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J.R. and G.A.B. thank GlaxoSmithKline (GSK) and the Engineering and Physical Sciences Research Council (EPSRC) for an industrial CASE studentship. MMA is supported by a studentship from the government of Libya, and MAU by a studentship from the Petroleum Technology Development Fund (PTDF), Abuja, Nigeria. A selective mono-N-arylation strategy of amidines under Chan-Lam conditions is described. During the reaction optimization phase, the isolation of a mononuclear Cu(II) complex provided unique mechanistic insight into the operation of Chan-Lam mono-N-arylation. The scope of the process is demonstrated, and then applied to access the first mono-N-arylated analogues of pentamidine. Sub-micromolar activity against kinetoplastid parasites was observed for several analogues with no cross-resistance in pentamidine and diminazene-resistant trypanosome strains and against Leishmania mexicana. A fluorescent mono-N-arylated pentamidine analogue revealed rapid cellular uptake, accumulating in parasite nuclei and the kinetoplasts. The DNA binding capability of the mono-N-arylated pentamidine series was confirmed by UV-melt measurements using AT-rich DNA. This work highlights the potential to use Chan-Lam mono-N-arylation to develop therapeutic leads against diamidine-resistant trypanosomiasis and leishmaniasis. Publisher PDF

Peptidomimetics designed to target voltage‐gated sodium channels have attracted significant attention as potential analgesics. However, voltage‐gated sodium channel (VGSC)‐blocking activity of these compounds has mainly been assessed using rat and/or mice homologs. In this study, we developed a novel series of conformationally constrained peptidomimetic analogues of the μ‐conotoxin KIIIA and assessed their activity against human VGSCs. Two of the mimetics block the currents of hNav1.4 and hNav1.6 channels. NMR derived structures of the mimetics provided excellent insight into the structural requirements for bioactivity. A lactam‐constrained analogue, previously reported to be active in mice, did not block the corresponding human VGSC. This work highlights important differences in VGSCs between species and validates the potential of peptidomimetics as human analgesics.

Modified peptides, such as stapled peptides, which replicate the structure of α-helical protein segments, represent a potential therapeutic advance. However, the 3D solution structure of these stapled peptides is rarely explored beyond the acquisition of circular dichroism (CD) data to quantify bulk peptide helicity; the detailed backbone structure, which underlies this, is typically undefined. Diastereomeric stapled peptides based on helical sections of three proteins (αSyn, Cks1 and CK1α) were generated; their overall helicity was quantified by CD; and the most helical peptide from each series was selected for structural analysis. Solution-phase models for the optimised peptides were generated using NMR-derived restraints and a modified CHARMM22 force field. Comparing these models with PDB structures allowed deviation between the stapled peptides and critical helical regions to be evaluated. These studies demonstrate that CD alone is not sufficient to assess the structural fidelity of a stapled peptide.

A range of 4-substituted prolines can be rapidly synthesized from a protected glycine Schiff base in only four steps and in 27-55% overall yield. Phase transfer catalysis allows direct access to both enantiomeric series, and the relative stereochemistry at the 4-position is readily controlled (>10:1 dr) through the choice of hydrogenation conditions.

A range of 4-substituted prolines can be rapidly synthesized from a protected glycine Schiff base in only four steps and in 27–55% overall yield. Phase transfer catalysis allows direct access to both enantiomeric series, and the relative stereochemistry at the 4-position is readily controlled (>10:1 dr) through the choice of hydrogenation conditions.

Summary A clinical examination of 1,675 children in three different locations in rural parts of Northern Rhodesia showed a high incidence of blindness and of other eye symptoms and skin changes generally ascribed to vitamin A deficiency. In order to verify this observation, plasmalevels of vitamin A and carotene were measured in 183 preschool and school children in these areas. Very low values of both vitamin A and carotene were found in a high proportion of unselected cases. It is our view, based on these observations, that lack of vitamin A is a significant health problem. It is thought to be a principal factor in the great number of eye diseases and blindness and is a factor in the poor general health status and in the high mortality rate (30 to 50 per cent) of these children by causing a lowered resistance to infectious diseases and parasitic infestations. Great improvements could accordingly beachieved by providing more carotene-containing foods in the diet such as red palm oil and by growing more vegetables rich in carotene. To change the diet and eating habits is not easy, but considerable success could be achieved by instruction of the children in the schools and by developing school gardens.