Organometallic nucleoside analogues: effect of hydroxyalkyl linker length on cancer cell line toxicity

A new series of chiral ferrocene derivatives containing both a hydroxyalkyl group and a thyminyl group on one cyclopentadienyl ring have been synthesised to probe structure–activity relationships in cancer cell line cytotoxicities. The stereoisomers of enantiomeric pairs of these so-called ferronucleosides have been studied and characterised by a combination of chiral analytical HPLC and single-crystal X-ray diffraction. Biological activity studies revealed that changing the length of the hydroxyalkyl group had marked effects on IC50 values, with compounds having shorter arms that more closely resemble endogenous nucleosides exhibiting lower cytotoxicities. The lipophilicities and electrochemical properties of this compound series have been studied to rationalise these trends and indicate future directions of study

Synthesis of ferrocene nucleic acid monomers and ferrocene containing drug candidates

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

Synthesis of ferrocene nucleic acid monomers and ferrocene containing drug candidates

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

Molecular boronic acid-based saccharide sensors

Boronic acids can reversibly bind diols, a molecular feature that is ubiquitous within saccharides, leading to their use in the design and implementation of sensors for numerous saccharide species. There is a growing understanding of the importance of saccharides in many biological processes and systems; while saccharide or carbohydrate sensing in medicine is most often associated with detection of glucose in diabetes patients, saccharides have proven to be relevant in a range of disease states. Herein the relevance of carbohydrate sensing for biomedical applications is explored, and this review seeks to outline how the complexity of saccharides presents a challenge for the development of selective sensors and describes efforts that have been made to understand the underpinning fluorescence and binding mechanisms of these systems, before outlining examples of how researchers have used this knowledge to develop ever more selective receptors