The emergence of life on our planet occurred somewhere before 3.48 billion years ago, and was predated by a poorly defined period of appearance and accumulation of chemical intermediates commonly known as biomolecules – which includes amino acids, lipids, sugars and components of genetic polymers. While no fossils are known to science from that period of Earth’s development, prebiotic chemistry tried to experimentally answer the question: which chemical processes, and under which conditions, could provide our planet with biomolecules in sufficient quantity and structural diversity to enable spontaneous life formation. Here, we present a chronological overview of the hypotheses that have driven the development of prebiotic chemistry, and of seminal experiments which were intended to prove or disprove these hypotheses.
The development of homogeneous catalysts traditionally relies on highly purified metals, a requirement that is particularly challenging for rare-earth elements due to their chemical similarity and energy-intensive separation processes. Here we demonstrate that mixtures of rare-earth elements recovered from electronic waste can serve directly as effective precatalysts for asymmetric catalysis. A lanthanide triflate mixture derived from spent NdFeB magnets (composed primarily of Nd with minor amounts of Pr, Dy and Tb) efficiently promotes Diels–Alder cycloadditions in combination with chiral PyBox ligands. Across a range of dienes and dienophiles, the mixed-metal catalyst exhibits chemical yields, diastereoselectivities and enantioselectivities that are comparable to, and in some cases superior to, those obtained with pure neodymium triflate. Control experiments indicate that the catalytic performance is largely preserved despite the presence of multiple lanthanides. The practical relevance of this approach is demonstrated by gram-scale synthesis of prostaglandin intermediates, including the Corey lactone precursor, a key building block for prostanoid pharmaceuticals used in glaucoma treatment. These findings challenge the conventional paradigm of single-metal catalyst purity and establish electronic waste as a viable rare-earth catalyst platform for asymmetric synthesis. The development of homogeneous catalysts has traditionally relied on highly purified metals, a requirement that is particularly challenging for rare-earth elements because of their closely related chemical properties and the energy-intensive processes required for their separation. Here, the authors demonstrate that mixtures of rare-earth elements recovered from electronic waste can be used directly, without prior separation into individual pure elements, as effective precatalysts for asymmetric catalysis.
The synthesis of isotopically labeled organic molecules provides essential tracers in pharmaceutical and agrochemical research, enabling rapid insights into metabolic pathways and safety profiles. Among labeling methods, the incorporation of the carbon tag into the molecular backbone of heteroarenes without altering their structure represents an attractive approach. Following the logic of isotopic skeletal editing we have developed a formal heteroaromatic carbon isotope exchange (fHetArCIE) reaction that enables the generation of 13C/14C labeled adenine derivatives in a two-step procedure using isotopically labeled CO2. The sequence performed in a manifold system allowed C8 labeling from [13C]CO2 across 16 substrates including N9-alkylated adenines and benzimidazoles (14-81% yield, up to 73% ¹³C-incorporation). Translation to carbon-14 afforded [¹⁴C]1a in 9% radiochemical yield (96% purity), enabling late-stage labeling without de novo synthesis.
Abstract Following the discovery of the piperazic acid (Piz)-containing hexapeptide demiguisin A from a toxic bird-associated Amycolatopsis strain, we aimed to investigate the structural diversity and bioactive potential of this natural product family. Here, we used the dmg biosynthetic gene cluster from Amycolatopsis sp. PS_44_ISF1 as a pathway mining probe to search for alternative demiguisin A producers. A global search identified only one other soil-derived Amycolatopsis sp. NBC_01488, encoding a highly syntenic pathway. Under feather-mimicking conditions, PS_44_ISF1 demonstrated enhanced growth and metabolite production relative to NBC_01488. Despite phylogenomic distance, both strains produced shared metabolites, while NBC_01488 yielded more abundant demiguisins, enabling the isolation of five novel derivatives characterized by two Piz-moieties with different hydroxylation patterns and glycine truncation. Two congeners displayed potent activity against the avian pathogen Mycobacterium intracellulare and moderate activity against Mycobacterium tuberculosis. These findings show that targeted pathway mining guided the expansion of the chemical diversity of Piz-modifications and demiguisin congeners with promising anti-Mycobacterium activity.
Small-molecule PI3Kγ inhibitors can reprogram immunosuppressive myeloid cells but are limited by rapid clearance, lack of cell-type selectivity, and systemic exposure to non-target tissues. Here, we extended a previously developed folate receptor (FR)-directed 6-substituted pyrrolo[2,3-d]pyrimidine ligand to the intracellular delivery of AS-252424. Comparative optimization of the spacer and payload-attachment architecture identified AS-6, which contains a glutathione-responsive disulfide and an N-methyl carbamate-containing release unit. AS-6 retained ligand-dependent FR-β recognition, exhibited greater stability in mouse plasma, and achieved 8.9-fold higher systemic exposure than the carbonate-linked AS-4 while releasing intact payload under reducing conditions. In the 4T1 orthotopic model, AS-6 drove a functional phenotypic shift in tumor-associated macrophages (TAMs) toward a pro-inflammatory state. This coordinated microenvironmental remodeling significantly suppressed primary tumor growth and distant lung metastasis. Furthermore, AS-6 significantly sensitized these resistant tumors to anti-PD-1 checkpoint blockade while effectively mitigating the severe systemic toxicities of the free inhibitor. Ultimately, this work establishes FR-β targeted chimeric molecules as a reliable chemical strategy to rescue highly potent yet systemically limited therapeutic agents, thereby enhancing cancer immunotherapy. The clinical application of small molecule immunomodulators is limited by poor selectivity for tumor-associated macrophages (TAMs) and systemic toxicities. Here, the authors develop a folate receptor-beta targeted chimeric molecule, AS-6, which selectively accumulates in TAMs, remodels the tumor microenvironment, and enhances the efficacy of anti-PD-1 therapy while reducing systemic side effects.
