. The optimization was not performed in a conventional manner with a one-factor-at-a-time process but with a Design of Experiments (DoE) approach. Beside a broad substrate scope the reaction was also employed to a robustness screen, a sensitivity assessment, and complemented with mechanistic considerations from cyclic voltammetry experiments.     

A Bis-Chelating / Ligand for the Synthesis of Heterobimetallic Platinum(II)/Rhenium(I) Complexes: Tools for the Optimization of a New Class of Platinum(II) Anticancer Agents

The two independent and coordination sites of a newly synthesized bis[2-(hydroxyphenyl)-1,2,4-triazole] platform have been exploited to prepare four monometallic neutral ()Pt^II complexes carrying DMSO, pyridine, triphenylphosphine, or N-heterocyclic carbene as the fourth ligand. Then, the second coordination site was used to introduce an IR-active rhenium tricarbonyl entity, affording the four corresponding heterobimetallic neutral Pt^II/Re^I complexes, as well as a cationic Pt^II/Re^I derivative. X-ray crystallographic studies showed that distortion of the organic platform occurred to accommodate the coordination geometry of both metal centers. No ligand exchange or transchelation occurred upon incubation of the Pt^II complexes in aqueous environment or in the presence of Fe^III, respectively. The antiproliferative activity of the ligand and complexes was first screened on the triple-negative breast cancer cell line MDA-MB-231. Then, the IC₅₀ values of the most active candidates were determined on a wider panel of human cancer cells (MDA-MB-231, MCF-7, and A2780), as well as on a nontumorigenic cell line (MCF-10A). Low micromolar activities were reached for the complexes carrying a DMSO ligand, making them the first examples of highly active, but hydrolytically stable, Pt^II complexes. Finally, the characteristic mid-IR signature of the {Re(CO)₃} fragment in the Pt/Re heterobimetallic complexes was used to quantify their uptake in breast cancer cells.     

Journey from Small-Molecule Diyne Structures to 2D Graphdiyne: Synthetic Strategies

Graphdiyne (GDY) exhibits unique characteristics of a highly conjugated π system, evenly distributed nanopores, and a direct band gap. This has encouraged multidisciplinary research groups to investigate its application in energy conversion and storage, catalysts, electronic devices, sensing, and separation. Herein, the achievements of synthetic strategies for preparing small-molecule diyne structures (GDY substructure), 1D nanoribbons, and 2D GDY are presented. These studies may help future investigations into the basic structure-related properties of GDY and synthetic methodology for the future developments of GDY-related 2D carbon materials.     

Chemoselective Hydrogenation of 6-Alkynyl-3-fluoro-2-pyridinaldoximes: Access to First-in-Class 6-Alkyl-3-Fluoro-2-pyridinaldoxime Scaffolds as New Reactivators of Sarin-Inhibited Human Acetylcholinesterase with Increased Blood–Brain Barrier Permeability

Novel 6-alkyl- and 6-alkenyl-3-fluoro-2-pyridinaldoximes have been synthesised by using a mild and efficient chemoselective hydrogenation of 6-alkynyl-3-fluoro-2-pyridinaldoxime scaffolds, without altering the reducible, unprotected, sensitive oxime functionality and the C−F bond. These novel 6-alkyl-3-fluoro-2-pyridinaldoximes may find medicinal application as antidotes to organophosphate poisoning. Indeed, one low-molecular-weight compound exhibited increased affinity for sarin-inhibited acetylcholinesterase (hAChE) and greater reactivation efficiency or resurrection for sarin-inhibited hAChE, compared with those of 2-pyridinaldoxime (2-PAM) and 1-({[4-(aminocarbonyl)pyridinio]methoxy}methyl)-2-[(hydroxyimino)methyl]pyridinium chloride (HI-6), two pyridinium salts currently used as antidote by several countries. In addition, the uncharged 3-fluorinated bifunctional hybrid showed increased in vitro blood–brain barrier permeability compared with those of 2-PAM, HI-6 and obidoxime. These promising features of novel low-molecular-weight alkylfluoropyridinaldoxime open up a new era for the design, synthesis and discovery of central non-quaternary broad spectrum reactivators for organophosphate-inhibited cholinesterases.     

Cyanide Bridged Platinum-Iron Complexes as Cisplatin Prodrug Systems: Design and Computational Study

The potential role of cyanide-bridged platinum-iron complexes as an anti-cancer Pt(IV) prodrug is studied. We present design principles of a dual-function prodrug that can upon reduction dissociate and release concurrently six cisplatin units and a ferricyanide anion per prodrug unit. The prodrug molecule is a unique complex of hepta metal centers consisting of a ferricyanide core with six Pt(IV) centers each bonded to the Fe(III) core through a cyano ligand. The functionality of the prodrug is addressed through density functional theory (DFT) calculations.     

CRISPR-Cas12a System for Biosensing and Gene Regulation

Clustered regularly interspaced short palindromic repeats (CRISPR) is a promising technology in the biological world. As one of the CRISPR-associated (Cas) proteins, Cas12a is an RNA-guided nuclease in the type V CRISPR-Cas system, which has been a robust tool for gene editing. In addition, due to the discovery of target-binding-induced indiscriminate single-stranded DNase activity of Cas12a, CRISPR-Cas12a also exhibits great promise in biosensing. This minireview not only gives a brief introduction to the mechanism of CRISPR-Cas12a but also highlights the recent developments and applications in biosensing and gene regulation. Finally, future prospects of the CRISPR-Cas12a system are also discussed. We expect this minireview will inspire innovative work on the CRISPR-Cas12a system by making full use of its features and advantages.     

The 4-GDDs of type 3562

We determine the 22 isomorphism classes of 4-GDDs with group type $3^5{6}^2$ and compare their automorphism groups. We also observe for the first time an example of a three dimensional Pasch triangle in a GDD.     

Development and assessment of an intrusive polynomial chaos expansion-based continuous adjoint method for shape optimization under uncertainties

This article contributes to the development of methods for shape optimization under uncertainties, associated with the flow conditions, based on intrusive Polynomial Chaos Expansion (iPCE) and continuous adjoint. The iPCE to the Navier–Stokes equations for laminar flows of incompressible fluids is developed to compute statistical moments of the Quantity of Interest which are, then, compared with those obtained through the Monte Carlo method. The optimization is carried out using a continuous adjoint-enabled, gradient-based loop. Two different formulations for the continuous adjoint to the iPCE PDEs are derived, programmed, and verified. Intrusive PCE methods for the computation of the statistical moments require mathematical development, derivation of a new system of governing equations and their numerical solution. The development is presented for a chaos order of two and two uncertain variables and can be used as a guide to those willing to extend this development to a different set of uncertain variables or chaos order. The developed method and software, programmed in OpenFOAM, is applied to two optimization problems pertaining to the flow around isolated airfoils with uncertain farfield conditions.     

Computational design of rasagiline derivatives: Searching for enhanced antioxidant capability

A set of new rasagiline derivatives is presented. They were designed to be antioxidant compounds with the potential to be used for treating neurodegenerative disorders. They are expected to be multifunctional molecules that can help reduce oxidative stress, which is thought to contribute to neurodegenerative disorders. The CADMA-Chem computational protocol was used to produce rasagiline derivatives and to evaluate their likeliness as oral drugs and antioxidants. Three of them were identified as the most promising ones. They are proposed to be better free radical scavengers than rasagiline. In addition, they are expected to keep the parent's molecule neuroprotective capability. Hopefully, the results presented here would promote further experimental and theoretical investigations on these compounds.