Prof Dr Alexander Titz
About
Alexander Titz studied chemistry at the Technical University Darmstadt and the University of Bordeaux I. For his diploma thesis, he moved to the Protein Structure Unit at Novartis Pharma in Basel. After receiving his doctorate from the University of Basel in 2008, covering the medicinal chemistry of carbohydrate-protein interactions, he conducted post-doctoral research at the Institute of Microbiology and Immunology at ETH Zürich (Swiss Federal Institute of Technology). In 2010, he was awarded the Klaus-Grohe Prize for medicinal chemistry of the GDCh.
After establishing a research group at the Zukunftskolleg of the University of Constance focusing on carbohydrate chemistry and inhibitors of bacterial biofilm formation, Alexander Titz has been head of the research group ‘Chemical Biology of Carbohydrates’ at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), an outpost of the Helmholtz Centre for Infection Research, since 2013. His group is furthermore part of the German Centre for Infection Research (DZIF), a national association of the German Centres for Health Research. Alexander Titz is teaching at Saarland University since 2014 and has been appointed Juniorprofessor for Chemical Biology in 2018.
Since 2017, the research in the Titz lab is funded by an ERC starting grant of the European Research Council. In 2018, Alexander Titz was awarded the Innovation Award in Medical/Pharmaceutical Chemistry by the German Chemical Society and the German Pharmaceutical Society as well as the Prize for a Young Medicinal Chemist in Academia of the European Federation of Medicinal Chemistry (EFMC). In 2019, Alexander obtained a call for the professorship for Organic Chemistry at the University of Osnabrück. Since 2020, Alexander Titz holds a professorship for Organic and Pharmaceutical Chemistry at Saarland University.
2024
Dual inhibitors of Pseudomonas aeruginosa virulence factors LecA and LasB
Metelkina O, Konstantinovic J, Klein A, Shafiei R, Fares M, Alhayek A, Yahiaoui S, Elgaher W, Haupenthal J, Titz* A, Hirsch* A (2024)
Chem. Sci. 15DOI: 10.1039/D4SC02703E
2023
The resuscitation-promoting factor (Rpf) from Micrococcus luteus and its putative reaction product 1,6-anhydro-MurNAc increase culturability of environmental bacteria
Guzman J, Raval D, Hauck D, Titz A, Poehlein A, Degenkolb T, Daniel R, Vilcinskas A (2023)
Access microbiology 5 (9)DOI: 10.1099/acmi.0.000647.v4
Switch-on luminescent sensing of unlabelled bacterial lectin by terbium(III) glycoconjugate systems
Wojtczak K, Zahorska E, Murphy I, Koppel F, Cooke G, Titz A, Byrne J (2023)
Chem. Commun. (Cambridge, U. K.) 59 (54): 8384-8387DOI: 10.1039/D3CC02300A
Pseudomonas aeruginosa LecB suppresses immune responses by inhibiting transendothelial migration
Sponsel J, Guo Y, Hamzam L, Lavanant A, Pérez-Riverón A, Partiot E, Muller Q, Rottura J, Gaudin R, Hauck D, …, Römer W, Mueller C (2023)
EMBO reports 24 (4)DOI: 10.15252/embr.202255971
Tackling the outer membrane: facilitating compound entry into Gram-negative bacterial pathogens
Saxena D, Maitra R, Bormon R, Czekanska M, Meiers J, Titz A, Verma S, Chopra S (2023)
npj Antimicrob Resist 1 (1)DOI: 10.1038/s44259-023-00016-1
Glycomimetics for the inhibition and modulation of lectins
Leusmann S, Ménová P, Shanin E, Titz A, Rademacher C (2023)
Chem. Soc. Rev. 52 (11): 3663-3740DOI: 10.1039/d2cs00954d
Neutralizing the Impact of the Virulence Factor LecA from Pseudomonas aeruginosa on Human Cells with New Glycomimetic Inhibitors
Zahorska E, Rosato F, Stober K, Kuhaudomlarp S, Meiers J, Hauck D, Reith D, Gillon E, Rox K, Imberty A, Römer W, Titz A (2023)
Angewandte Chemie (International ed. in English) 62 (7)DOI: 10.1002/anie.202215535
2022
Targeting undruggable carbohydrate recognition sites through focused fragment library design
Shanina E, Kuhaudomlarp S, Siebs E, Fuchsberger F, Denis M, da Silva Figueiredo Celestino Gomes P, Clausen M, Seeberger P, Rognan D, Titz A, Imberty A, Rademacher C (2022)
Commun Chem 5 (1): 1-11DOI: 10.1038/s42004-022-00679-3
NamZ1 and NamZ2 from the Oral Pathogen Tannerella forsythia Are Peptidoglycan Processing Exo-β-N-Acetylmuramidases with Distinct Substrate Specificities
Borisova M, Balbuchta K, Lovering A, Titz A, Mayer C (2022)
J. Bacteriol. 204 (3)DOI: 10.1128/jb.00597-21
Targeting the Central Pocket of the Pseudomonas aeruginosa Lectin LecA
Siebs E, Shanina E, Kuhaudomlarp S, da Silva Figueiredo Celestino Gomes P, Fortin C, Seeberger P, Rognan D, Rademacher C, Imberty A, Titz A (2022)
Chembiochem : a European journal of chemical biology 23 (3)DOI: 10.1002/cbic.202100563
β-Boronic Acid-Substituted Bodipy Dyes for Fluorescence Anisotropy Analysis of Carbohydrate Binding
Hoffmann C, Jourdain M, Grandjean A, Titz A, Jung G (2022)
Analytical chemistry 94 (16): 6112-6119DOI: 10.1021/acs.analchem.1c04654
Pineapple Lectin AcmJRL binds SARS-CoV-2 Spike Protein in a carbohydrate-dependent fashion
Meiers J, Dastbaz J, Adam S, Rasheed S, Kirsch S, Meiser P, Gross P, Müller R, Titz A (2022)
Chembiochem : a European journal of chemical biologyDOI: 10.1002/cbic.202200463
The Glycan-Specificity of the Pineapple Lectin AcmJRL and its Carbohydrate-Dependent Binding of the SARS-CoV-2 Spike Protein
Meiers J, Dastbaz J, Adam S, Rasheed S, Kirsch S, Meiser P, Gross P, Müller R, Titz A (2022)
BookDOI: 10.1101/2022.05.27.493400
Lectin-Targeted Prodrugs Activated by Pseudomonas aeruginosa for Self-Destructive Antibiotic Release
Meiers J, Rox K, Titz A (2022)
Journal of medicinal chemistry 65 (20): 13988-14014DOI: 10.1021/acs.jmedchem.2c01214
Discovery of N-β-l-Fucosyl Amides as High-Affinity Ligands for the Pseudomonas aeruginosa Lectin LecB
Mala P, Siebs E, Meiers J, Rox K, Varrot A, Imberty A, Titz A (2022)
Journal of medicinal chemistry 65 (20): 14180-14200DOI: 10.1021/acs.jmedchem.2c01373
Targeting extracellular lectins of Pseudomonas aeruginosa with glycomimetic liposomes
Metelkina O, Huck B, O'Connor J, Koch M, Manz A, Lehr C, Titz A (2022)
Journal of Materials Chemistry B 10 (4): 537-548DOI: 10.1039/d1tb02086b
Nano-in-Microparticles for Aerosol Delivery of Antibiotic-Loaded, Fucose-Derivatized, and Macrophage-Targeted Liposomes to Combat Mycobacterial Infections: In Vitro Deposition, Pulmonary Barrier Interactions, and Targeted Delivery
Huck B, Thiyagarajan D, Bali A, Boese A, Besecke K, Hozsa C, Gieseler R, Furch M, Carvalho-Wodarz C, Waldow F, …, Loretz B, Lehr C (2022)
Advanced healthcare materials 11 (11)DOI: 10.1002/adhm.202102117
2021
Short Peptides and Their Mimetics as Potent Antibacterial Agents and Antibiotic Adjuvants
Panjla A, Kaul G, Chopra S, Titz A, Verma S (2021)
ACS chemical biology 16 (12): 2731-2745DOI: 10.1021/acschembio.1c00626
A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN
Wawrzinek R, Wamhoff E, Lefebre J, Rentzsch M, Bachem G, Domeniconi G, Schulze J, Fuchsberger F, Zhang H, Modenutti C, …, Ernst B, Rademacher C (2021)
J. Am. Chem. Soc. 143 (45): 18977-18988DOI: 10.1021/jacs.1c07235
Towards the sustainable discovery and development of new antibiotics
Miethke M, Pieroni M, Weber T, Brönstrup M, Hammann P, Halby L, Arimondo P, Glaser P, Aigle B, Bode H, …, Moser H, Müller R (2021)
Nature reviews. Chemistry 5 (10): 726-749DOI: 10.1038/s41570-021-00313-1
Non-Carbohydrate Glycomimetics as Inhibitors of Calcium(II)-Binding Lectins
Kuhaudomlarp S, Siebs E, Shanina E, Topin J, Joachim I, da Silva Figueiredo Celestino Gomes P, Varrot A, Rognan D, Rademacher C, Imberty A, Titz A (2021)
Angew. Chem. Int. Ed. 60 (15): 8104-8114DOI: 10.1002/anie.202013217
The exo-β-N-acetylmuramidase NamZ from Bacillus subtilis is the founding member of a family of exo-lytic peptidoglycan hexosaminidases
Müller M, Calvert M, Hottmann I, Kluj R, Teufel T, Balbuchta K, Engelbrecht A, Selim K, Xu Q, Borisova M, Titz A, Mayer C (2021)
The Journal of biological chemistry 296DOI: 10.1016/j.jbc.2021.100519
2020
Protein-observed 19F NMR of LecA from Pseudomonas aeruginosa
Shanina E, Siebs E, Zhang H, Silva D, Joachim I, Titz A, Rademacher C (2020)
GlycobiologyDOI: 10.1093/glycob/cwaa057
Directing Drugs to Bugs: Antibiotic-Carbohydrate Conjugates Targeting Biofilm-Associated Lectins of Pseudomonas aeruginosa
Meiers J, Zahorska E, Röhrig T, Hauck D, Wagner S, Titz A (2020)
Journal of medicinal chemistry 63 (20): 11707-11724DOI: 10.1021/acs.jmedchem.0c00856
A rapid synthesis of low-nanomolar divalent LecA inhibitors in four linear steps from d -galactose pentaacetate
Zahorska E, Kuhaudomlarp S, Minervini S, Yousaf S, Lepsik M, Kinsinger T, Hirsch A, Imberty A, Titz A (2020)
Chem. Commun. 56 (62): 8822-8825DOI: 10.1039/d0cc03490h
Expression, Purification, and Functional Characterization of Tectonin 2 from Laccaria bicolor: A Six-Bladed Beta-Propeller Lectin Specific for O-Methylated Glycans
Wohlschlager T, Titz A, Künzler M, Varrot A (2020)
Methods Mol Biol 2132: 669-682DOI: 10.1007/978-1-0716-0430-4_58
2019
Lectin antagonists in infection, immunity, and inflammation
Meiers J, Siebs E, Zahorska E, Titz A (2019)
Current opinion in chemical biology 53: 51-67DOI: 10.1016/j.cbpa.2019.07.005
Anti-biofilm Agents against Pseudomonas aeruginosa: A Structure-Activity Relationship Study of C-Glycosidic LecB Inhibitors
Sommer R, Rox K, Wagner S, Hauck D, Henrikus S, Newsad S, Arnold T, Ryckmans T, Brönstrup M, Imberty A, …, Hartmann R, Titz A (2019)
Journal of medicinal chemistry 62 (20): 9201-9216DOI: 10.1021/acs.jmedchem.9b01120
Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis
Siebert D, Sommer R, Pogorevc D, Hoffmann M, Wenzel S, Müller R, Titz A (2019)
Beilstein journal of organic chemistry 15: 2922-2929DOI: 10.3762/bjoc.15.286
Induction of rare conformation of oligosaccharide by binding to calcium-dependent bacterial lectin: X-ray crystallography and modelling study
Lepsik M, Sommer R, Kuhaudomlarp S, Lelimousin M, Paci E, Varrot A, Titz A, Imberty A (2019)
European journal of medicinal chemistry 177: 212-220DOI: 10.1016/j.ejmech.2019.05.049
2018
Bivalent LecA inhibitors targeting Pseudomonas aeruginosa LecA
Zahorska E, Minervini S, Kuhaudomlarp S, Imberty A, Titz A (2018)
Patent (EP19306432.6)
N-Acetylmuramic Acid (MurNAc) Auxotrophy of the Oral Pathogen Tannerella forsythia: Characterization of a MurNAc Kinase and Analysis of Its Role in Cell Wall Metabolism
Hottmann I, Mayer V, Tomek M, Friedrich V, Calvert M, Titz A, Schäffer C, Mayer C (2018)
Frontiers in microbiology 9DOI: 10.3389/fmicb.2018.00019
Crystal Structures of Fungal Tectonin in Complex with O-Methylated Glycans Suggest Key Role in Innate Immune Defense
Sommer R, Makshakova O, Wohlschlager T, Hutin S, Marsh M, Titz A, Künzler M, Varrot A (2018)
Structure (London, England : 1993) 26 (3): 391-402DOI: 10.1016/j.str.2018.01.003
Glycomimetic, Orally Bioavailable LecB Inhibitors Block Biofilm Formation of Pseudomonas aeruginosa
Sommer R, Wagner S, Rox K, Varrot A, Hauck D, Wamhoff E, Schreiber J, Ryckmans T, Brunner T, Rademacher C, …, Imberty A, Titz A (2018)
Journal of the American Chemical Society 140 (7): 2537-2545DOI: 10.1021/jacs.7b11133
Virtual Screening Against Carbohydrate-Binding Proteins: Evaluation and Application to Bacterial Burkholderia ambifaria Lectin
Dingjan T, Gillon É, Imberty A, Pérez S, Titz A, Ramsland P, Yuriev E (2018)
Journal of chemical information and modeling 58 (9): 1976-1989DOI: 10.1021/acs.jcim.8b00185
Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections
Calvert M, Jumde V, Titz A (2018)
Beilstein journal of organic chemistry 14: 2607-2617DOI: 10.3762/bjoc.14.239
2017
An efficient synthesis of 1,6-anhydro-N-acetylmuramic acid from N-acetylglucosamine
Calvert M, Mayer C, Titz A (2017)
Beilstein journal of organic chemistry 13: 2631-2636DOI: 10.3762/bjoc.13.261
Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging
Wagner S, Hauck D, Hoffmann M, Sommer R, Joachim I, Müller R, Imberty A, Varrot A, Titz A (2017)
Angewandte Chemie (International ed. in English) 56 (52): 16559-16564DOI: 10.1002/anie.201709368
Photorhabdus luminescens lectin A (PllA): A new probe for detecting α-galactoside-terminating glycoconjugates
Beshr G, Sikandar A, Jemiller E, Klymiuk N, Hauck D, Wagner S, Wolf E, Koehnke J, Titz A (2017)
J Biol Chem 292 (48): 19935-19951DOI: 10.1074/jbc.M117.812792
Ciprofloxacin-loaded lipid-core nanocapsules as mucus penetrating drug delivery system intended for the treatment of bacterial infections in cystic fibrosis
Torge A, Wagner S, Chaves P, Oliveira E, Guterres S, Pohlmann A, Titz A, Schneider M, Beck R (2017)
Int J Pharm 527 (1-2): 92-102DOI: 10.1016/j.ijpharm.2017.05.013
Efficient Two Step β-Glycoside Synthesis from N-Acetyl d-Glucosamine: Scope and Limitations of Copper(II) Triflate-Catalyzed Glycosylation
Sommer R, Hauck D, Titz A (2017)
ChemistrySelect 2 (15)DOI: 10.1002/slct.201700161
Photoswitchable Janus glycodendrimer micelles as multivalent inhibitors of LecA and LecB from Pseudomonas aeruginosa
Hu Y, Beshr G, Garvey C, Tabor R, Titz A, Wilkinson B (2017)
Colloids and surfaces. B, Biointerfaces 159: 605-612DOI: 10.1016/j.colsurfb.2017.08.016
2016
Novel Strategies for the Treatment of Pseudomonas aeruginosa Infections
Wagner S, Sommer R, Hinsberger S, Lu C, Hartmann R, Empting M, Titz A (2016)
Journal of medicinal chemistry 59 (13): 5929-69DOI: 10.1021/acs.jmedchem.5b01698
Inhibitors of Pseudomonas aeruginosa LecB
Sommer R, Titz A (2016)
Patent (WO2016/151066 A1)
The virulence factor LecB varies in clinical isolates: consequences for ligand binding and drug discovery
Sommer R, Wagner S, Varrot A, Nycholat C, Khaledi A, Häussler S, Paulson J, Imberty A, Titz A (2016)
Chem Sci 7 (8): 4990-5001DOI: 10.1039/c6sc00696e
O-Alkylated heavy atom carbohydrate probes for protein X-ray crystallography: Studies towards the synthesis of methyl 2-O-methyl-L-selenofucopyranoside
Sommer R, Hauck D, Varrot A, Imberty A, Künzler M, Titz A (2016)
Beilstein journal of organic chemistry 12: 2828-2833DOI: 10.3762/bjoc.12.282
Development of a competitive binding assay for the Burkholderia cenocepacia lectin BC2L-A and structure activity relationship of natural and synthetic inhibitors
Beshr G, Sommer R, Hauck D, Siebert D, Hofmann A, Imberty A, Titz A (2016)
Med Chem Commun 7 (3): 519-530DOI: 10.1039/C5MD00557D
Development and optimization of a competitive binding assay for the galactophilic low affinity lectin LecA from Pseudomonas aeruginosa
Joachim I, Rikker S, Hauck D, Ponader D, Boden S, Sommer R, Hartmann L, Titz A (2016)
Org. Biomol. Chem. 14 (33): 7933-48DOI: 10.1039/c6ob01313a
2015
Cinnamide Derivatives of d-Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa
Sommer R, Hauck D, Varrot A, Wagner S, Audfray A, Prestel A, Möller H, Imberty A, Titz A (2015)
ChemistryOpen 4 (6): 756-67DOI: 10.1002/open.201500162
Parasite Glycobiology: A Bittersweet Symphony
Rodrigues J, Acosta-Serrano A, Aebi M, Ferguson M, Routier F, Schiller I, Soares S, Spencer D, Titz A, Wilson I, Izquierdo L (2015)
PLoS Pathog. 11 (11)DOI: 10.1371/journal.ppat.1005169
Synthesis of mannoheptose derivatives and their evaluation as inhibitors of the lectin LecB from the opportunistic pathogen Pseudomonas aeruginosa
Hofmann A, Sommer R, Hauck D, Stifel J, Göttker-Schnetmann I, Titz A (2015)
Carbohydrate research 412: 34-42DOI: 10.1016/j.carres.2015.04.010
Bisecting Galactose as a Feature of N-Glycans of Wild-type and Mutant Caenorhabditis elegans
Yan S, Brecker L, Jin C, Titz A, Dragosits M, Karlsson N, Jantsch V, Wilson I, Paschinger K (2015)
Mol Cell Proteomics 14 (8): 2111-25DOI: 10.1074/mcp.M115.049817
2014
Methylated glycans as conserved targets of animal and fungal innate defense
Wohlschlager T, Butschi A, Grassi P, Sutov G, Gauss R, Hauck D, Schmieder S, Knobel M, Titz A, Dell A, …, Aebi M, Künzler M (2014)
Proceedings of the National Academy of Sciences of the United States of America 111 (27): 2787-96DOI: 10.1073/pnas.1401176111
A biophysical study with carbohydrate derivatives explains the molecular basis of monosaccharide selectivity of the Pseudomonas aeruginosa lectin LecB
Sommer R, Exner T, Titz A (2014)
PLoS ONE 9 (11)DOI: 10.1371/journal.pone.0112822
Amphiphilic cationic β(3R3)-peptides: membrane active peptidomimetics and their potential as antimicrobial agents
Mosca S, Keller J, Azzouz N, Wagner S, Titz A, Seeberger P, Brezesinski G, Hartmann L (2014)
Biomacromolecules 15 (5): 1687-95DOI: 10.1021/bm500101w
2013
Glycomimetics as Pseudomonas aeruginosa lectin inhibitors
Titz A (2013)
Patent (WO2013152848A1)
Biofilme Neue Forschungsansätze zur Therapie bakterieller Infektionskrankheiten
Titz A (2013)
GIT Labor-Fachzeitschrift (2): 120-121
Discovery of two classes of potent glycomimetic inhibitors of Pseudomonas aeruginosa LecB with distinct binding modes
Hauck D, Joachim I, Frommeyer B, Varrot A, Philipp B, Möller H, Imberty A, Exner T, Titz A (2013)
ACS chemical biology 8 (8): 1775-84DOI: 10.1021/cb400371r
New approaches to control infections: anti-biofilm strategies against gram-negative bacteria
Sommer R, Joachim I, Wagner S, Titz A (2013)
Chimia (Aarau) 67 (4): 286-90DOI: 10.2533/chimia.2013.286
2012
Conformational Constraints: Nature Does It Best with Sialyl Lewis x
Titz A, Marra A, Cutting B, Smieško M, Papandreou G, Dondoni A, Ernst B (2012)
Eur. J. Org. Chem. 2012 (28)DOI: 10.1002/ejoc.201200744
2010
Core beta-galactosyltransferase and uses thereof
Titz A, Butschi A, Aebi M, Wilson I, Hengartner M, Künzler M (2010)
Patent (WO2010/136209A1)
Caenorhabditis elegans N-glycan core beta-galactoside confers sensitivity towards nematotoxic fungal galectin CGL2
Butschi A, Titz A, Wälti M, Olieric V, Paschinger K, Nöbauer K, Guo X, Seeberger P, Wilson I, Aebi M, Hengartner M, Künzler M (2010)
PLoS Pathog. 6 (1)DOI: 10.1371/journal.ppat.1000717
Probing the carbohydrate recognition domain of E-selectin: the importance of the acid orientation in sLex mimetics
Titz A, Patton J, Smiesko M, Radic Z, Schwardt O, Magnani J, Ernst B (2010)
Bioorg Med Chem 18 (1): 19-27DOI: 10.1016/j.bmc.2009.11.024
2009
Molecular basis for galactosylation of core fucose residues in invertebrates: identification of caenorhabditis elegans N-glycan core alpha1,6-fucoside beta1,4-galactosyltransferase GALT-1 as a member of a novel glycosyltransferase family
Titz A, Butschi A, Henrissat B, Fan Y, Hennet T, Razzazi-Fazeli E, Hengartner M, Wilson I, Künzler M, Aebi M (2009)
J Biol Chem 284 (52): 36223-33DOI: 10.1074/jbc.M109.058354
2008
Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists?
Titz A, Patton J, Alker A, Porro M, Schwardt O, Hennig M, Francotte E, Magnani J, Ernst B (2008)
Bioorg Med Chem 16 (2): 1046-56DOI: 10.1016/j.bmc.2007.07.025
2007
Mimetics of Sialyl Lewis<sup>x</sup>: The Pre-Organization of the Carboxylic Acid is Essential for Binding to Selectins
Titz A, Ernst B (2007)
CHIMIA 61 (4): 194-197DOI: 10.2533/chimia.2007.194
2006
A safe and convenient method for the preparation of triflyl azide, and its use in diazo transfer reactions to primary amines
Titz A, Radic Z, Schwardt O, Ernst B (2006)
Tetrahedron Lett. 47 (14)DOI: 10.1016/j.tetlet.2006.01.157
Complexation of copper(II)-Chelidamate: A multifrequency-pulsed electron paramagnetic resonance and electron nuclear double resonance analysis
Ramic E, Eichel R, Dinse K, Titz A, Schmidt B (2006)
J. Phys. Chem. B 110 (41): 20655-63DOI: 10.1021/jp061940u
2004
Electrochemical synthesis of dimerizing and nondimerizing orthoquinone monoketals
Deffieux D, Fabre I, Titz A, Léger J, Quideau S (2004)
The Journal of organic chemistry 69 (25): 8731-8DOI: 10.1021/jo048677i
Copper dipicolinates as peptidomimetic ligands for the Src SH2 domain
Schmidt B, Jiricek J, Titz A, Ye G, Parang K (2004)
Bioorg Med Chem Lett 14 (16): 4203-6DOI: 10.1016/j.bmcl.2004.06.018