Selective Alkylation of C‐Rich Bulge Motifs in Nucleic Acids by Quinone Methide Derivatives

A quinone methide precursor featuring a bis‐cyclen anchoring moiety has been synthesized and its capacity to alkylate oligonucleotide targets quantified in the presence and absence of divalent metal ions (Zn²⁺, Ni²⁺ and Cd²⁺). The oligonucleotides were designed for testing the sequence and secondary structure specificity of the reaction. Gel electrophoretic analysis revealed predominant alkylation of C‐rich bulges, regardless of the presence of divalent metal ions or even the bis‐cyclen anchor. This C‐selectivity appears to be an intrinsic property of the quinone methide electrophile as reflected by its reaction with an equimolar mixture of the 2′‐deoxynucleosides. Only dA‐N1 and dC‐N3 alkylation products were detected initially and only the dC adduct persisted for detection under conditions of the gel electrophoretic analysis.     

Photosensitized Thymine Dimerization via Delocalized Triplet Excited States

A new mechanism of photosensitized formation of thymine (Thy) dimers is proposed, which involves generation of a delocalized triplet excited state as the key step. This is supported by chemical evidence obtained by combining one benzophenone and two Thy units with different degrees of freedom, whereby the photoreactivity is switched from a clean Paternò–Büchi reaction to a fully chemo‐, regio‐, and stereoselective [2+2] cycloaddition.     

Light‐Controlled Histone Deacetylase (HDAC) Inhibitors: Towards Photopharmacological Chemotherapy

Cancer treatment suffers from limitations that have a major impact on the patient’s quality of life and survival. In the case of chemotherapy, the systemic distribution of cytotoxic drugs reduces their efficacy and causes severe side effects due to nonselective toxicity. Photopharmacology allows a novel approach to address these problems because it employs external, local activation of chemotherapeutic agents by using light. The development of photoswitchable histone deacetylase (HDAC) inhibitors as potential antitumor agents is reported herein. Analogues of the clinically used chemotherapeutic agents vorinostat, panobinostat, and belinostat were designed with a photoswitchable azobenzene moiety incorporated into their structure. The most promising compound exhibits high inhibitory potency in the thermodynamically less stable cis form and a significantly lower activity for the trans form, both in terms of HDAC activity and proliferation of HeLa cells. This approach offers a clear prospect towards local photoactivation of HDAC inhibition to avoid severe side effects in chemotherapy.     

Dioxygen‐Mediated Decarbonylative CH Alkylation of Heteroaromatic Bases with Aldehydes

An operationally simple and economical method for the direct alkylation of heteroaromatic bases employing readily available aldehydes as alkyl radical precursors and molecular oxygen as a reagent is presented. This simple transformation demonstrates a broad substrate scope with respect to aldehydes and nitrogen heterocycles, enabling the introduction of several medicinally important yet challenging alkyl moieties, such as ethyl, isopropyl, tert‐butyl, and cyclohexyl to the different classes of heterocyclic bases in good to excellent yields.     

Direct Photoredox‐Catalyzed Reductive Difluoromethylation of Electron‐Deficient Alkenes

Photoredox‐catalyzed reductive difluoromethylation of electron‐deficient alkenes was achieved in one step under tin‐free, mild and neutral conditions. This protocol affords a facile method to introduce RCF₂ (R=H, Ph, Me, and CH₂N₃) groups at sites β to electron‐withdrawing groups. It was found that TTMS (tris(trimethylsilyl)silane) served nicely as both the H‐atom donor and the electron donor in the catalytic cycle. Experimental and DFT computational results provided evidence that RCF₂ (R=H, Ph, Me) radicals are nucleophilic in nature.