Synthesis and evaluation of pseudosaccharin amine derivatives as potential elastase inhibitions [Elektronische Ressource] / vorgelegt von Rode Haridas Baburado

Rode Haridas

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Informations

• Publié par: ernst-moritz-arndt-universitat_greifswald
• Publié le: 01 janvier 2006
• Nombre de lectures: 12
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Synthesis and evaluation of pseudosaccharin amine
derivatives as potential elastase inhibitors






INAUGURALDISSERTATION


zur
Erlangung des akademischen Grades
Doctor rerum naturalium (Dr. rer. nat.)
an der
Mathematisch-Naturwissenschaftlichen Fakultät
der
Ernst-Moritz-Arndt-Universität Greifswald














Vorgelegt von
Rode Haridas Baburao
geb. am 03.12.1974
Greifswald, Dezember 2005 in Aambi (Indien)
















































Dekan: Prof. Dr. J. -P. Hildebrandt
1. Gutachter: Prof. Dr. H. -H. Otto
2. Gutachter: Prof. Dr. T. Schirmeister
Tag der Promotion: 01.02.2006


















Dedicated to my parents












































“In chemistry, one’s ideas, however beautiful, logical, elegant, imaginative that
they may be in their own right, are simply without value unless they are
actually applicable to the one physical environment we have- in short, they
are only good if they work!”

R. B. Woodward Publications

1) Rode, H. B.; Sprang, T.; Besch, A.; Loose, J.; Otto, H.-H. Pseudosaccharin amine
derivatives: synthesis and elastase Inhibitory activity. Die Pharmazie 2005, 60(10),
723-731.

2) Rode, H.; Koerbe, S.; Besch, A.; Methling, K.; Loose, J.; Otto, H.-H. Synthesis and
in vitro evaluation of pseudosaccharin amine derivatives as potential elastase
inhibitors. Bioorg. Med. Chem. 2005, in press.

Presentation

1) Rode, H.; Besch, A.; Otto, H.-H. Studies on pseudosaccharin derivatives. A poster
presented at the annual meeting of the Medicinal Chemistry “Frontiers in Medicinal
Chemistry” Erlangen, 15-17 March 2004.
































List of abbrevations
aq. Aqueous
BTAC Benzyl triethyl ammonium chloride
BOC tert-Butoxycarbonyl
δ Chemical shift in ppm
CC Column chromatography
J Coupling constant in Hz
dec. Decomposition
DSC Differential scanning calorimetry
CDCl Deuterochloroform 3
°C Degree Celsius
DBU 1,8-Diazabicyclo[5.4.0]undec-7-en
DCM Dichloromethane
[D]DMSO Deuterodimethylsulfoxide 6
DMF Dimethylformamide
DMSO Dimethylsulfoxide
EtOH Ethanol
AcOEt Ethyl acetate
g Gram
HDTMAB Hexadecyltrimethylammonium bromide
HPLC High performance liquid chromatography
HLE Human Leukocyte Elastase
K Inhibitor constant i
LG Leaving group
IBCF Isobutyl chloroformate
IR Infrared
M.p. Melting point
MeOH Methanol
µM Micromolar
mg Milligram
mM Millimolar
pNA 4-Nitroanilide
NMM N-Methyl morpholine
NMR Nuclear magnetic resonance
PPE Porcine Pancreatic Elastase
KI Potassium iodide
R Ratio of front f
T Retention time RList of abbrevations
RP-HPLC Reverse phase high performance liquid chromatography
rt Room temperature
THF Tetrahydrofuran
TMS Tetramethylsilane
TLC Thin layer chromatography
TEA Triethylamine
UV Ultraviolet light


Amino acids
Ala Alanine
Asp Aspartic acid
Glu Glutamic
Phe Phenylalanine
Gly Glycine
His Histidine
Ile Isoleucine
Leu Leucine
Met Methionine
α-Me-Ala α-Methyl alanine
Pro Proline
Tyr Tyrosine
Ser Serine
Val Valine






Table of contents
Table of contents
1. Introduction and theoretical background .............................................................1
1.1. Human Leukocyte Elastase (HLE) ....................................................................1
1.2. Porcine Pancreatic Elastase (PPE)...................................................................2
1.3. Leukocyte Elastase-related diseases................................................................2
1.3.1. ARDS and Lung injury...............................................................................2
1.3.2. Cystic fibrosis (CF) ....................................................................................2
1.3.3. Pulmonary emphysema.............................................................................3
1.3.4. Smoking-related chronic bronchitis ...........................................................3
1.3.5. Ischaemic-reperfusion injury......................................................................4
1.3.6. Rheumatoid arthritis (RA)..........................................................................4
1.3.7. Gastric mucosal injury .........4
1.4. Mechanism of peptide hydrolysis by HLE .........................................................4
1.5. Elastase Inhibitors .............................................................................................8
1.5.1. Peptide based inhibitors ............................................................................8
1.5.2. Heterocyclic Inhibitors .............................................................................12
1.5.2.1. Enzyme-activated inhibitors.............................................................12
1.5.2.2. Heterocyclic acylating agents ..........................................................13
1.5.3. Nonheterocyclic alkylating/acylating agents ............................................14
2. Aim of the work .....................................................................................................17
3. Results and Discussion........................................................................................19
3.1. Pseudosaccharinamines from (1,1-dioxobenzo[d]isothiazol-3-
ylsulfanyl)acetonitrile .......................................................................................19
3.2. Pseudosaccharinamine synthesis from thiosaccharinates..............................24
3.3. Pseudosaccharinamine synthesis from 3-ethoxybenzo[d]isothiazole 1,1-
dioxide .............................................................................................................26
3.4. Pseudosaccharinamine derivatives from 3-chlorobenzo[d]isothiazole 1,1-
dioxide and their further modifications.............................................................32
3.4.1. Pseudosaccharinamines .........................................................................32
3.4.2. Amide and methyl ester derivatives.........................................................33
3.4.3. Ester hydrolysis .......................................................................................35
3.4.4. Different ester derivatives containing pseudosaccharinamines...............37
3.4.5. Alcohol derivative: (2S,3S)-2-(1,1-dioxobenzo[d]isothiazol-3-ylamino)-
3-methylpentan-1-ol.................................................................................40
3.4.6. Pseudosaccharin amine containing thiazole or thiophene ring
analogues................................................................................................41 Table of contents
3.4.7. Nitration of 3-(1,1-dioxobenzo[d]isothiazol-3-ylamino)thiophene-2-
carboxylic acid methyl ester ....................................................................47
3.5. Peptide synthesis ............................................................................................50
3.6. Enzyme assay .................................................................................................58
3.6.1. Reversible inhibition ................................................................................58
3.6.2. Inhibitory activity of the compounds ........................................................61
3.7. Molecular mechanics and docking studies......................................................69
3.7.1. Molecular Mechanics...............................................................................69
3.7.2. Docking....................................................................................................69
4. Conclusions...........................................................................................................78
5. Experimental..........................................................................................................80
5.1. General Information.......................................................................................