P-Stereogenic C ₂ diphosphine ligands with a hydrazine backbone are reported. The ligands exist as a mixture of atropo- and nitrogen inversion isomers in slow exchange.

The ability of oligonucleotides to silence specific genes or inhibit the biological activity of specific proteins has generated great interest in their use as research tools and therapeutic agents. Unfortunately, their biological applications meet the limitation of their poor cellular accessibility. Developing an appropriate delivery system for oligonucleotides is essential to achieve their efficient cellular uptake. In the present work a series of phosphorothioate lipid-oligonucleotide hybrids were synthesized introducing covalently single or double lipid tails at both 3'- and 5'-termini of an antisense oligonucleotide. Gene transfections in cultured cells showed antisense luciferase inhibition without the use of a transfecting agent for conjugates modified with the double-lipid tail at 5'-termini. The effect of the double lipid-tailed modification was further studied in detail in several model membrane systems as well as in cellular uptake experiments. During these studies the spontaneous formation of self-assembled microstructures is clearly observed. Lipidation allowed the efficient incorporation of the oligonucleotide in HeLa cells by a macropinocytosis mechanism without causing cytotoxicity in cells or altering the binding properties of the oligonucleotide conjugates. In addition, both single- and double-tailed compounds showed a similar behavior in lipid model membranes, making them useful in nucleotide-based technologies.

Translation of genetic information into peptide products is one of the fundamental processes of biology. How this occurred prebiotically, in the absence of enzyme catalysts, is an intriguing question. Nucleic acid-templated synthesis (NATS) promotes reactions by bringing building blocks tethered to complementary DNA strands into close proximity and has been shown to enable peptide synthesis without enzymes—it could therefore serve as a model for prebiotic translation of information stored in nucleic acid sequences into functional peptides. The decomposition of highly reactive DNA adapters has so far limited the effectiveness of NATS, but these studies have been performed exclusively in aqueous solution. Deep eutectic solvents (DESs) have been proposed as a feasible solvent for prebiotic replication of nucleic acids, and here are studied as media for prebiotic translation using NATS as a model. DESs are shown to enhance the stability of DNA-conjugated activated esters, the precursors of peptides. However, this enhanced stability was coupled with decreased amine reactivity that hampered the formation of peptide bonds in DESs. These properties are exploited to demonstrate the storage of DNA-conjugated activated esters in a DES followed by transfer into aqueous buffer to activate the NATS of peptides “on demand.” These findings, together with the reported functions of DESs in prebiotic processes, shed light on how DESs could have facilitated the non-enzymatic translation of genetic information into functional peptides on the early Earth.

The selectivity of nucleic acid hybridisation can be exploited to template chemical reactions, enabling materials discovery by chemical evolution. However, to date the range of reactions that can be used has been limited to those that are compatible with aqueous media, since the addition of organic co-solvents can have a large impact on the stability of nucleic acid duplexes. Peptide nucleic acids (PNAs) are promising in this regard because previous studies have suggested they may be stable as duplexes in high organic content solvent mixtures. Here, we use micro-differential scanning calorimetry (micro-DSC) to confirm for the first time that double-stranded PNA (dsPNA) is stable in N,N-dimethylformamide (DMF)/water mixtures up to 95 vol% DMF. Using fluorescence, we corroborate these results and show that the isothermal annealing of PNA in high DMF content solution is also rapid. These findings suggest that PNA could enable the use of a range of water-sensitive chemistries in nucleic acid templating applications.

The synthesis of artificial sequence‐defined polymers that match and extend the functionality of proteins is an important goal in materials science. One way of achieving this is to program a sequence of chemical reactions between precursor building blocks by means of attached oligonucleotide adapters. However, hydrolysis of the reactive building blocks has so far limited the length and yield of product that can be obtained using DNA‐templated reactions. Here, we report an architecture for DNA‐templated synthesis in which reactants are tethered at internal abasic sites on opposite strands of a DNA duplex. We show that an abasic site within a DNA duplex can protect a nearby thioester from degradation, significantly increasing the yield of a DNA‐templated reaction. This protective effect has the potential to overcome the challenges associated with programmable, sequence‐controlled synthesis of long non‐natural polymers by extending the lifetime of the reactive building blocks.

The synthesis of artificial sequence‐defined polymers that match and extend the functionality of proteins is an important goal in materials science. One way of achieving this is to program a sequence of chemical reactions between precursor building blocks by means of attached oligonucleotide adapters. However, hydrolysis of the reactive building blocks has so far limited the length and yield of product that can be obtained using DNA‐templated reactions. Here, we report an architecture for DNA‐templated synthesis in which reactants are tethered at internal abasic sites on opposite strands of a DNA duplex. We show that an abasic site within a DNA duplex can protect a nearby thioester from degradation, significantly increasing the yield of a DNA‐templated reaction. This protective effect has the potential to overcome the challenges associated with programmable, sequence‐controlled synthesis of long non‐natural polymers by extending the lifetime of the reactive building blocks.