Chemistry of organometallic nucleic acid components: personal perspectives and prospects for the future

Abstract

Organometallic modifications of biologically important compounds such as drugs, secondary natural products, peptides, and nucleic acids, to name just a few, represent a well-established strategy for the development of new anticancer and antimicrobial agents. Supported by these reasons, over 12 years ago, we initiated a research program into organometallic modifications of nucleic acid components. This account summarizes key results regarding the synthetic chemistry and biological activities of the obtained compounds. As synthetic chemists, our main goal over the last 12 years has been to develop new strategies that allow for the exploration of the chemical space of organometallic nucleic acid components. Accordingly, we have developed a Michael addition reaction-based methodology that enabled the synthesis of an entirely new class of glycol nucleic acid (GNA) constituents. Concerning GNA chemistry, we also reported the synthesis of the first-ever ferrocenyl GNA-RNA “mixed” dinucleoside phosphate analog. Recently, we developed a Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction-based approach for the synthesis of novel 1,2,3-triazole-linked (“click”) nucleosides. The high value of this approach is because it allows for the introduction of functional (e.g., luminescent and redox-active) groups that protrude from the main oligomer sequence. With respect to biological activity studies, we identified several promising anticancer and antimicrobial compounds. Furthermore, we found that simple ferrocenyl-nucleobase conjugates have potential as modulators of Aβ_21–40 amyloid aggregation. The final section of this article serves as a guide for future studies, as it presents some challenging goals yet to be achieved within the rapidly growing field of nucleic acid chemistry.