Table Of ContentProgress in Drug Research 72
Series Editor: K.D. Rainsford
Jan Ježek
Jan Hlaváček
Jaroslav Šebestík
Biomedical
Applications
of Acridines
Derivatives, Syntheses, Properties and
Biological Activities with a Focus on
Neurodegenerative Diseases
Progress in Drug Research
Volume 72
Series editor
K.D. Rainsford, Sheffield Hallam University,
Biomedical Research Centre, Sheffield, UK
More information about this series at http://www.springer.com/series/4857
ž áč
Jan Je ek Jan Hlav ek
(cid:129)
Š í
Jaroslav ebest k
Biomedical Applications
of Acridines
Derivatives, Syntheses, Properties
and Biological Activities with a Focus
on Neurodegenerative Diseases
123
Jan Ježek Jaroslav Šebestík
Academy of Sciences Academy of Sciences
Institute of Organic Chemistry Institute of Organic Chemistry
andBiochemistry andBiochemistry
Prague Prague
Czech Republic Czech Republic
Jan Hlaváček
Academy of Sciences
Institute of Organic Chemistry
andBiochemistry
Prague
Czech Republic
ISSN 0071-786X ISSN 2297-4555 (electronic)
Progressin DrugResearch
ISBN978-3-319-63952-9 ISBN978-3-319-63953-6 (eBook)
DOI 10.1007/978-3-319-63953-6
LibraryofCongressControlNumber:2017947442
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To memory of the late Dr. Dušan
Drahoňovský, who contributed to the concept
of human friendly science. He served as a
very kind and good teacher of organic
chemistry at Charles University, Prague.
When we had started to study organic
synthesis at University of Pardubice, Dušan’s
nickname was Acridine, because he had been
devoted to carry out acridine synthesis since
high school age.
Acknowledgements
This work was supported by the Czech Science Foundation (14-00431S,
17-00121S), Research Project RVO 61388963. Molecular graphics and analyses
were performed with the UCSF Chimera package. Chimera is developed by the
Resource for Biocomputing, Visualization, and Informatics at the University of
California, San Francisco (supported by NIGMS P41-GM103311).
vii
Contents
1 Introduction.... .... .... ..... .... .... .... .... .... ..... .... 1
References.. .... .... .... ..... .... .... .... .... .... ..... .... 3
2 Nomenclature... .... .... ..... .... .... .... .... .... ..... .... 5
References.. .... .... .... ..... .... .... .... .... .... ..... .... 6
3 Syntheses .. .... .... .... ..... .... .... .... .... .... ..... .... 9
3.1 Syntheses of Acridine Ring and Its Precursors... .... ..... .... 9
3.2 Acridine-Peptide Conjugates. .... .... .... .... .... ..... .... 26
3.3 Acridines as Catalysts. ..... .... .... .... .... .... ..... .... 31
References.. .... .... .... ..... .... .... .... .... .... ..... .... 33
4 Interactions of Acridines with Nucleic Acids... .... .... ..... .... 47
4.1 DNA.. .... .... .... ..... .... .... .... .... .... ..... .... 47
4.2 DNA Quadruplexes .. ..... .... .... .... .... .... ..... .... 51
4.3 RNA.. .... .... .... ..... .... .... .... .... .... ..... .... 54
4.4 PNA.. .... .... .... ..... .... .... .... .... .... ..... .... 56
4.5 Acridine Metal Complexes.. .... .... .... .... .... ..... .... 57
4.6 Structural Aspects of Nucleic Acid Binding. .... .... ..... .... 59
References.. .... .... .... ..... .... .... .... .... .... ..... .... 64
5 Interactions with Proteins. ..... .... .... .... .... .... ..... .... 73
5.1 Interactions with Nucleic Acids Processing Proteins... ..... .... 73
5.1.1 Topoisomerases..... .... .... .... .... .... ..... .... 74
5.1.2 Transcription Factors. .... .... .... .... .... ..... .... 76
5.1.3 RecA Protein.. ..... .... .... .... .... .... ..... .... 76
5.1.4 Telomerase ... ..... .... .... .... .... .... ..... .... 76
5.2 Interactions with Other Proteins .. .... .... .... .... ..... .... 77
5.3 Structural Aspects of Acridine Interactions with Proteins.... .... 83
References.. .... .... .... ..... .... .... .... .... .... ..... .... 90
ix
x Contents
6 Applications for Treatment of Neurodegenerative Diseases.... .... 99
6.1 Alzheimer’s Disease.. ..... .... .... .... .... .... ..... .... 104
6.1.1 Multitargeted Strategy in AD .. .... .... .... ..... .... 108
6.2 Parkinson’s Disease .. ..... .... .... .... .... .... ..... .... 112
6.3 Prion Diseases .. .... ..... .... .... .... .... .... ..... .... 114
6.4 Other Neurodegenerative Diseases .... .... .... .... ..... .... 118
References.. .... .... .... ..... .... .... .... .... .... ..... .... 121
7 Some Application of Selective Toxicities of Acridines.... ..... .... 135
7.1 Antiparasitic Drug ... ..... .... .... .... .... .... ..... .... 135
7.2 Cancer Treatment.... ..... .... .... .... .... .... ..... .... 146
7.3 Antibacterial Drugs... ..... .... .... .... .... .... ..... .... 153
7.4 Antiviral Drugs.. .... ..... .... .... .... .... .... ..... .... 154
References.. .... .... .... ..... .... .... .... .... .... ..... .... 155
8 Pharmacokinetics and Metabolism of Acridine Drugs ... ..... .... 165
References.. .... .... .... ..... .... .... .... .... .... ..... .... 181
9 Acridine on Dendrimeric Carriers... .... .... .... .... ..... .... 187
9.1 Application for Drug and Gene Delivery ... .... .... ..... .... 188
References.. .... .... .... ..... .... .... .... .... .... ..... .... 190
10 Acridines Used for Staining .... .... .... .... .... .... ..... .... 193
References.. .... .... .... ..... .... .... .... .... .... ..... .... 201
11 Miscellaneous... .... .... ..... .... .... .... .... .... ..... .... 207
References.. .... .... .... ..... .... .... .... .... .... ..... .... 209
12 Conclusions and Outlook . ..... .... .... .... .... .... ..... .... 211
Index .... .... .... .... .... ..... .... .... .... .... .... ..... .... 213
Acronyms
The three-letter code used for amino acids follows the rules of the IUPAC-IUB
CommissiononBiochemicalNomenclature.[1]Theone-lettercodeusedforamino
acids follows the rules of the IUPAC-IUB Joint Commission on Biochemical
Nomenclature. [2] These articles show also how to read formulas of peptides used
in this work. [3] Selected abbreviations are commonly used especially for
description of acridines in peptide conjugates and neurodegenerative disorders:
AAAcr 9-(p-aminomethylphenylamino)acridine-4-carboxylic acid
Ab amyloid b
AC04 5-(acridin-9-yl-methylidene)-3-(4-methyl-benzyl)-
thiazolidine-2,4-dione
Acd b-(9,10H-acridon-2-yl)alanine
AChE Acetylcholinesterase
ACMA 9-amino-6-chloro-2-methoxyacridine
Acr Acridin-9-yl
ACRAMTU 1-[2-(acridin-9-yl-amino)ethyl]-1,3-dimethylthiourea
Acr4CA 4-(2-methylaminoethylaminocarbonyl)-acridin-9-yl
AD Alzheimer’s disease
ADE Amyloid degrading enzymes
AHMA 3-(9-acridinylamino)-5-hydroxy-methylaniline
ALS Amyotrophic lateral sclerosis
AO Acridine orange
Aol 3,6-bis-(dimethylamino)acridin-9-yl
APP Amyloid precursor protein
BACE b-secretase
BBB Blood–brain barrier
BChE Butyrylcholinesterase
BRACO19 N,N’-(9-(4-(dimethylamino)phenylamino)acridine-3,6-diyl) bis
(3-(pyrrolidin-1-yl)propan-amide) trihydrochloride
BSE Bovine spongiform encephalopathy
xi
