Stereoselective alkylation of saturated heterocycles
Related Articles
Abundant ammonia and nitrogen-rich soluble organic matter in samples from asteroid (101955) Bennu
Organic matter in meteorites reveals clues about early Solar System chemistry and the origin of molecules important to life, but terrestrial exposure complicates interpretation. Samples returned from the B-type asteroid Bennu by the Origins, Spectral Interpretation, Resource Identification, and Security–Regolith Explorer mission enabled us to study pristine carbonaceous astromaterial without uncontrolled exposure to Earth’s biosphere. Here we show that Bennu samples are volatile rich, with more carbon, nitrogen and ammonia than samples from asteroid Ryugu and most meteorites. Nitrogen-15 isotopic enrichments indicate that ammonia and other N-containing soluble molecules formed in a cold molecular cloud or the outer protoplanetary disk. We detected amino acids (including 14 of the 20 used in terrestrial biology), amines, formaldehyde, carboxylic acids, polycyclic aromatic hydrocarbons and N-heterocycles (including all five nucleobases found in DNA and RNA), along with ~10,000 N-bearing chemical species. All chiral non-protein amino acids were racemic or nearly so, implying that terrestrial life’s left-handed chirality may not be due to bias in prebiotic molecules delivered by impacts. The relative abundances of amino acids and other soluble organics suggest formation and alteration by low-temperature reactions, possibly in NH3-rich fluids. Bennu’s parent asteroid developed in or accreted ices from a reservoir in the outer Solar System where ammonia ice was stable.
Site-specific activation of the proton pump inhibitor rabeprazole by tetrathiolate zinc centres
Proton pump inhibitors have become top-selling drugs worldwide. Serendipitously discovered as prodrugs that are activated by protonation in acidic environments, proton pump inhibitors inhibit stomach acid secretion by covalently modifying the gastric proton pump. Despite their widespread use, alternative activation mechanisms and potential target proteins in non-acidic environments remain poorly understood. Employing a chemoproteomic approach, we found that the proton pump inhibitor rabeprazole selectively forms covalent conjugates with zinc-binding proteins. Focusing on DENR, a protein with a C4 zinc cluster (that is, zinc coordinated by four cysteines), we show that rabeprazole is activated by the zinc ion and subsequently conjugated to zinc-coordinating cysteines. Our results suggest that drug binding, activation and conjugation take place rapidly within the zinc coordination sphere. Finally, we provide evidence that other proton pump inhibitors can be activated in the same way. We conclude that zinc acts as a Lewis acid, obviating the need for low pH, to promote the activation and conjugation of proton pump inhibitors in non-acidic environments.
Directed synthesis of N1/N3-histidine modified by 2-hydroxyethylthioethyl and identification in sulfur mustard-exposed plasma
Sulfur mustard (HD) alkylates biomolecules such as proteins, generating specific biomarkers. This study employs steric hindrance, electronic effects, and solvent effects through an occupancy-removal strategy to synthesize regioisomers [N1-HETE]-His and [N3-HETE]-His, overcoming isomer separation challenges in conventional methods. Density functional theory (DFT) calculations revealed hexafluoroisopropanol (HFIP)’s critical role in directing HD’s regioselective alkylation: HFIP modulates steric and electronic environments to preferentially target N1 or N3 sites of histidine imidazole rings, with predictions validated experimentally. The method further enables selective detection of the isomers in HD-contaminated plasma via standard addition, advancing absolute quantification. This work not only establishes a precision synthesis platform for biomarkers but also elucidates HFIP’s unique role in imidazole regioselectivity, offering insights for medicinal chemistry and HD toxicology. These findings hold implications for HD exposure tracking, mechanism analysis, clinical diagnostics, and antidote development.
A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours
Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8+ T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (Elovl1) as a metabolic target to sustain effector functions and memory phenotypes in CD8+ T cells. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. Elovl1-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, ELOVL1 in CD8+ T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, Elovl1 targeting synergizes with anti-PD-1 to promote effective T cell responses.
Direct stereoselective C(sp3)–H alkylation of saturated heterocycles using olefins
Despite cross-coupling strategies that enable the functionalization of aromatic heterocycles, the enantioselective C(sp3)–H alkylation of readily available saturated hydrocarbons to construct C(sp3)–C(sp3) bonds remains a formidable challenge. Here we describe a nickel-catalysed enantioselective C(sp3)–H alkylation of saturated heterocycles using olefins, providing an efficient strategy for the stereoselective construction of C(sp3)–C(sp3) bonds. Using readily available and stable olefins and simple saturated nitrogen and oxygen heterocycles as prochiral nucleophiles, the coupling reactions proceed under mild conditions and exhibit broad scope and high functional group tolerance. Furthermore, the enantio- and diastereoselective C(sp3)–H alkylation of saturated hydrocarbons with alkenyl boronates has been achieved, enabling the synthesis of versatile alkyl boronates containing 1,2-adjacent C(sp3) stereocentres. Application of this approach to the late-stage modification of natural products and drugs, as well as to the enantioselective synthesis of a range of chiral building blocks and natural products, is demonstrated.
Responses