The impact of macrocycle conformation on the taxadiene-forming carbocation cascade: insight gained from sobralene, a recently discovered verticillene isomer

This is an accepted manuscript of an article published by American Chemical Society in Journal of Organic Chemistry on 26/02/2020, available online: https://doi.org/10.1021/acs.joc.0c00369 The accepted version of the publication may differ from the final published version.Copyright © 2020 American Chemical Society. DFT calculations on the carbocation intermediates that connect the biosynthetic pathways leading to the sand fly pheromone sobralene and taxadiene have been made. Establishment of the conformation of the macrocyclic carbocation intermediate required to produce the (Z)-C8,C9 alkene bond in sobralene has identified new conformations of the verticillyl carbocation intermediates on the taxadiene biosynthetic pathway. These "sobralene-like" carbocation conformations provide an exothermic pathway to taxadiene and are validated by comparison to closely related structures (X-ray and NMR).The University of NottinghamPublished versio

Sidechain Diversification of Grandifloracin Allows Identification of Analogues with Enhanced Anti-Austerity Activity against Human PANC-1 Pancreatic Cancer Cells

© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. The natural product (+)-grandifloracin is a potent “anti-austerity” agent, able to suppress the ability of various pancreatic cancer cell lines to tolerate conditions of nutrient deprivation. Such anti-austerity agents represent a promising approach to cancer chemotherapy. Here we report the synthesis and biological evaluation of racemic analogues of grandifloracin bearing diverse sidechains, of which two show enhanced potency in comparison with the natural product. Additionally, several unexpected by-products containing modifications of the grandifloracin core were isolated, identified and similarly evaluated for biological activity.We thank EPSRC (DTP studentship to B.E.A.) and Cancer Research at Bath (CR@B) for funding. The biological investigation was supported by a grant from the Japanese Society for the Promotion of Science (JSPS Kakenhi #16 K08319) and the Kobayashi International Scholarship Foundation to S.A.Published versio

Synthesis of triazole-linked morpholino oligonucleotides via Cu1 catalysed cycloaddition

Triazole-linked morpholino (TLMO) oligonucleic acids were synthesised using the CuI catalysed (3 + 2) azide–alkyne cycloaddition (CuAAC) reaction. The modified DNA analogues were incorporated into 13-mer sequences via solid phase synthesis. UV melting experiments showed that the TLMO modification gives higher Tm values than the corresponding TLDNA modification

A strategy towards the synthesis of plumarellide based on biosynthesis speculation, featuring a transannular 4+2 type cyclisation from a cembranoid furanoxonium ion intermediate

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Total Synthesis of (+)-Grandifloracin by Iron Complexation of a Microbial Arene Oxidation Product

(+)-Grandifloracin was synthesized from sodium benzoate by means of a dearomatizing dihydroxylation that proceeds with unusual regioselectivity. Iron diene complexes formed from the arene oxidation product permit the use of otherwise inaccessible transformations. The synthetic material was shown to be antipodal to the natural product, thus determining the absolute configuration of grandifloracin for the first time

Total Synthesis of (+)-Grandifloracin by Iron Complexation of a Microbial Arene Oxidation Product

(+)-Grandifloracin was synthesized from sodium benzoate by means of a dearomatizing dihydroxylation that proceeds with unusual regioselectivity. Iron diene complexes formed from the arene oxidation product permit the use of otherwise inaccessible transformations. The synthetic material was shown to be antipodal to the natural product, thus determining the absolute configuration of grandifloracin for the first time

Radical 1,4-aryl transfer in arylcarboxamides leading to phthalimides, biaryls and enantiomerically enriched beta-arylethylamines

5-exo Cyclisation of vinyl-, aryl- and alkyl-radicals onto the aryl group of arylcarboxamides is followed by β-scission of the resulting spirocyclohexadienyl radicals with ejection of a carbamoyl radical. The fate of this radical depends on the substrate but, in the cases studied, either 5-endo cyclisation or direct reduction follows to give phthalimides, biaryls or β-arylethylamines. © 2008 Elsevier Ltd. All rights reserved

Sobralene, a new sex-aggregation pheromone and likely shunt metabolite of the taxadiene synthase cascade, produced by a member of the sand fly Lutzomyia longipalpis species complex

© 2018 The Authors. Published by Elsevier. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1016/j.tetlet.2018.03.088© 2018 The Authors A new sex-aggregation pheromone, sobralene, produced by the sand fly Lutzomyia longipalpis from Sobral (Ceará State, Brazil) is shown to have the novel 6,12-membered ring-fused diterpene structure 3. It is proposed that sobralene is a likely shunt metabolite of the taxadiene synthase-catalysed cyclisation of geranygeranyl diphosphate.The Wellcome Trust (WT091689MF) funded part of this research program in Lancaster University.Published versio

Comparison of gene expression profiles between human and mouse monocyte subsets

Blood of both humans and mice contains 2 main monocyte subsets. Here, we investigated the extent of their similarity using a microarray approach. Approximately 270 genes in humans and 550 genes in mice were differentially expressed between subsets by 2-fold or more. More than 130 of these gene expression differences were conserved between mouse and human monocyte subsets. We confirmed numerous of these differences at the cell surface protein level. Despite overall conservation, some molecules were conversely expressed between the 2 species' subsets, including CD36, CD9, and TREM-1. Other differences included a prominent peroxisome proliferator-activated receptor γ (PPARγ) signature in mouse monocytes, which is absent in humans, and strikingly opposed patterns of receptors involved in uptake of apoptotic cells and other phagocytic cargo between human and mouse monocyte subsets. Thus, whereas human and mouse monocyte subsets are far more broadly conserved than currently recognized, important differences between the species deserve consideration when models of human disease are studied in mice