Natural Products Targeting Clinically Relevant Enzymes E-Book
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- Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
The past decade has seen the reappearance of natural products as a valuable source of potent therapeutics. Here, experts on bioactive natural products cover the full spectrum of clinically relevant enzymes that are known to be targeted by natural products. Key enzymes include acetylcholine esterase, angiotensin-I-converting enzyme, cyclooxygenase, dihydrofolate reductase, phospholipase A2, respiratory complexes, and many more.
By connecting the diversity of medicinal natural product sources with their potential clinical applications, this volume serves as a companion for the medicinal chemist looking for innovative small molecule compounds as well as for pharmacologist interested in the clinical effects and mode of action of herbal and traditional medicines.
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Table of Contents
Cover
Title Page
Copyright
List of Contributors
Chapter 1: Natural Products as Enzyme Inhibitors
1.1 Why Are Natural Products Good Enzyme Inhibitors?
1.2 Drawbacks of Natural Products
1.3 The Future of Natural Products Drug Discovery
1.4 Conclusion
References
Chapter 2: Molecular Targets of Clinically Relevant Natural Products from Filamentous Marine Cyanobacteria
2.1 Introduction
2.2 Histone Deacetylase Inhibitors
2.3 Proteasome Inhibitors
2.4 Protease Enzymes
2.5 Protein Kinase C Modulators
2.6 Interference of the Actin and Microtubule Filaments
2.7 Sec61 Protein Translocation Channel Inhibitors
2.8 Prohibitin Inhibitors
2.9 Sodium Channels Modulators
2.10 Conclusions
References
Chapter 3: Natural Angiotensin Converting Enzyme (ACE) Inhibitors with Antihypertensive Properties
3.1 Introduction
3.2 Mechanisms of Blood Pressure Regulation
3.3 The Treatment of Hypertension
3.4 Natural Products as Angiotensin Converting Enzyme Inhibitors
3.5 Conclusions
References
Chapter 4: Phospholipase A2 Inhibitors of Marine Origin
4.1 Relevance of Marine Organisms
4.2 Inflammation
4.3 Marine Molecules as PLA
2
Inhibitors
4.4 Conclusion
References
Chapter 5: β-Secretase (BACE1) Inhibitors from Natural Products
5.1 Introduction
5.2 Flavonoids
5.3 Chromones
5.4 Phenolic Acids and Tannins
5.5 Stilbenes and Derivatives
5.6 Coumarins
5.7 Benzoquinones and Anthraquinones
5.8 Alkaloids
5.9 Terpenes
5.10 Lignans
5.11 Fatty Acid
5.12 Saccharides, Peptides and Amino Acid Derivatives
5.13 BACE1 Inhibitory Active Extracts of Natural Products
5.14 Bioassays for the Discovery of BACE1 Inhibitors
5.15 Prospective
Acknowledgements
References
Chapter 6: Hypoglycaemic Effects of Plants Food Constituents via Inhibition of Carbohydrate-Hydrolysing Enzymes: From Chemistry to Future Applications
6.1 Introduction
6.2 α-Amylase
6.3 α-Glucosidase
6.4 Hypoglycaemic Natural Compounds
6.5 Conclusions and Future Perspective
Abbreviations
References
Chapter 7: Natural Products Targeting Clinically Relevant Enzymes of Eicosanoid Biosynthesis Implicated in Inflammation and Cancer
7.1 Introduction
7.2 Eicosanoid Biosynthetic Pathways
7.3 Eicosanoid Biosynthetic Pathways in Inflammation and Cancer
7.4 Natural Products as Anti-inflammatory Agents
7.5 Conclusions and Future Directions
References
Chapter 8: Anti-HIV Natural Products
8.1 Introduction
8.2 Ribosome-Inactivating Proteins
8.3 Reverse Transcriptase Inhibitors
8.4 Inhibitors of HIV Reverse Transcriptase Associated RNase H
8.5 HIV-1 Protease Inhibitors
8.6 HIV-1 Integrase Inhibitors
8.7 Discussion
Acknowledgements
References
Chapter 9: Natural Inhibitors of Mitochondrial Respiratory Chain: Therapeutic and Toxicological Implications
9.1 Introduction: The Structure of the Electron Transport Chain
9.2 Natural Inhibitors of the Respiratory Chain
9.3 Therapeutic, Agrochemical and Toxicological Implications
9.4 Conclusions
References
Chapter 10: Targeting Enzymatic Pathways with Marine-Derived Clinical Agents
10.1 Marine Environment as an Established Source of Drug Candidates
10.2 Enzyme-Targeting Derived Effects of Marine-Derived Approved Drugs
10.3 Marine-Derived Agents in Clinical Development Targeting Relevant Enzymatic Pathways
10.4 Concluding Remarks
Acknowledgements
References
Chapter 11: Anti-Malarial Drug Discovery: New Enzyme Inhibitors
11.1 Introduction
11.2 Falcipain (FP-2) Inhibitors
11.3 Purine Nucleoside Phosphorylase Inhibitors (PNP)
11.4 Dihydrofolate Reductase (DHFR) and Thymidylate Synthase (TS) Inhibitors
11.5 Hypoxanthine-Guanine-(Xanthine) Phosphoribosyltransferase Inhibitors
11.6 Conclusion
Acknowledgement
References
Chapter 12: Natural Plant-Derived Acetylcholinesterase Inhibitors: Relevance for Alzheimer’s Disease
12.1 Introduction
12.2 Natural Acetylcholinesterase Inhibitors
12.3 Conclusion
Acknowledgements
References
Index
End User License Agreement
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Guide
Cover
Table of Contents
Begin Reading
List of Illustrations
Chapter 1: Natural Products as Enzyme Inhibitors
Figure 1.1 Examples of ‘privileged’ scaffolds found in natural products.
Chapter 2: Molecular Targets of Clinically Relevant Natural Products from Filamentous Marine Cyanobacteria
Figure 2.1 Largazole, largazole thiol and synthetic analogues.
Figure 2.2 Santacruzamate A, SAHA and synthetic analogue.
Figure 2.3 Carmaphycins, epoxomicin and salinosporamide A.
Scheme 2.1 Mechanism of action of carmaphycins.
Figure 2.4 Serine protease inhibitors from marine cyanobacteria.
Figure 2.5 Almiramide A, gallinamide A and synthetic analogues.
Figure 2.6 Grassystatins, tasiamides B and F and synthetic analogues.
Figure 2.7 Aplysiatoxin and synthetic analogues.
Figure 2.8 Dolastatin 10, brentuximabvedotin and bisebromoamide.
Figure 2.9 Apratoxin A and synthetic analogues.
Figure 2.10 Aurilide, antillatoxin, hoiamide A, kalkitoxin and jamaicamide A.
Chapter 3: Natural Angiotensin Converting Enzyme (ACE) Inhibitors with Antihypertensive Properties
Figure 3.1 Schematic representation of the ACE active site joined with an inhibitor.
Figure 3.2 Mechanisms of the renin–angiotensin–aldosterone system, the effect of ACE inhibitors and their relation to blood pressure regulation.
Figure 3.3 Basic structure of flavonoid compounds (a) compared with a typical non-flavonoid structure such as resveratrol (b).
Figure 3.4 Structural diagram that quantitatively assesses the effect of the addition or elimination of different structural elements from the flavonoid core on the ACEI activity of luteolin at 100 μM. The presence or absence impact order of each functional group was: absence of C2═C3 double bond (10.7 times less activity by comparing naringenin vs apigenin) > presence of 4′-
O
-methoxylation (4.6 times less activity by comparing diosmetin e luteolin) ≈ absence of 4-carbonyl group (3.8 times less activity by comparing epicatechin vs luteolin) > absence of 3′-hydroxylation (2.3 times less activity by comparing apigenin vs luteolin) > presence of 3-hydroxylation (1.8 times less activity by comparing quercetin vs luteolin) > presence of 3-
O
-glycosylation (1.6 times less activity by comparing rutin vs luteolin).
Chapter 4: Phospholipase A2 Inhibitors of Marine Origin
Figure 4.1 Mechanism of production of pro-inflammatory mediators by release of AA of cell membranes, through two main pathways.
Figure 4.2 Identity of compounds isolated from diverse species of sponges with activity in calcium-dependent PLA2 enzyme inhibition, represented in Table 4.1.
Figure 4.3 Identity of compounds isolated from organisms other than sponges with activity in calcium-dependent PLA2 enzyme inhibition, represented in Table 4.2.
Chapter 6: Hypoglycaemic Effects of Plants Food Constituents via Inhibition of Carbohydrate-Hydrolysing Enzymes: From Chemistry to Future Applications
Figure 6.1 Micranthin (
1
), sintenin (
2
) and (4β,10α-dihydroxy-5β,7β,8β
H
-guaia-1,11(13)dien-12,8α-olide) (
3
) from
Achillea biebersteinii
.
Figure 6.2 1β-
E-O-p
-Methoxycinnamoyl-bemadienolide (
4
), 1β-
O
-(
E
-cinnamoyl)-6α-hydroxy-9-epi-polygodial (
5
), 1β-
O
-(
E
-cinnamoyl)-6α-hydroxypolygodial (
6
), and 1β-
O-E
-cinnamoylpolygodial (
7
) isolated from
Zygogynum pancheri.
Figure 6.3 Labdane diterpenes (
E
)-labda-8(17), 12-diene-15, 16-dial (
8
) and (
E
)-8β, 17-epoxylabd-12-ene-15, 16-dial (
9
) from
Alpinia nigra
.
Figure 6.4 Triterpenes and hederagenin and oleanolic acid derivatives (
10–17
).
Figure 6.5 Chemical structure of 5-methyl-isoxazole-3-methyl carboxylate (
18
) and tricyclic quinazoline alkaloids (
19–23
).
Figure 6.6 Chemical structures of erinidine (
24
), berberine (
25
), dioscoretine (
26
), lupanine (
27
) and 2-thionosparteine (
28
).
Figure 6.7 Chemical structures of anolides (
29–31
) from
Withania somnifera
.
Chapter 7: Natural Products Targeting Clinically Relevant Enzymes of Eicosanoid Biosynthesis Implicated in Inflammation and Cancer
Figure 7.1 Metabolism of Arachidonic acid via the COX, LOX and CYP pathways. COX, cyclooxygenase; CYP, cytochrome P450; EETs, epoxyeicosatrienoic acids; e-LOX-3, epidermis type LOX-3; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; HPETE, hydroperoxyeicosatetraenoic acid; LOX, lipoxygenase; PGG
2
, prostaglandin G2; PGH
2
, prostaglandin H2.
Figure 7.2 Dynamic balance among the PUFA metabolic pathways of AA and LA through LOXs and COX-2 during tumorogenesis. AA, arachidonic acid; COX, cyclooxygenase; e-LOX-3, epidermis type LOX-3; EOS, esterified ω-hydroxyacyl-sphingosine; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; LTA
4
, leukotriene A
4
; LTB
4
, leukotriene B
4
; LA, lenoleic acid; LOX, lipoxygenase; PUFA, polyunsaturated fatty acid; PGE
2
, prostaglandin E
2
.
Chapter 9: Natural Inhibitors of Mitochondrial Respiratory Chain: Therapeutic and Toxicological Implications
Figure 9.1 Scheme depicting the mitochondrial electron transport chain. Electrons from NADH are used by complex I to reduce ubiquinone (CoQ, UQ) to ubiquinol (UQH
2
), which is subsequently used by complex II to reduce cytochrome
c
in the inter-membrane space (IMS). Complex IV then uses the reduced cytochrome
c
to reduce molecular oxygen, the ultimate electron acceptor, generating water. Additional electrons are provided by complex II at the level of ubiquinone. For each NADH molecule, 10 protons are translocated from the matrix to the IMS, generating an electrochemical gradient that drives the complex V (F
1
F
O
ATPase) to synthesize ATP.
Figure 9.2 Examples of inhibitors of complex I: rotenone, piericidin A, ajudazol A, eliamid, nafuredin, ukulactone (ukulactones A and B have the same planar structure).
Figure 9.3 Examples of acetogenins (ACGs) from diverse structural types: montecristin (linear ACG); muricin (mono-THF ACG with one adjacent ─OH group); annonacin (mono-THF ACG with two adjacent ─OH groups); gigantecin (non-adjacent bis-THF ACG); squamocin and laherradurin (adjacent bis-THF ACGs); rollicosin (miscellaneous ACG).
Figure 9.4 Examples of inhibitors of complex II: atpenin A5, caulerpin and siccanin.
Figure 9.5 Examples of inhibitors of complex III: antimycin A3, strobilurin A, chaeotochromin A, AS2077715, ascochlorin and mahanine.
Figure 9.6 Examples of inhibitors of complexes IV (metarhizin A) and V (citreoviridin, oligomycin A).
Figure 9.7 Examples of ETC inhibitors used as fungicidal or anti-protozoan agents: ametoctradin, azoxystrobin, atovaquone and pentamidine.
Figure 9.8 Examples of ETC inhibitors used as anti-diabetic agents: guanidine, metformin.
Figure 9.9 Examples of ETC inhibitors involved in drug toxicity issues: MPTP, simvastatin.
Chapter 10: Targeting Enzymatic Pathways with Marine-Derived Clinical Agents
Figure 10.1 Marine-derived agents approved by the FDA and EMA, and naturally occurring parent metabolites.
Figure 10.2 Marine-derived agents in clinical development.
Chapter 11: Anti-Malarial Drug Discovery: New Enzyme Inhibitors
Figure 11.1 Structure of potent compounds
1
,
2
and
3
.
Figure 11.2 Structure of natural product symplostatin 4 (
Sym4
).
Figure 11.3 Lead compound
4
along with most potent compound
5
.
Figure 11.4 General structure of different vinyl ketones
6–10
.
Figure 11.5 General structure of cinnamic acid-4-aminoquinoline conjugates
11
and
12
.
Figure 11.6 General structure of chalcone–coumarin conjugates
13
and most potent compound
14
.
Figure 11.7 Most potent thiazolidine-2,4-diones based compound
15
.
Figure 11.8 General structure of pyrido[1,2-
a
]pyrimidin-4-ones based compounds
16–19
.
Figure 11.9 Structure of compound
20
,
21
(K11017)
22
(leupeptin) and target scaffold
23
.
Figure 11.10 Structure of potent FP-2 inhibitors
24
,
25
and
26
.
Figure 11.11 Functionalized phthalimides
27
and
28
as potent FP-2 inhibitors.
Figure 11.12 Structure of plumbagin, rhein and positive control, cladribine.
Figure 11.13 Human uridine phosphorylase (
31–33
) and purine-based PNP transition state inhibitors (
34–40
).
Figure 11.14 Structure of potent compounds
41
,
42
and
43
.
Figure 11.15 2-Amino-5-nitro-
N
-hydroxybenzamidine
44
and its complex with metals
45
and
46
.
Figure 11.16 Most potent 4-aminoquinoline-1,3,5-triazine conjugate
47
.
Figure 11.17
S
-benzylated guanylthiourea based potent compound
48
.
Figure 11.18 Most potent 7-chloroquinoline-β-lactam conjugate
49
.
Figure 11.19 General structure of 4-aminoquinoline-1,3,5-triazine hybrids
50
.
Figure 11.20 General structure of urea-linked 4-aminoquinoline-1,3,5-triazine compounds
51
.
Figure 11.21 General structure of 4-aminoquinoline-1,3,5-triazine conjugates
52
.
Figure 11.22 Chemical structure of orally available antimalarial drug candidate
53
.
Figure 11.23 Chemical structure of pyrimethamine (PYR) and compound
54
.
Figure 11.24 General structure of FPEPs
55
and FPMPs
56
.
Figure 11.25 Structure of PEEG, compounds
57
,
58
and
59
.
Figure 11.26 Acyclic aza-C-nucleoside derivatives
60
,
61
and
62
.
Figure 11.27 General structure of aza-ANPs
63
, their prodrugs
64
and most potent compound
65
.
List of Tables
Chapter 1: Natural Products as Enzyme Inhibitors
Table 1.1 Current clinical status of marine drugs.
Chapter 2: Molecular Targets of Clinically Relevant Natural Products from Filamentous Marine Cyanobacteria
Table 2.1 A summary of
in vivo
and
in vitro
studies performed on largazole (
1
).
Table 2.2 Serine protease inhibitors from marine cyanobacteria.
Chapter 3: Natural Angiotensin Converting Enzyme (ACE) Inhibitors with Antihypertensive Properties
Table 3.1 Classification and thresholds of different blood pressure levels.
Table 3.2 ACE inhibitory activity for pure flavonoids, flavonoid glycosides and their metabolites.
Table 3.3 ACE inhibition values obtained from pure non-flavonoid phenolic compounds.
Table 3.4 ACE inhibition values obtained from different polyphenol rich extracts.
Table 3.5 Examples of the most important natural sources used to obtain ACE inhibitor peptides with the related peptide sequences, ACE inhibitory activity and antihypertensive activity.
Chapter 4: Phospholipase A2 Inhibitors of Marine Origin
Table 4.1 Inhibitory effect of sponge-derived compounds against different calcium-dependent PLA
2
.
Table 4.2 Inhibitory effect of various nonsponge-derived compounds against different calcium-dependent PLA
2
.
Chapter 6: Hypoglycaemic Effects of Plants Food Constituents via Inhibition of Carbohydrate-Hydrolysing Enzymes: From Chemistry to Future Applications
Table 6.1
In vitro
α-amylase and α-glucosidase inhibitory activity (IC
50
values) of natural compounds.
Chapter 8: Anti-HIV Natural Products
Table 8.1 Natural products with HIV-1 reverse transcriptase inhibitory activity.
Table 8.3 Natural products with HIV-1 integrase inhibitory activity.
Chapter 9: Natural Inhibitors of Mitochondrial Respiratory Chain: Therapeutic and Toxicological Implications
Table 9.1 Examples of natural inhibitors of complex I.
Table 9.2 Examples of natural inhibitors of complex II.
Table 9.3 Examples of natural inhibitors of complex III.
Table 9.4 Examples of natural inhibitors of complex IV.
Table 9.5 Examples of natural inhibitors of complex V.
Chapter 12: Natural Plant-Derived Acetylcholinesterase Inhibitors: Relevance for Alzheimer’s Disease
Table 12.1 Natural AChE inhibitors.
Table 12.2 Selected alkaloid-based naturally occurring molecules with inhibition against AChE activity.
Table 12.3 Selected non-alkaloid-based naturally occurring molecules with inhibition against AChE activity.
Natural Products Targeting Clinically Relevant Enzymes
Edited by
Paula B. Andrade Patrícia Valentão David M. Pereira
Editors
Prof. Paula B. Andrade
Universidade do Porto
REQUIMTE/LAQV
Rua de Jorge Viterbo Ferreira, 228
4050-313 Porto
Portugal
Prof. Patrícia Valentão
Universidade to Porto
REQUIMTE/LAQV
Rua de Jorge Viterbo Ferreira, 228
4050-313 Porto
Portugal
Prof. David M. Pereira
Universidade do Porto
REQUIMTE/LAQV
Rua de Jorge Viterbo Ferreira, 228
4050-313 Porto
Portugal
Cover
fotolia/mozZz und fotolia/Vidoslava
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Library of Congress Card No.: applied for
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A catalogue record for this book is available from the British Library.
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Cover Design Grafik-Design Schulz
List of Contributors
Catarina Andrade
REQUIMTE/LAQV Universidade do Porto
Laboratório de Farmacognosia Departamento de Química Faculdade de Farmácia
Rua de Jorge Viterbo Ferreira, Nº 228,
4050-213 Porto
Portugal
Paula B. Andrade
REQUIMTE/LAQV
Universidade do Porto
Laboratório de Farmacognosia Departamento de Química Faculdade de Farmácia
Rua de Jorge Viterbo Ferreira, Nº 228,
4050-213 Porto
Portugal
Anna Arola-Arnal
Universitat Rovira i Virgili
Biochemistry and Biotechnology Department
Marcel lí Domingo s/n
43007 Tarragona
Spain
Vasundhra Bhandari
University of Hyderabad
Department of Animal Biology
School of Life Sciences
Hyderabad
500046 Telangana
India
Anupam Bishayee
Larkin University
Department of Pharmaceutical Sciences
College of Pharmacy
Miami, FL 33169
USA
Marco Bonesi
University of Calabria
Department of Pharmacy
Health and Nutritional Sciences
Rende (CS)
Italy
Nady Braidy
UNSW Medicine
School of Psychiatry, NPI
Barker Street
Randwick
NSW 2031
Australia
Francisca I. Bravo
Universitat Rovira i Virgili
Biochemistry and Biotechnology Department
Marcel lí Domingo s/n
43007 Tarragona
Spain
Helen Chan
Genning Partners Company Limited
Causeway Bay; Institute of Medical Research Central; and Vita Green
Pharmaceutical (Hong Kong), Ltd. Tai Po, N.T.
Hong Kong
China
Chi Fai Cheung
The Chinese University of Hong Kong
School of Biomedical Sciences
Faculty of Medicine Shatin, N.T.,
Hong Kong
China
Ramesh Dasari
Texas State University
Department of Chemistry and Biochemistry
San Marcos TX 78666
USA
Shobha Ediga
University of Hyderabad
Department of Animal Biology
School of Life Sciences
Hyderabad
500046 Telangana
India
Wei-Shuo Fang
Institute of Materia Medica
Chinese Academy of Medical Science
Beijing 100050
China
Priyanka Voori Giri
University of Hyderabad
Department of Animal Biology
School of Life Sciences
Hyderabad
500046 Telangana
India
Nelson G. M. Gomes
REQUIMTE/LAQV
University of Porto
Laboratory of Pharmacognosy
Department of Chemistry
Faculty of Pharmacy
R. Jorge Viterbo Ferreira Nº.
2284050-313 Porto
Portugal
Na Guo
Institute of Materia Medica
Chinese Academy of Medical Science
Beijing 100050
China
Tharusha Jayasena
UNSW Medicine
School of Psychiatry, NPI
Barker Street
Randwick NSW 2031
Australia
Robert Kiss
Université Libre de Bruxelles
Campus de la Plaine
Laboratoire de Cancérologie et de Toxicologie
Expérimentale
Faculté de Pharmacie
CP205/1, Boulevard du Triomphe
1050 Brussels
Belgium
Alexander Kornienko
Texas State University
Department of Chemistry and Biochemistry
San Marcos TX 78666
USA
Naresh Kumar
University of Hyderabad
Department of Animal Biology
School of Life Sciences
Hyderabad
500046 Telangana
India
Vipan Kumar
Guru Nanak Dev University
Department of Chemistry
Grand Trunk Road
Amritsar 143005
India
Florence Lefranc
Université Libre de Bruxelles
Service de Neurochirurgie
Hôpital Erasme
808 Route de Lennik
1070 Brussels
Belgium
Monica R. Loizzo
University of Calabria
Department of Pharmacy Health and Nutritional Sciences Rende (CS)
Italy
Maria Margalef
Universitat Rovira i Virgili
Biochemistry and Biotechnology Department
Marcel lí Domingo s/n
43007 Tarragona
Spain
Begoña Muguerza
Universitat Rovira i Virgili
Biochemistry and Biotechnology Department
Marcel lí Domingo s/n
43007 Tarragona
Spain
Seyed M. Nabavi
Baqiyatallah University of Medical Sciences
Applied Biotechnology Research Center
Tehran
Iran
Charlene Cheuk Wing Ng
GKT School of Medicinal Education
King's College London SEI IUL
United Kingdom
Tzi Bun Ng
The Chinese University of Hong Kong
School of Biomedical Sciences
Faculty of Medicine Shatin, N.T.,
Hong Kong
China
Nuria de Pedro
Life Length
Parque Científico de Madrid
Faraday 7
Campus de Cantoblanco
28049 Madrid Spain
Fernando Peláez
CNIO – Spanish National Cancer Research Centre Biotechnology Programme
C/Melchor Fernández Almagro, 3
28029 Madrid
Spain
David M. Pereira
REQUIMTE/LAQV
Universidade do Porto
Laboratório de Farmacognosia Departamento de Química Faculdade de Farmácia
Rua de Jorge Viterbo Ferreira, Nº 228, 4050-213 Porto
Portugal
Renato B. Pereira
REQUIMTE/LAQV
University of Porto
Laboratory of Pharmacognosy
Department of Chemistry
Faculty of Pharmacy
R. Jorge Viterbo Ferreira Nº. 228
4050-313 Porto
Portugal
Anne Poljak
UNSW Medicine
School of Psychiatry, NPI
Barker Street
Randwick NSW 2031
Australia
Raghu Raj
Guru Nanak Dev University
Department of Chemistry
Grand Trunk Road
Amritsar 143005
India
Chintalapally V. Rao
University of Oklahoma
Center for Cancer Prevention
and Drug Development
Health Sciences Center
Oklahoma city, OKUSA
Luca Rastrelli
University of Salerno
Department of Pharmacy
Fisciano (SA)
Italy
Pallu Reddanna
University of Hyderabad
Department of Animal Biology
School of Life Sciences
Hyderabad
500046 Telangana
India
Gorla V. Reddy
University of Hyderabad
Department of Animal Biology
School of Life Sciences
Hyderabad
500046 Telangana
India
Perminder Sachdev
UNSW Medicine
School of Psychiatry, NPI
Barker Street
Randwick NSW 2031
Australia
Tânia Silva
REQUIMTE/LAQV
Universidade do Porto
Laboratório de Farmacognosia Departamento de Química Faculdade de Farmácia
Rua de Jorge Viterbo Ferreira Nº 228 4050-213 Porto
Portugal
Sandhya Singh
University of Hyderabad
Department of Animal Biology
School of Life Sciences
Hyderabad
500046 Telangana
India
Eduardo Sobarzo-Sánchez
University of Santiago de Compostela
Laboratory of Pharmaceutical Chemistry
Department of Organic Chemistry Faculty of Pharmacy 15782 Santiago de Compostela
Spain
and
Universidad Central de Chile
Instituto de Investigación e Innovación en Salud
Facultad de Ciencias de la Salud
Chile
Deyang Sun
Institute of Materia Medica
Chinese Academy of Medical Science
Beijing 100050
China
Lik Tong Tan
Nanyang Technology University
National Institute of Education
1 Nanyang Walk
Singapore 637616
Singapore
Dinesh K. Tiwari
University of Hyderabad
Department of Animal Biology
School of Life Sciences
Hyderabad
500046 Telangana
India
José R. Tormo
Chemistry Area
Fundación MEDINA
Parque Tecnológico de la Salud
Av. Conocimiento 34
18016 Granada Spain
Tak Fu Tse
Genning Partners Company Limited
Causeway Bay; Institute of Medical Research Central; and Vita Green
Pharmaceutical (Hong Kong), Ltd. Tai Po, N.T.
Hong Kong
China
Rosa Tundis
University of Calabria
Department of Pharmacy
Health and Nutritional Sciences Rende (CS)
Italy
Patrícia Valentão
REQUIMTE/LAQV
Universidade do Porto Laboratório de Farmacognosia Departamento de Química Faculdade de Farmácia
Rua de Jorge Viterbo Ferreira, Nº 228
4050-213 Porto
Portugal
Jack Ho Wong
The Chinese University of Hong Kong
School of Biomedical Sciences
Faculty of Medicine Shatin, N.T.,
Hong Kong
China
Shuang Yang
Institute of Materia Medica
Chinese Academy of Medical Science
Beijing 100050
China
Nagendra S. Yarla
University of Hyderabad
Department of Animal Biology
School of Life Sciences
Hyderabad
500046 Telangana
India
Chapter 1Natural Products as Enzyme Inhibitors
David M. Pereira, Catarina Andrade, Patrícia Valentão and Paula B. Andrade
REQUIMTE/LAQV, Universidade do Porto, Laboratório de Farmacognosia Departamento de Química, Faculdade de Farmácia, Rua de Jorge Viterbo Ferreira, Nº 228, 4050-213, Porto, Portugal
1.1 Why Are Natural Products Good Enzyme Inhibitors?
Natural products are widely distributed and their unique properties have been explored for centuries by our earliest ancestors to treat diseases and injuries. Throughout evolution, the potential of natural products as modulators of biological functions has been increasingly realized [1].
Over the past decades, there has been a decrease in the use of natural products by pharmaceutical companies as a starting point for drug discovery, essentially due to the belief that natural products were somehow incompatible with drug discovery approaches that were based on high-throughput screening directed towards molecular targets [2]. Furthermore, there was also the assumption that combinatorial chemistry techniques would be able to generate all the chemical diversity needed for successful lead discovery. However, the results of many large combinatorial screening collections have proved to be quite discouraging and it has already been recognized that diversity within biologically relevant ‘chemical space’ is more important than library size. To a certain point, libraries of synthetic molecules have been designed to mimic the chemical properties of the natural compounds [3].
Despite the deficiency of investment in natural products as main leads in drug discovery over the past decades, 34% of the medicines approved by the US Food and Drug Administration (FDA) between 1981 and 2010 were actually natural products or directly derived from them [4].
The great potential of molecules of natural origin in drug discovery arises from their remarkable chemical and structural diversity. About 40% of the chemical scaffolds found in natural products are indeed absent in today’s medicinal chemistry synthetic libraries. For this reason, the use of nature-inspired molecules is a good complement to synthetically produced molecules [5, 6].
One of the most relevant reasons for the success of natural products as a source of bioactive molecules arises from their ‘drug-likeness’, which frequently surpasses that of synthetic compounds. Considering their biosynthetic processes in living organisms, it is not surprising that natural molecules display greater similarity and binding potential with biological structures, thus increasing the probability of an effective interaction with different biological targets [6].
One of the most outstanding features of natural products is their three-dimensional conformation, which is attributed to the complex and unique structure that is mostly beyond the synthetic capacity of medicinal chemistry. Natural products are often described for their ‘privileged’ scaffold, allowing them to work as ligands for a diverse array of enzymes and receptors. This term, first mentioned by Evans in the late 1980s, was originally used to address the benzodiazepines scaffold, privileged by their ability to bind not only to their receptors at the central and peripheral nervous system, but also to cholecystokinin receptors. In this way, and according to Evans’s definition, a privileged structure displays affinity to several receptors/proteins [7, 8]. In 2010, Matthew et al., presented an exhaustive review by providing a comprehensive list of privileged scaffolds found in both synthetic drugs and natural ones. Spiket-p, integramycin and routiennocin, despite having the same scaffold (6,6-spiroacetal), display different bioactivities and are found in different species, which demonstrates the evolution-driven predisposition for repetition, once a suitable solution to a particular biochemical problem has been found (Figure 1.1). This can also explain the non-random patterning of macromolecular structures in living systems. Consequently, 6,6-spiroacetal is a ‘privileged’ scaffold found in a number of natural products displaying the ability to bind to different targets thereby exerting different pharmacological effects [9].
Figure 1.1 Examples of ‘privileged’ scaffolds found in natural products.
Adapted from [9].)
Considering the enormous variety of compounds occupying the ‘chemical space’, it can easily be assumed that natural products cover distinct regions when compared with synthetic ones, having wider and more drug-like properties. Rosén et al. demonstrated throughout computational screenings that natural products cover parts of the chemical space that lack representation by medicinal chemistry compounds and, by doing so, these compounds may be useful for novel leads [10].
For obvious reasons, the difference between natural products and other sources of molecules, with relevance to their ability to display biological properties, has a chemical basis [11, 12]. In general, the composition of natural molecules is distinct from that of synthetic ones, as they display fewer nitrogen, sulfur or halogen atoms, being richer in oxygen and containing more hydrogen bond donors. The sterical complexity of natural products also plays a role in this equation, these molecules presenting a larger number of rings and, overall, more chiral centres.
But why? Why do natural products present such chemical traits? The obvious answer is that they are not randomly synthesized, instead resulting from biosynthetic processes that are highly targeted. For this reason, these molecules are meant to interact with molecular targets that are, themselves, three-dimensional and chiral. In addition, the enzymes involved in the biosynthesis are usually chiral in the way they usually yield a single isomer, a trait not always found in medicinal chemistry, where racemic mixtures are frequently produced [12]. Enzymes involved in their natural biosynthesis, as well as the molecular targets the natural product is meant to interact with, are inherently three-dimensional and chiral as human enzymes are. Thus, there is actually a link that can explain why natural products can display good results as enzyme inhibitors [12].
The fact that the majority of natural products exhibits such characteristics, shows that they result from an evolutionary drive that selects molecules displaying a certain arrangement of atoms [12, 13]. In addition, the probability of finding a bioactive molecule is much higher in natural products when compared with a randomly synthesized molecule [8]. This is not surprising if we consider that it arises from nature’s own high-throughput screening: not only are molecules prone to display the well-defined three-dimensional structure described above, but they are also produced to target well-conserved biological targets in a certain mechanism of action, meaning that they are synthesized to display some kind of activity towards a biological target [9, 14].
Another striking difference between natural products and randomly synthesized molecules rests in the underlying synthesis strategy in both cases. Unlike combinatorial chemistry, which can make use of tens of thousands of different scaffolds as building blocks, no such mechanism is available in nature. In fact, for biosynthesis, nature has a limited number of building blocks available from a small number of biosynthetic pathways and, for this reason, any chemical novelty can only be achieved by branching out intermediates and creating a multitude of biosynthetic routes, ultimately generating different chemical entities. A different strategy is adopted in combinatorial chemistry, in which it is frequent to follow the same sequence of reactions using different starting molecules.
Nature’s chemistry is, in its essence, oxophilic and, hence, it has the enzymatic tools performing site-selective C─H activation, in order to introduce oxygen atoms and discriminate between functional groups with different degrees of oxidation [15, 16]. Natural products have coexisted over time with several species and environments, thus undergoing the same iterative cycle of improvements and evolution with ever changing biotic systems.
Several natural compounds or their derivatives act as enzyme inhibitors in different therapeutic areas, such as in the treatment of cancer, diabetes, hypertension and infectious diseases [17]. Teprotide, isolated from Bothrops jararaca venom, is a classic example. This compound displayed long-lasting in vivo activity against angiotensin-converting enzyme and was chosen as a lead compound for the development of angiotensin carboxypeptidase inhibitors [18]. Galanthamine, an anti-cholinesterase drug isolated from the snowdrop plant Galanthus nivalis L., has been prescribed broadly for the treatment of Alzheimer’s [19]. Vialinin A, a p-terphenyl compound obtained from the edible Chinese mushroom Thelephora vialis plant, strongly inhibits tumour necrosis factor-α production and release [20].
Given the complex structural variety of these products, it is reasonable to question the likelihood of these compounds actually presenting viability as orally active drugs. In 1997, Lipinski provided a set of four parameters common to 90% of more than 2000 drugs and candidate drugs at, or beyond, phase II clinical trials. These parameters state that in order for a candidate drug to be drug-like it should have less than five donor groups of hydrogen, less than five hydrogen acceptor groups, a molecular weight lower than 500 Da and log P lower than 5. However, it is irrefutable that many biologically active natural compounds do not fulfil all of these requirements. In this way, 12 of the 24 natural drugs approved between 1970 and 2006 do not agree with Lipinski’s rule [11, 21]. Actually, in 2006 only 51% of all FDA-approved small molecule drugs were used orally and comply with this rule [22].
Nonetheless, it is important to take into account that Lipinski’s rules leave out some aspects that are imperative to discuss. For example, natural products frequently benefit from transport mechanisms, which results in characteristics, such as molecular weight, to be less important regarding intestinal absorption [11].
1.2 Drawbacks of Natural Products
Despite the general potential of natural products in drug discovery, there are still some drawbacks that can hinder pharmaceutical development. Technologies and methodologies that allow natural products to be used effectively and efficiently in drug discovery are not yet fully matured to the point of sustaining the demand of pharmaceutical companies, thus leading to a loss of interest in their development over the past decades [23].
One of the most relevant issues is related to the difficulty in scaling-up. Indeed, given the fact that most bioactive natural products are secondary metabolites, they are frequently found in small amounts in a given extract/species and cannot meet the pharmaceutical market demand, which can reach a scale of hundreds to thousands of kilograms per year [24]. However, as we will discuss subsequently, this situation can be addressed by relying on biotechnological approaches, such as fermentation, provided their cost does not limit the economic sustainability, which is pivotal to guarantee the progression to preclinical development. In this regard, it should be highlighted that the recent advances in drug discovery from non-conventional sources, such as marine organisms or extremophiles, may frequently result in a problem of tractability, as the bioactive molecules may be produced by symbiotic organisms [23, 25, 26].
Another aspect regarding drug discovery is the lack of high-quality libraries of natural products, due to the difficulty in their construction and maintenance. Nonetheless, when screening natural product libraries, rediscovery of known compounds is also a leading problem because of the lack of robust dereplication methodologies for both natural product sourcing and compounds in the natural product libraries [23].
Another constraint is the lack of novelty. As expected, most of the times when a sample is under study within a context of activity-guided isolation, the probability of finding an already known molecule is quite high. In certain cases, when novel molecules are obtained, structure elucidation can be challenging for some classes of natural compounds with high chemical complexity [12]. When a new lead compound is found, molecular modifications of the lead structure may be a challenge mainly due to the complexity of these compounds that, as referred above, display many functional groups that need to be protected for analogue synthesis [23].
