Synthesis of ferrocene nucleic acid monomers and ferrocene containing drug candidates

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Kedge, Jonathan L. (2017). Synthesis of ferrocene nucleic acid monomers and ferrocene containing drug candidates. University of Birmingham. Ph.D.

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Abstract

The first ferrocene nucleic acid (FcNA) was reported by the Tucker group in 2012. Furnished with two nucleobases and two hydroxyl groups, the tetrasubstituted metallocene assumes the position traditionally occupied by the two sugars of a dinucleotide. This thesis describes the successful synthesis of two FcNA monomers; a tetrasubstituted dithyminyl variation and a disubstituted control compound bearing no nucleobases. These monomers were oligomerised, their binding characteristics assessed by thermal melting studies, and compared to other monomers belonging to the group. Through the study of these compounds the Tucker group has demonstrated that FcNA monomers behave similarly to conventional nucleic acids, displaying selective H-bonding and π-stacking interactions within a hybrid duplex. A preliminary methodology for the production of diguaninyl FcNA monomers was also explored.

As published in 2014, the corresponding disubstituted systems, in which a hydroxyl and a nucleobase are linked through a sugar-like ferrocene unit, are also being investigated as potential nucleoside analogues. Adding to the groups growing library, a number of related compounds were synthesised in which the hydroxyl linker length, the planar chirality, the substitution pattern of the ferrocene and the nucleobase were varied. The compounds were electrochemically characterised and assessed for their biological activity which revealed interesting structure-activity-relationships involving both the redox potentials and chirality.

Following the example of ferroquine and ferrocifen, in which existing pharmaceuticals are modified through the incorporation of ferrocene, the synthesis and preliminary biological activity of novel ferrocenyl β-blockers, in which the metallocene replaces the napthol unit of the prototypical β-blocker propranolol, is reported herein.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):