文献类型：期刊文献

英文题名：Synthesis of azetidines and pyrrolidines via iodocyclisation of homoallyl amines and exploration of activity in a zebrafish embryo assay

作者：Feula, Antonio[1,2];Dhillon, Sundeep S.[3];Byravan, Rama[2];Sangha, Mandeep[2];Ebanks, Ronald[2];Salih, Mariwan A. Hama[2];Spencer, Neil[4];Male, Louise[5];Magyary, Istvan[6];Deng, Wei-Ping[1];Mueller, Ferenc[3];Fossey, John S.[2]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[2]Univ Birmingham, Sch Chem, Birmingham B15 2TT, W Midlands, England;[3]Univ Birmingham, Sch Clin & Expt Med, Coll Med & Dent Sci, Birmingham B15 2TT, W Midlands, England;[4]Univ Birmingham, Sch Chem, NMR Spect Facil, Birmingham B15 2TT, W Midlands, England;[5]Univ Birmingham, Sch Chem, XRay Crystallog Facil, Birmingham B15 2TT, W Midlands, England;[6]Univ Kaposvar, Fac Anim Sci, Dept Nat Protect, H-7400 Kaposvar, Hungary

年份：2013

卷号：11

期号：31

起止页码：5083

外文期刊名：ORGANIC & BIOMOLECULAR CHEMISTRY

收录：;EI(收录号：20133116552743);WOS:【SCI-EXPANDED(收录号:WOS:000322855300006)，CCR-EXPANDED(收录号:WOS:000322855300006)】；

基金：The authors thank the University of Birmingham and ERDF AWM II for support. AF thanks The School of Chemistry, University of Birmingham for a studentship and the EPSRC for underpinning support. MARS thanks the HCDP - Ministry of Higher Education-Kurdistan Region for financial support. JSF is extremely grateful to the Leverhulme Trust (F/00351/P and F/00094/BC) for early funding, East China University of Science and Technology for a visiting professorship, the Natural Science Foundation of China for a research fellowship (no. 21050110426) and the Royal Society Industry Fellowship scheme (2012/R1) for on-going support. FM and SSD thank the Marie Curie ITN project BOLD (Biology of liver and pancreatic development and disease) and "ZF-Health" Integrating projects in the Framework 7 programme of the European Commission for their financial support. The EPSRC UK National Crystallography Service at the University of Southampton are thanked for the collection of the crystallographic data.60

语种：英文

外文关键词：Controlled drug delivery - Assays - Isomerization - Synthesis (chemical) - Targeted drug delivery - Amines

摘要：Room temperature iodocyclisation of homoallylamines stereoselectively delivers functionalised 2-(iodomethyl)azetidine derivatives in high yield. Increasing reaction temperature from 20 degrees C to 50 degrees C switches the reaction outcome to realise the stereoselective formation of functionalised 3-iodopyrrolidine derivatives. It was shown that these pyrrolidines are formed via thermal isomerisation of the aforementioned azetidines. Primary and secondary amines could be reacted with iodomethyl azetidine derivatives to deliver stable methylamino azetidine derivatives. With subtle changes to the reaction sequences homoallyl amines could be stereoselectively converted to either cis- or trans-substituted 3-amino pyrrolidine derivatives at will. The stereochemical divergent synthesis of cis and trans substituted pyrrolidines supports an ion part, aziridinium, isomerisation pathway for azetidine to pyrrolidine isomerisation. Six azetidine derivatives were probed in a zebrafish embryo developmental assay to detect potential biological effects through the analysis of morphology and motility behaviour phenotypes. The range of effects across the probed molecules.demonstrates the suitability of this assay for screening azetidine derivatives. One of the probed molecules, rac-(((cis)-1-benzyl-4-phenylazetidin-2-yl)methyl)piperidine, exhibited particularly interesting effects in the developmental assay presenting with hypopigmentation and reduced circulation amongst others. This shows that the zebrafish embryo provides a fast, sensitive and effective way to screen new compounds and in the future in combination with existing in vivo and in vitro assays it will become an integral part in drug discovery and development.