Cover picture: Microscope image of unfunctionalised polystyrene resin taken using a FTIR microscope.

Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. MTH1 is one of the "housekeeping" enzymes that are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal and chemically distinct tool compounds to those published in the literature to allow us to test the hypothesis that inhibition of MTH1 has wide applicability in the treatment of cancer. Here we present the work that led to the discovery of three structurally different series of MTH1 inhibitors with excellent potency, selectivity, and proven target engagement in cells. None of these compounds elicited the reported cellular phenotype, and additional siRNA and CRISPR experiments further support these observations. Critically, the difference between the responses of our highly selective inhibitors and published tool compounds suggests that the effect reported for the latter may be due to off-target cytotoxic effects. As a result, we conclude that the role of MTH1 in carcinogenesis and utility of its inhibition is yet to be established.

The relation between congenital heart block and maternal connective-tissue disease was studied by antibody screening of serum samples obtained in connection with 45 cases of isolated congenital complete heart block. Serum was available from 41 mothers (17 who had connective-tissue disease and 24 who were healthy) and 21 children. Thirty-four mothers had antibody to a soluble tissue ribonucleoprotein antigen called Ro(SS-A), which was identified by immunodiffusion. Anti-Ro(SS-A) was found in seven of eight serum samples collected from affected children when they were less than three months old but in none of 13 samples obtained when these children were older. It appears that maternal anti-Ro(SS-A) antibody crosses the placenta and is a marker for risk of congenital complete heart block; its absence from maternal serum suggests that a child is unlikely to be affected. Anti-Ro(SS-A) or a related antibody is probably involved in the pathogenesis of congenital complete heart block.

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Conventional approaches to Pd-catalyzed alkene 1,2-carboamination rely upon the combination of a nucleophilic nitrogen-based component and an internal C-based or external oxidant. In this study, we outline an umpolung approach, which is triggered by oxidative initiation at an electrophilic N-based component and employs "standard" organometallic nucleophiles to introduce the new carbon-based fragment. Specifically, oxidative addition of a Pd(0)-catalyst into the N-O bond of O-pentafluorobenzoyl oxime esters generates imino-Pd(II) intermediates, which undergo 5-exo cyclization with sterically diverse alkenes. The resultant alkyl-Pd(II) intermediates are intercepted by organometallic nucleophiles or alcohols, under carbonylative or noncarbonylative conditions, to provide 1,2-carboamination products. This approach provides, for the first time, a unified strategy for achieving alkene 1,2-amino-acylation, -carboxylation, -arylation, -vinylation, and -alkynylation. For carbonylative processes, orchestrated protodecarboxylation of the pentafluorobenzoate leaving group underpins reaction efficiency. This process is likely a key feature in related Narasaka-Heck cyclizations and accounts for the efficacy of O-pentafluorobenzoyl oxime esters in aza-Heck reactions of this type.

Optimization of compound lipophilicity is a key aspect of drug discovery. The aim of this work was to compare the lipophilicity modulations induced by 16 distinct known and novel fluoroalkyl motifs on three parent models. Fifty fluorinated compounds, with 28 novel experimental aliphatic logP values, are involved in discussing various lipophilicity trends. As well as confirming known trends, a number of novel lipophilicity reducing motifs are introduced. Tactics to reduce lipophilicity are discussed, such as "motif extensions" and "motif rearrangements", including with concomitant extension of the carbon chain, as well as one-

1. Metabolic changes associated with Ramadan fasting were studied in eleven Asian pregnant mothers. This was compared with a group of control mothers undergoing a normal physiological fast.2. At the end of the Ramadan fast day there was a significant fall in glucose, insulin, lactate and carnitine, and a rise in triglyceride, non-esterified fatty acid and 3-hydroxybutyrate. When compared with the control group, none of the Ramadan mothers had a completely normal set of biochemical values at the end of the fast day.3. Pregnancy outcome in the two groups was comparable. 4. We are wary of the metabolic departures from normal observed in the Ramadan fasting mothers. If asked we advise mothers to take up the dispensation from fasting during pregnancy which is allowed.An important aspect of the Muslim religion is the fast of Rosa during Ramadan. During Ramadan all healthy adults are obliged to fast from sunrise to sunset. The length of the fast therefore depends on the exact time of sunrise and sunset in the country where the person lives. The duration of the fast in temperate climates such as Britain averages about 18 h/d when Ramadan occurs during the spring and summer. This is dependent on the exact time of sunrise and sunset, but is approximately observed between 02.30 and 19.30 hours here. Pregnant women are allowed to postpone their fast until after delivery, but about three quarters of mothers attending this hospital continue to observe it for various reasons (Eaton & Wharton, 1982), for example, convenience when eating as a family, and social pressures. However, they often ask about the possible harmful effects of fasting both to themselves and their babies.Although there is some evidence of metabolic stress in Ramadan (Prentice et al. 1983), the work was carried out in the deprived conditions of the tropics where the prevalence of endemic malnutrition, tropical infection and drought may have compounded the effect of fasting during pregnancy. The better environmental conditions of the Muslim population in Britain provides an opportunity to study the metabolic effect of Ramadan fasting without these complicating factors. Moreover, a previous study in Birmingham of nonpregnant Muslim diabetics (Barber et al. 1979) concluded that fasting was safe. This study was designed to determine the metabolic effects of Ramadan fasting during pregnancy in healthy mothers living in Britain. M E T H 0 D S PatientsAs part of a larger study of glucose metabolism in pregnancy all mothers booking at this hospital in time were invited to attend a clinic at 17 weeks and again at 28 weeks for a more detailed assessment than is usually possible in a routine antenatal clinic. Some of these mothers were selected to take part in this Ramadan study as follows.

Fluorination is commonly employed to optimize bioactivity and pharmaco-kinetic properties of drug candidates. Aliphatic fluorination often reduces the lipophilicity (log P), but polyfluoroalkylation typically increases lipophilicity. Hence, identification of polyfluorinated motifs that nonetheless lead to similar or even reduced lipophilicities is of interest to expand the arsenal of medicinal chemistry tools in tackling properties such as compound metabolic stability or off-target selectivity. We show that changing a CF 3 -group of a perfluoroalkyl chain to a methyl group leads to a drastic reduction in lipophilicity. We also show that changing a C−F bond of a trifluoromethyl group, including when incorporated as part of a perfluoroalkyl group, to a C−Me group, leads to a reduction in log P, despite the resulting chain elongation. The observed lipophilicity trends were identified in fluorinated alkanol models and reproduced when incorporated in analogues of a drug candidate, and the metabolic stability of these motifs was demonstrated.