The amount of research activity concerning alpha-methylene-gamma-butyrolactones and alpha-alkylidene-gamma-butyrolactones has increased dramatically in recent years. This Review summarizes the structural types, biological activities, and biosynthesis of these compounds, concentrating on publications from the past 10 years. Traditional approaches to alpha-methylene-gamma-butyrolactones and alpha-alkylidene-gamma-butyrolactones are then reviewed together with novel approaches, including those from our own research group, reported more recently.

Natural products have been fundamental in the development of new therapeutic agents predicated on the inhibition of heat shock protein 90 (Hsp90). This Perspective describes the influential role of the benzoquinone ansamycin geldanamycin and the resorcylic acid macrolactone radicicol not only in driving forward drug discovery programs but also in inspiring organic chemists to develop innovative methodology for the synthesis of natural products and analogues with improved properties.

The benzoquinone ansamycin geldanamycin and its derivatives are inhibitors of heat shock protein Hsp90, an emerging target for novel therapeutic agents both in cancer and in neurodegeneration. However, toxicity of these compounds to normal cells has been ascribed to reaction with thiol nucleophiles at the quinone 19-position. We reasoned that blocking this position would ameliorate toxicity, and that it might also enforce a favourable conformational switch of the trans-amide group into the cis-form required for protein binding. We report here an efficient synthesis of such 19-substituted compounds and realization of our hypotheses. Protein crystallography established that the new compounds bind to Hsp90 with, as expected, a cis-amide conformation. Studies on Hsp90 inhibition in cells demonstrated the molecular signature of Hsp90 inhibitors: decreases in client proteins with compensatory increases in other heat shock proteins in both human breast cancer and dopaminergic neural cells, demonstrating their potential for use in the therapy of cancer or neurodegenerative diseases.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Employers of chemistry graduates are seeking a range of transferable skills from prospective employees, and academics are increasingly seeking to build employability skill development opportunities into the undergraduate curriculum. However, research suggests that undergraduates do not recognise or value such skill development without prompting. This recognition is essential if graduates are to be able to articulate their skills in the employment process. This study involves research amongst almost 1000 undergraduates studying chemistry at two institutions, using open-ended questions to collect qualitative data. The extent to which students recognised course-related skills development and understood the skills that employers are looking for was investigated, as was their desire to develop additional skills. Similarities and differences in student views between institutions are discussed, as well as trends across year levels and by gender. Results indicate that undergraduates studying chemistry are most likely to value and recognise development of some key skills sought by employers (teamwork, communication, thinking/problem solving, organisation/time management and laboratory/practical skills), but are very unlikely to value or recognise others (numeracy, independent learning, commercial awareness, interpersonal, research, computer/IT, creativity/innovation, flexibility/adaptability and initiative). Opportunities to develop the latter skills and recognition of the value of doing so will require improved communication with students and/or provision of new experiences within the curriculum.

The aims of teaching laboratories is an important and ever-evolving topic of discussion amongst teaching staff at teaching institutions. It is often assumed that both teaching staff and students are implicitly aware of these aims, although this is rarely tested or measured. This assumption can lead to mismatched beliefs between students and teaching staff and, if not corrected for, could lead to negative learning gains for students and become a source of frustration for teaching staff. In order to measure and identify this gap in a manner that could be readily generalised to other institutions, a single open question – ‘What do you think the aims of doing a practical chemistry course are?’ – was distributed to students and teaching staff at two Australian universities and one UK university. Qualitative analysis of the responses revealed that students and teaching staff held relatively narrow views of teaching laboratories, particularly focusing on aims more in line with expository experiences (e.g. development of practical skills or enhances understanding of theory). Whilst some differences were noted between students at the three institutions, the large amount of similarities in their responses indicated a fairly common perception of laboratory aims. Of the three groups, academics actually held the narrowest view of teaching laboratories, typically neglecting the preparation of students for the workforce or the simple increase in laboratory experience the students could gain. This study highlights gaps between the perceptions of students and teaching staff with regards to laboratory aims alongside revealing that all three groups held relatively simplified views of teaching laboratories.

Although having shown signs of closing in recent years, the Black attainment gap in UK Higher Education continues to be significant and, as such, has received considerable attention in the literature, media, and government. The reasons behind the attainment gap are complex, requiring further research in the area. On observing a possible trend in Black students’ lower attendance, the following research questions were postulated: Is there any evidence to suggest that Black students are overrepresented among those students who have a low attendance track record? If so, what are the reasons to explain this overrepresentation, and how can this be addressed? Quantitative attendance data analysis suggested that at one department Black students were indeed more likely to disengage from their course than non-Black students. With limited prior studies, particularly within STEM subjects, the exploration of Black students’ experiences in STEM departments at two UK universities of differing student ethnicity demographic, but similar staff ethnicity demographic, is reported herein, using a methodology that has not been used in STEM within higher education to our knowledge. The results reveal that Black students often do not feel represented or welcome at university, frequently turning to their university societies rather than their department/school for support where they feel more able to relate to others of similar ethnicity and discuss their experiences. Furthermore, they may benefit from a greater diversity of teaching and assessment approaches than is currently on offer, moving away from traditional lectures and with a greater emphasis on small group teaching. While some minor differences were observed between the students’ experiences at institutions of differing student ethnicity demographic, the findings show that the lack of representation in the staff body, the use of “traditional” teaching approaches ,and the practice of “spreading” Black (and other minority ethnic) students evenly across small teaching groups are very likely having a detrimental effect, with the knock-on consequences of reduced attendance, course engagement, and attainment.

A short formal total synthesis of the marine natural product diazonamide A is described. The route is based on indole oxidative rearrangement, and a number of options were investigated involving migration of tyrosine or oxazole fragments upon oxidation of open chain or macrocyclic precursors. The final route proceeds from 7-bromoindole by sequential palladium-catalysed couplings of an oxazole fragment at C-2, followed by a tyrosine fragment at C-3. With the key 2,3-disubstituted indole readily in hand, formation of a macrocyclic lactam set the stage for the crucial oxidative rearrangement to a 3,3-disubstituted oxindole. Notwithstanding the concomitant formation of the unwanted indoxyl isomer, the synthesis successfully delivered, after deprotection, the key oxindole intermediate, thereby completing a formal total synthesis of diazonamide A.