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

Phase 2 of CATALISE: a multinational and multidisciplinary Delphi consensus study of problems with language development: Terminology

BACKGROUND: Lack of agreement about criteria and terminology for children's language problems affects access to services as well as hindering research and practice. We report the second phase of a study using an online Delphi method to address these issues. In the first phase, we focused on criteria for language disorder. Here we consider terminology. METHODS: The Delphi method is an iterative process in which an initial set of statements is rated by a panel of experts, who then have the opportunity to view anonymised ratings from other panel members. On this basis they can either revise their views or make a case for their position. The statements are then revised based on panel feedback, and again rated by and commented on by the panel. In this study, feedback from a second round was used to prepare a final set of statements in narrative form. The panel included 57 individuals representing a range of professions and nationalities. RESULTS: We achieved at least 78% agreement for 19 of 21 statements within two rounds of ratings. These were collapsed into 12 statements for the final consensus reported here. The term ‘Language Disorder’ is recommended to refer to a profile of difficulties that causes functional impairment in everyday life and is associated with poor prognosis. The term, ‘Developmental Language Disorder’ (DLD) was endorsed for use when the language disorder was not associated with a known biomedical aetiology. It was also agreed that (a) presence of risk factors (neurobiological or environmental) does not preclude a diagnosis of DLD, (b) DLD can co-occur with other neurodevelopmental disorders (e.g. ADHD) and (c) DLD does not require a mismatch between verbal and nonverbal ability. CONCLUSIONS: This Delphi exercise highlights reasons for disagreements about terminology for language disorders and proposes standard definitions and nomenclature

Acceptability of healthcare interventions : an overview of reviews and development of a theoretical framework

Abstract Background It is increasingly acknowledged that \u2018acceptability\u2019 should be considered when designing, evaluating and implementing healthcare interventions. However, the published literature offers little guidance on how to define or assess acceptability. The purpose of this study was to develop a multi-construct theoretical framework of acceptability of healthcare interventions that can be applied to assess prospective (i.e. anticipated) and retrospective (i.e. experienced) acceptability from the perspective of intervention delivers and recipients. Methods Two methods were used to select the component constructs of acceptability. 1) An overview of reviews was conducted to identify systematic reviews that claim to define, theorise or measure acceptability of healthcare interventions. 2) Principles of inductive and deductive reasoning were applied to theorise the concept of acceptability and develop a theoretical framework. Steps included (1) defining acceptability; (2) describing its properties and scope and (3) identifying component constructs and empirical indicators. Results From the 43 reviews included in the overview, none explicitly theorised or defined acceptability. Measures used to assess acceptability focused on behaviour (e.g. dropout rates) (23 reviews), affect (i.e. feelings) (5 reviews), cognition (i.e. perceptions) (7 reviews) or a combination of these (8 reviews). From the methods described above we propose a definition: Acceptability is a multi-faceted construct that reflects the extent to which people delivering or receiving a healthcare intervention consider it to be appropriate, based on anticipated or experienced cognitive and emotional responses to the intervention. The theoretical framework of acceptability (TFA) consists of seven component constructs: affective attitude, burden, perceived effectiveness, ethicality, intervention coherence, opportunity costs, and self-efficacy. Conclusion Despite frequent claims that healthcare interventions have assessed acceptability, it is evident that acceptability research could be more robust. The proposed definition of acceptability and the TFA can inform assessment tools and evaluations of the acceptability of new or existing interventions

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