A novel sequence-selective pyrrolobenzodiazepine (PBD) dimer 5 (SJG-136) has been developed that comprises two C2-exo-methylene-substituted DC-81 (3) subunits tethered through their C8 positions via an inert propanedioxy linker. This symmetric molecule is a highly efficient minor groove interstrand DNA cross-linking agent (XL(50) = 0.045 microM) that is 440-fold more potent than melphalan. Thermal denaturation studies show that, after 18 h incubation with calf thymus DNA at a 5:1 DNA/ligand ratio, it increases the T(m) value by 33.6 degrees C, the highest value so far recorded in this assay. The analogous dimer 4 (DSB-120) that lacks substitution/unsaturation at the C2 position elevates melting by only 15.1 degrees C under the same conditions, illustrating the effect of introducing C2-exo-unsaturation which serves to flatten the C-rings and achieve a superior isohelical fit within the DNA minor groove. This behavior is supported by molecular modeling studies which indicate that (i) the PBD units are covalently bonded to guanines on opposite strands to form a cross-link, (ii) 5 has a greater binding energy compared to 4, and (iii) 4 and 5 have equivalent binding sites that span six base pairs. Dimer 5 is significantly more cytotoxic than 4 in a number of human ovarian cancer cell lines (e.g., IC(50) values of 0.0225 nM vs 7.2 nM, respectively, in A2780 cells). Furthermore, it retains full potency in the cisplatin-resistant cell line A2780cisR (0.024 nM), whereas 4 loses activity (0.21 microM) with a resistance factor of 29.2. This may be due to a lower level of inactivation of 5 by intracellular thiol-containing molecules. A dilactam analogue (21) of 5 that lacks the electrophilic N10-C11/N10'-C11' imine moieties has also been synthesized and evaluated. Although unable to interact covalently with DNA, 21 still stabilizes the helix (Delta T(m) = 0.78 degrees C) and has significant cytotoxicity in some cell lines (i.e., IC(50) = 0.57 microM in CH1 cells), presumably exerting its effect through noncovalent interaction with DNA.

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Aim:The aim of this study was to explore what is known about food literacy programmes targeting adolescents, including identification of the constituents of food literacy addressed, assessment of programme effectiveness, and description of programme design or delivery specific to adolescents. Methods: A review of the peer-reviewed literature surrounding adolescent food literacy was conducted using scholarly electronic databases. Programme reports were identified in the grey literature using online searching and cross-referencing to support the research aim. Programmes from 2000 to 2012 targeting adolescents aged 13-17 years were included. Results: A total of 19 peer-reviewed papers and four grey literature programmes met the search criteria. Interventions focused on practical cooking and/or food preparation skills and targeted younger adolescent age groups. Programmes were most commonly held in schools and community settings. The majority of programmes (n = 16/23) did not use a theoretical basis for their development. Programme evaluation encompassed the use of pre-and post-intervention questionnaires and focus groups. Only nine studies included a dietary behaviour-based outcome measure. Although 19 of the 23 studies reviewed reported positive changes related to the intervention, these did not include significant changes in diet quality or cooking frequency at home. Conclusions: Few existing adolescent food literacy programmes have demonstrated a positive impact on dietary behaviours to date. Adolescent target groups present unique challenges in programme development and delivery. However, the physical, social and emotional health needs of this age group and potential to influence lifelong behaviours highlight the need to design effective and age-appropriate adolescent food literacy programmes.