Nucleic acid chemical stability

Freier SM, Altmarm K-H (1997) The ups and downs of nucleic acid duplex stability structure-stability studies on chemically-modified DNA RNA duplexes. Nucleic Acids Res 25 4429 443... 

Recent developments in drug discovery and drug development spurred the need for novel analytical techniques and methods. In the last decade, the biopharmaceutical industry set the pace for this demand. The nature of the industry required that novel techniques should be simple, easily applicable, and of high resolution and sensitivity. It was also required that the techniques give information about the composition, structure, purity, and stability of drug candidates. Biopharmaceuticals represent a wide variety of chemically different compounds, including small organic molecules, nucleic acids and their derivatives, and peptides and proteins. 

In 2004, Rayner and coworkers reported a dynamic system for stabilizing nucleic acid duplexes by covalently appending small molecules [34]. These experiments started with a system in which 2-amino-2 -deoxyuridine (U-NH ) was site-specifically incorporated into nucleic acid strands via chemical synthesis. In the first example, U-NH was incorporated at the 3 end of the self-complementary U(-NH2)GCGCA DNA. This reactive amine-functionalized uridine was then allowed to undergo imine formation with a series of aldehydes (Ra-Rc), and aldehyde appendages that stabilize the DNA preferentially formed in the dynamic system. Upon equilibration and analysis, it was found that the double-stranded DNA modified with nalidixic aldehyde Rc at both U-NH positions was amplified 34% at the expense of Ra and Rb (Fig. 3.16). The Rc-appended DNA stabilizing modification corresponded to a 33% increase in (melting temperature). Furthermore, imine reduction of the stabilized DNA complex with NaCNBH, resulted in a 57% increase in T. ... 

Pogocki D, Schoenich C. Chemical stability of nucleic acid-derived drugs. J Pharm Sci 2000 89(4) 443 456. 

Metal ions are usually required to promote and stabilize functionally active or native conformations of nucleic acids, as well as to mediate nucleic acid-protein interactions. However, metal ions can also cause structural transformation of nncleic acids, or denature their native structures. In addition to structural roles, some metal compounds can indnce cleavage (i.e. scission, fragmentation, or depolymerization) and modification (withont cleavage) of nucleic acids. Metal-nucleic acid interactions can be either nonspecific or dependent on the chemical nature of nucleotide residues, nucleic acid sequence, or secondary and/or tertiary structure of nucleic acids. The specificity of these interactions is dependent... 

Recent reports indicate that divalent transition metal ions, such as Cu +, forming links between two artificial hydroxypyridone nucleobases can efficiently replace the hydrogen bonding between natural nucleobases, A-T and G-C, in oligonucleotides. Such artificial metal-mediated base pairs results in a moderate increase in the thermal stability of the duplex. They could lead to nucleic acid materials with novel chemical and physical properties. Such ohgonucleotide derivatives are of interest for the design of biosensors, nanomolecular wires, and switches. 

Another obvious requirement of a nonaqueous solvent is chemical stability under a variety of conditions. Thus, methanol, especially after standing in the presence of air, may contain small amounts of formaldehyde which can react with groups on proteins and nucleic acids. Forma-mide, A, A-dimethylformamide, and related compounds, are slowly decomposed by acid or base in the solvent, and the possibility exists that such decomposition may be catalyzed to some extent by a protein dissolved in the solvent. Thus Rees and Singer (1956) found that the apparent osmotic pressure of a solution of insulin in lV,A -dimethylformamide continually increased over a period of a week at 25°C but reached equilibrium at 13.8°C, which might have been due to the slow decomposition of the solvent on the solution side of the osmotic membrane at the higher temperature. 

---