The natural product Rocaglamide (1), isolated from the tree Aglaia elliptifolia, is a compelling but also challenging lead structure for crop protection. In laboratory assays, the natural product shows highly interesting insecticidal activity against chewing pests and beetles, but also phytotoxicity on some crop plants. Multi- step syntheses with control of stereochemistry were required to probe the structure- activity relationship (SAR), and seek simplified analogues. After a significant research effort, just two areas of the molecule were identified which allow modification whilst maintaining activity, as will be highlighted in this paper.

Four series of C-10 non-acetal dimers were prepared from key trioxane alcohol 10beta-(2-hydroxyethyl)deoxoartemisinin (9b). All of the dimers prepared displayed potent low nanomolar antimalarial activity versus the K1 and HB3 strains of Plasmodium falciparum. The most potent compound assayed was phosphate dimer 14a, which was greater than 50 times more potent than the parent drug artemisinin and about 15 times more potent than the clinically used acetal artemether. In contrast to their potent activity versus malaria parasites, virtually all of the dimers expressed poor anticancer activity apart from the trioxane phosphate ester dimers 14a and 14b, which expressed nanomolar growth inhibitory (GI(50)) values versus a range of cancer cell lines in the NCI 60 human cell line screen. Further detailed studies on these dimers in vitro in HL60 cells demonstrate that both phosphate ester dimers (14a and 14b) are more potent than the anticancer agent doxorubicin. Interestingly, phosphate ester monomers 9c and 9d, antimalarially active in the low nanomolar region versus P. falciparum, are inactive as anticancer agents even at concentrations in the millimolar region. This observation emphasizes the importance of two trioxane units for high antiproliferative activity, and we propose that the nature of the linker in dimers of this type plays a crucial role in imparting potent anticancer activity.

[reaction: see text] A new total synthesis of (-)-agelastatin A (1) has been achieved from the chiral oxazolidinone (-)-3. Although enone transposition was problematic when the Michael ring closure of 2 was attempted with strong base, the desired cyclization could be effected with Hunig's base after the pyrrole nucleus was brominated. Subsequent reduction and monobromination afforded synthetic (-)-agelastatin A (1).

[reaction: see text] An enantiospecific total synthesis of Weinreb's advanced intermediate 2 for (-)-agelastatin A has been achieved from the Hough-Richardson aziridine 8. Noteworthy reactions in our sequence include the highly regioselective trans-diaxial ring-opening of 8 with azide ion to set up the vicinal diamido functionality present within (-)-2 and the Grubbs-Hoveyda ring-closing metathesis (RCM) reaction that was used to construct its cyclopentene core.

This paper describes the generation of a dynamic combinatorial library of sialic acid analogues using sialic acid aldolase. Addition of wheat germ agglutinin to the equilibrating libraries results in selective amplification of one or more members.

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Angewandte Chemie International EditionVolume 41, Issue 18 p. 3405-3407 Communication Enzymatic Generation and In Situ Screening of a Dynamic Combinatorial Library of Sialic Acid Analogues† Roger J. Lins Dr., Roger J. Lins Dr. Department of Chemistry Edinburgh Protein Interaction Centre The University of Edinburgh, King's Buildings West Mains Road, Edinburgh EH9 3JJ (UK) Fax: (+44) 131-650-4717 or (+44) 131-650-4743Search for more papers by this authorSabine L. Flitsch Prof., Sabine L. Flitsch Prof. s.flitsch@ed.ac.uk Department of Chemistry Edinburgh Protein Interaction Centre The University of Edinburgh, King's Buildings West Mains Road, Edinburgh EH9 3JJ (UK) Fax: (+44) 131-650-4717 or (+44) 131-650-4743Search for more papers by this authorNicholas J. Turner Prof., Nicholas J. Turner Prof. n.turner@ed.ac.uk Department of Chemistry Edinburgh Protein Interaction Centre The University of Edinburgh, King's Buildings West Mains Road, Edinburgh EH9 3JJ (UK) Fax: (+44) 131-650-4717 or (+44) 131-650-4743Search for more papers by this authorEd Irving Dr., Ed Irving Dr. Ultrafine Synergy House, Guildhall Close Manchester Science Park, Manchester M15 6SY (UK)Search for more papers by this authorStuart A. Brown Dr., Stuart A. Brown Dr. Ultrafine Synergy House, Guildhall Close Manchester Science Park, Manchester M15 6SY (UK)Search for more papers by this author Roger J. Lins Dr., Roger J. Lins Dr. Department of Chemistry Edinburgh Protein Interaction Centre The University of Edinburgh, King's Buildings West Mains Road, Edinburgh EH9 3JJ (UK) Fax: (+44) 131-650-4717 or (+44) 131-650-4743Search for more papers by this authorSabine L. Flitsch Prof., Sabine L. Flitsch Prof. s.flitsch@ed.ac.uk Department of Chemistry Edinburgh Protein Interaction Centre The University of Edinburgh, King's Buildings West Mains Road, Edinburgh EH9 3JJ (UK) Fax: (+44) 131-650-4717 or (+44) 131-650-4743Search for more papers by this authorNicholas J. Turner Prof., Nicholas J. Turner Prof. n.turner@ed.ac.uk Department of Chemistry Edinburgh Protein Interaction Centre The University of Edinburgh, King's Buildings West Mains Road, Edinburgh EH9 3JJ (UK) Fax: (+44) 131-650-4717 or (+44) 131-650-4743Search for more papers by this authorEd Irving Dr., Ed Irving Dr. Ultrafine Synergy House, Guildhall Close Manchester Science Park, Manchester M15 6SY (UK)Search for more papers by this authorStuart A. Brown Dr., Stuart A. Brown Dr. Ultrafine Synergy House, Guildhall Close Manchester Science Park, Manchester M15 6SY (UK)Search for more papers by this author First published: 16 September 2002 https://doi.org/10.1002/1521-3773(20020916)41:18<3405::AID-ANIE3405>3.0.CO;2-PCitations: 41 † We are grateful to Ultrafine for a postdoctoral fellowship (R.J.L.) and to the Wellcome Trust for financial support. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Reversible formation of carbon–carbon bonds under physiological conditions by enzyme catalysis allows the generation and in situ screening of a dynamic mixture of biologically significant compounds. Generation of the dynamic library by incubation of the three sugars 1 a–c with two equivalents of sodium pyruvate in the presence of N-acetylneuraminic acid aldolase and wheat germ agglutinin resulted in amplification of sialic acid 1 a (see scheme). Citing Literature Volume41, Issue18September 16, 2002Pages 3405-3407 RelatedInformation

The insecticidal activity found for rocaglamide and its congeners, prompted us to establish a short and efficient synthesis of the natural product and some synthetic ‘halo-aryl’ analogues. Pd-catalysed cross-coupling reactions of the bromo analogue were then explored in order to gain a suitable access to a broad range of unnatural analogues. The key step of our approach is a keto-aldehyde acyloin ring-closure followed by a Stiles carboxylation.

A series of novel phosphinates, derived from 4-phosphonomethylphenylalanine, are described as isosteres of phosphotyrosine. Benzyl (or alkyl) phosphinomethylphenylalanine derivatives were prepared by alkylation of an amino acid P-H phosphinate.

The carbocyclic analogue of (+/-)-Rocaglamide 1, in which the ring oxygen of the 2,3-dihydrobenzofuran has been replaced by a methylene group, was synthesised in 10 steps from cyclopentanone. A key feature of this route is a highly efficient intramolecular condensation reaction which cleanly leads to the tricyclic skeleton. (C) 1999 Elsevier Science Ltd. All rights reserved.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.