1st lecture - International Center for Chemical and Biological

Report
CHEM-705
Biosynthesis and Isolation of Natural
Products and Bioassay Screenings
Set A
February - 2014
Prof. Dr. Shaheen Faizi
1
CHEM-705
Biosynthesis of Natural Product
Set A
First – Third Lectures
Prof. Dr. Shaheen Faizi
2
• The people of understanding remember Allah
standing, sitting and reclining, and ponder
over the creation of the heavens and the
earth, which impels them to supplicate: “O
Lord! Thou hast not created all this without
purpose. Glory be to thee.”
(3:191)
3
CHEM-705
Biosynthesis and Isolation of Natural
Products and Bioassay Screenings
a)
Bioassay screening
-
Prof. Dr. Iqbal Choudhary (7)
Dr. Talat Makhmoor (6)
Dr. Shabana Simjee (7)
b)
Isolation techinques
–
Dr. Mussharaf (20)
c)
Biosynthesis
-
Prof. Dr. Shaheen Faizi (30)
Prof. Dr. Sabira Begum (30)
Total Number = 100
4
Biosynthesis of Natural Products
a) Natural Products
b) Biosynthesis
Natural Products
From
Plants, animals, microorganisms, marine organisms
as medicines
as templates
Compounds which have biological activities and are derived from natural sources, e.g., plants,
animals and microorganisms, are defined as natural products. Natural products have been used by
human societies for millennia. (a)Dwight D. Baker, Min Chu, Uma Oza and Vineet Rajgarhia, The
value of natural products to future pharmaceutical discovery, Nat. Prod. Rep., 2007, 24, 1225–1244,
b) G. M. Cragg, P. G. Grothaus, D. J. Newman, Natural products in drug discovery: Recent
advances, In plant bioactive and drug discovery: Principles, practice, and perspectives, V. CechinelFilo, ed. 2012, vol. 17 of Wiley series. John Wiley & Sons. pp. 1-42,
http://www.nlm.nih.gov/hmd/collections/archives/index.html,
c) http://www.botanical-online.com/theimportanceofplants.htm d) M. S. Butler, Natural products to
drugs: natural product derived compounds in clinical trials, Nat. Prod. Rep., 2008, 25(3), 475-516.
5
OH
O
OH
PLANTS
H
Glc
Barbaloin
OH
OH
OH
Aloe barbadensis
(Liliaceae)
Glc
OH
COOH
O
HO
(Anthranol tautomer)
1
OH
O
4
H
HO
Galacturonic acid 1
4
COOH
O
O
HO
OH
O
CH2OCOCH3
O
HOH2C
OH
O
HO
OH
O
OH
O
O
HO
HO
O
HOH2C
O
O
OH
HOH2C
Pectin (400-1000 residues)
Glucomannans
6
O
OH
O
OH
OAc
H
OH
Coleus forskohlii
(Labiatae / Lamiaceae)
Forskolin
(Diterpene)
H
H
O
O
O
O
O
O
H
O
O
O
Artemisia annua
(Composetae / Asteraceae)
H
Artemisinin
(Sesquiterpene lactone containing
a rare peroxide linkage)
H
OEt
Arteether
7
N
N
N
H MeO C
2
OH
H
N
Me
MeO
Catharanthus roseus
(Apocynaceae)
OAc
OH
H CO Me
2
Vinblastine
(Alkaloid)
Chromic acid
(Controlled oxidation)
N-demethylation using
Streptomyces albogriseolus
N
N
N
H MeO C
2
OH
H
N
CHO
MeO
Vincristine
OAc
OH
H CO Me
2
8
O
O
OH
O
HO
HO
1
4
O
O
OH
1
4
H
O
D
OH
O
1
4
1
O
OH
A
H
OH
O
O
H
OH
Digitoxin
(Steroidal glycoside)
Digitalis purpurea
(Scrophulaciaceae)
O
O
H
C
O
D
H
H
H
A
H
B
HO
H
Agave sisalana
(Agavaceae)
Hecogenin
(Steroid)
9
OH
B
Rha
Glu
O
O
A
C
OH
O
Naringin
(Flavanone glycoside)
Citrus paradisi
(Rutaceae)
O
O
CH3
CH3
CH3
CH3
CH3
H
O
OH
H
O
CH3
H
HO
O
C
H
D
O
O
O
OH
O
H
A
O
B
OH
O
OH
H
-Sitosterolglucoside
Citrus aurantium
(Sour orange)
J. Agric. Food Chem., 2010, 58, 180-186
Phytother. Res., 2009, 23, 948-954
Chem. Rev., 2011, 111, 7437-7522
Limonexic acid
10
J. Agric. Food Chem., 2007, 55, 10067-10080
H
O
O
S
S
1-Propenyl
sulphenic acid
(Z)-Propanethial S-oxide
(onion lachrmatory factor)
Allium sepa - Onion
(Alliaceae)
O
H
NH2
S
COOH
S-allyl L-cystein sulphoxide
allinase
OH
S
x2
allyl sulphenic acid
-H2O
O
Allium sativum - garlic
(Alliaceae)
S
S
Allicin
(diallyl thiosalphinate)
(in crushed bulbs)
11
Animal
O
O
C
H
H
A
OH
HO
H
Bufo spp. (Toad)
Bufalin
J. Nat. Prod. 2013, 76, 865-872
J. Nat. Prod, 2013, 76, 1078-1084
Insect
N
N
Stenusine
Stenus similis
beetles
(Z)-3(2-Methyl-1-butenyl) pyridine
J. Nat. Prod, 2011, 74, 2231-2234
12
Microorganisms
Fungus
Penicillium griseofulvum
Penicillium patulm
O
OCH3
H3CO
OCH3
O
O
O
H3CO
O
O
OH
O
OH
Cl
Griseofulvin
(antifungal, used for dermatophyte infection)
Penicillic acid
(carcinogen)
Patulin
(carcinogen)
13
Streptomyces orchidaceus
Streptomyces venezuelae
Clavicep spp.
OH
CH2OH
Ergots (seed like)
CH3
HO
NHCOCHCl2
O
N
NH
H
NH2
H
O
N
H
O
D-Cycloserine
(simplest substance with antibiotic activity)
NO2
Chloramphenicol
(+) Lysergic acid
Ergoline
14
H
Marine Natural Product
N
N
OH
N
N
Pyrinadine A
Tet. Lett., 2006, 47, 997-998.
Cribrochalina sp. (Sponge)
O
HO
O
OH
Dysidera avara (Sponge)
Avarol
(Sesquiterpene hydroquinone)
Avarone
(Quinone)
Nat. Prod. Rep., 2011, 28, 400-410.
15
O
Cl
OH
I
Br
Br
OH
Br
I
Cl
Cl
Br
Br
O
Volatile halogenated hydrocarbons
Asparagopsis of taxiforms
Red Alga
Nat. Prod. Rep., 2011, 28, 186-195
OH
OH
OH
O
CH3
O
O
CH3
CH3
Ieodomycins A
Ieodomycins B
Marine Bacillus sp.
J. Nat. Prod., 2011, 74, 1606-1612
O
H3C
Streptomyces sp.
(Deep-sea actinomycete)
O
CH3
N
H
O
Streptokordin
(Cytotoxic and antibiotic)
J. Nat. Prod., 2007, 24, 777-797
16
Natural products from plant-associated microorganisms
According to a recent review, the classification and documenting of terrestrial flora have been intensively investigated, with estimates of the
number of higher plant species ranging from 300 000 to as high as 500 000. In terms of pharmacological and phytochemical investigation,
however, estimates are as low as 6% and 15%, respectively. Furthermore, the marine environment remains virtually unexplored as a potential
source of novel drugs, and until recently, the investigation had largely been restricted to tropical and subtropical regions.
The power of Nature as applied to plant secondary metabolite production can be augmented through the use of chemical elicitors and selected
derivatives of biosynthetic precursors. Thus, exposure of the roots of hydroponically grown plants to chemical elicitors induces the selective
and reproducible production of bioactive compounds, while the feeding of seedlings of Catharanthus roseus with various tryptamine
analogues has resulted in the production of non-natural terpene indole alkaloids related to the vinca alkaloids.
With the current ability to cultivate only a vanishingly small number of naturally accurring microorganisms, the study of either terrestrial or
marine natural microbial ecosystems has been severely limited. As a result, it has been estimated that less than 1% of microorganisms seen
microscopically have been cultivated. Nevertheless, despite this limitation, a most impressive number of highly effective microbially derived
chemotherapeutic agents has been discovered and developed. Given the observation that “a handful of soil contains billions of microbial
organisms”, and the assertion that “the workings of the biosphere depend absolutely on the activities of the the microbial world”, the
microbial universe clearly presents a vast untapped resource for drug discovery.
There is mounting evidence that many bioactive compounds isolated from various macro-organisms, which can include plants, marine,
terrestrial invertebrates, and even fungi, are actually metabolites synthesized by symbiotic bacteria.
The discovery of a bacterium – fungus – plant interaction occurring in the case of rice seedling blight provides an interesting example of an
even more complex symbiotic-pathogenic relationship.
17
It is a fact that plants have been relatively extensively studied as sources of bioactive metabolites, but the role of endophytic microbes that
reside in the tissues between living plant cells has only recently started receiving attention. The relationships between endophytes and their
host plants may vary from symbiotic to pathogenic, and studies are revealing an interesting realm of novel chemistry. Among the wide
range of new bioactive molecules reported, are peptide antibiotics, the coronamycins (structure not determined), isolated from a
Streptomyces species associated with an epiphytic vine (Monastera species) found in the Peruvian Amazon.
Histrocally, the major impediments to the development of a natural product lead have been limited availability and structural complexity.
Natural products are often produced in trace quantities, and biomass is limited or, in the case of microbial sources, unculturable. The
discovery of novel natural products has been revolutionized by advances in genomic mining and the engineering biosynthetic pathways.
These methods can also be utilized to enable large-scale production of natural products in the native or engineered organisms.
Nature has been a source of medicinal products for millennia, and during the past century, many useful drugs have been developed from
natural sources, particularly plants. It is clear that Nature will continue to be a major source of new drug leads. The drug potential of the
marine environment remains relatively unexplored, but it is becoming increasingly evident that the realm of microorganisms offers a vast
untapped potential. With the advent of genetic techniques that permit the isolation and expression of biosynthetic cassettes, microbes and
their marine invertebrate hosts may well be the new frontier for natural products lead discovery. Plant endophytes also offer an exciting
new resource, and research continues to reveal that many of the important drugs originally thought to be produced by plants are probably
products of an interaction with endophytic microbes residing in the tissues between living plant cells. This has been further accentuated by
the recent report of the isolation of hypericin form an endophytic fungus from Hypericum perforatum. Effective drug development will
depend on multidisciplinary collaboration embracing natural product lead discovery and optimization through the application of total and
diversity-oriented synthesis and combinatorial chemistry and biochemistry, combined with good biology.
18
1
S. Kusari and M. Spiteller, Are we ready for industrial production of bioactive plant secondary metabolites utilizing
endophytes? Nat. Prod. Rep., 2011, 28, 1203-1207.
2
R. N. Kharwar, A. Mishra, S. K. Gond, A. Stierle and D. Stierle, Anticancer compounds derived from fungal
endophytes: their importance and future challenges, Nat. Prod. Rep., 2011, 28, 1208-1228.
3
C.-L. Shao, C.-Y. Wang, Y.-C. Gu, M.-Y. Wei, J.-H. Pan, D.-S. Deng, Z.-G. She, Y.-C. Lin, Penicinoline, a new
pyrrolyl 4-quinolinone alkaloid with an unprecedented ring system from an endophytic fungus Penicillium sp. Bio.
Med. Chem. Lett., 2010, 20, 3284-3286.
4
5
Y. Zhang, T. Han, Q. Ming, L. Wu, K. Rahman, L. Qin, Alkaloids produced by endophytic fungi: a review, Nat. Prod.
Commun., 2012, 7, 963-8.
J. M. Crawford and J. Clardy, Bacterial symbionts and natural products, Chem. Commun. 2011, 47, 7559-7566.
6
S. Kusari, S. P. Pandey, M. Spiteller, Untapped mutualistic paradigms linking host plant and endophytic fungal
production of similar bioactive secondary metabolities, Phytochem., 2012,
http://dx.doi.org/10.1016/j.phytochem.2012.07.021.
7
S. Kusari, C. Hertweck, M. Spiteller, Chemical ecology of endophytic fungi: origins of secondary metabolites, Chem.
& Biol., 2012, 19, 792-798.
8
E. Adelin, C. Servy, S. Cortial, H. Lévaique, M.-T. Martin, P. Retailleau, G. L. Goff, B. Bussaban, S. Lumyong, J.
Quazzani, Isolation structure elucidation and biological activity of metabolites from Sch-642305-producing
endophytic fungus Phomopsis sp. CMU-LMA, Phytochem., 2011, 72, 2406-2412.
9
Q. Ming, T. Han, W. Li, Q. Zhang, H. Zhang, C. Zheng, F. Huagn, K. Rahman, L. Qin, Tanshinone IIA and tanshinone
I production by Trichoderma atroviride D16, an endophytic fungus in Salvia miltiorrhiza, Phytomed., 2012, 19, 330333.
19
10 M. Tadych, J. F. White, Endophytic Microbes, In Encyclo. Microbiol., 2009, 431-442.
11
Gordon M. Gragg, Paul G. Grothaus, and David J. Newman, Impact of natural products on developing new anticancer agents, Chem. Rev. 2009, 109, 30120-3043.
12
A. A. Leslie Guantilaka, Natural products from plant-associated microorganisms: Distribution, structural
diversity, bioactivity, and implication of their occurrence, J. Nat. Prod. 2006, 69, 509-526.
13
G. Strobel, B. Daisy, U. Castillo and J. Harper, Natural products from endophytic microorganisms, J. Nat. Prod.
2004, 67, 257-268.
14
Li-Li Xua, Ting Han, Jin-ZhongWu, Qiao-Yan Zhang, Hong Zhang, Bao-Kang Huang, Khalid Rahman, Lu-Ping
Qin, Comparative research of chemical constituents, antifungal and antitumor properties of ether extracts of
Panax ginseng and its endophytic fungus, Phytomedicine, 2009, 16, 609–616.
15
Hua Wei Zhang, Yong Chun Song and Ren Xiang Tan, Biology and chemistry of endophytes, Nat. Prod. Rep.,
2006, 23, 753-771.
16
Ravindra N. Kharwar, Ashish Mishra, Surendra K. Gond, Andrea Stierle and Donald Stierle, Anticancer
compounds derived from fungal endophytes: their importance and future challenges, Nat. Prod. Rep., 2011, 28,
1208-1228.
17
Stefan Schulz and Jeroen S. Dickschat, Bacterial volatiles: the smell of small organisms, Nat. Prod. Rep.,
2007, 24, 814-842.
18
Jörn Piel; Metabolites from symbiotic bacteria, Nat. Prod. Rep., 2009, 26, 338-362.
19
J. Piel, Metabolites from symbiotic bacteria, Nat. Prod. Rep., 2009, 26, 338-62.
20
G. Strobel and B. Daisy, Bioprospecting for microbial endophytes and their natural products, Microbio. &
Molecul. Biol. Rev., 2003, 491-502.
20
Plant associated microorganisms
H
N
N
H
COOH
Penicillium sp.
Mangrove plant
Mangrove endophytic
fungus
O
Bio. & Med. Chem. Lett., 2010, 20, 3284-3286
Trichoderma atroviride
Endophytic fungus
Salvia miltiorrhiza
O
O
O
OH
O
O
O
21
Tanshinone
Tanshinone IIA
Ferruginol
Phytomed., 2012, 19, 330-333
Phytoalexins
(Stress compounds)
O
H3CO
OH
Allixin
(from garlic)
H3C
O
1
H3CO
O
2
OH
3
O
4
Pisatin (pea)
H
O
O
1
HO
O
A
C
2
3
B
4
OH
O
OH
Kievitone
HO
Phytochem. (2010), 71, 1191-1197
Mole. Plant (2010) 74, 2231-2234
Chem. Pharm. Bull. 405 (2002) 50, 354
Phytochem. (1986) 25, 979
22
Naturally occurring organohalogen compounds
It is sometimes assumed by the lay press, environmental activists, politicians, and others,
that organohalogen compounds – organic chemicals containing one or more carbon –
chlorine, carbon – bromine, carbon – iodine, or carbon – fluorine bond – are generally not
found in nature. One purpose of this account is to document that not only are naturally
occurring organohalogen compounds ubiquitous in our environment, but concentrations of
some of these chemicals exceed their anthropogenic levels. In addition, previously
unknown naturally occurring organohalogen compounds are continually being isolated and
characterized from a variety of marine and terrestrial plant and animal sources.
The explosion of activity in the area of organohalogen natural product chemistry is certain
to continue. The continued improvements in isolation, analytical, and spectroscopic
techniques over the past few years ensure the fact that even the most structurally complex
organohalogen natural products can and will be identified. As our understanding of natural
enzymatic halogenation reaction continues to increase, it will be possible to separate more
accurately natural from anthropogenic sources of halogenated chemicals.
OH
O
MeO2C
O
Br
I
Br
Br
Cl
O
OH
Cl
O
23
Now it is well known that naturally occurring organohalogen compounds are
abundant in plants, fungi, microorganisms, and especially marine invertebrates.
Surprisingly, although fluorine is the most abundant halogen in Earth’s crust,
fluorinated natural products are very rare. Since the first organo-fluorine
compound, fluoroacetate (1), was identified in 1943 from the South African plant
Dichapetalum cyosum, only eighteen (18) fluorine-containing secondary
metabolites have been isolated from plants and microorganisms. These include
fatty acid homolgues (e.g 2), fluorothreonine (3), nucleocidin (4) and 5fluorouracils (e.g 5).
F
O
( )11
F
F
CO2H
HO2C
OH
(2)
(1)
H2N
S
O
O
F
OH OH
(4)
CO2H
O
N
O
N
HO
(3)
NH2
N
O
CO2H
N
Enhanced production of the
fluorinated nucleoside antibiotic
nucleocidin by a rifR-resistant
mutant of Streptomyces calvus
IFO13200,
Actinomycetologica
(2009) 23:51-55.
F
HN
O
N
HO
(5)
24
Because of fluorine’s unusual properties (high electronegativity, small Van der Waals
radius, high dissociation energy of C-F), fluorinated compounds have found myriad
applications such as foaming agents, blood substitutes, refrigerants, anaesthetics,
lubricants and catalysts. In the pharmaceutical and agricultural sectors, the number of
fluorinated compounds is ever increasing; 20-25% of currently available drugs and
approximately 28% of agrochemicals contain at least one fluorine atom.
O
O
F
F
N
OH
O
N
N
O
N
HN
O
Carmofur
Antitumor
(Schering) 1981
Ciprofloxacin (1983) (Bayer)
antibiotic
improved pharmacokinetic profile
F
O
N
OH
O
F
N
(R)
F
(s)
O
N
s
Ac
F
N
N
H
N
N
Voriconazole
antifungal
(Pifzer) 2002
Linezolid (Pharmacia) 2000
antibiotic
N
CF3
O
Me
N
H
Fluoxetine
(Prozac) antidepressant
(Elly Lilly) 1986
25
1
G. W. Gribble, Naturally occurring organohalogen compounds – a survey, J. Nat. Prod., 1992, 55, 1353-1395.
2
D. B. Harper and D. O. Hagan, The fluorinated natural products, Nat. Prod. Rep., 1994, 123-133.
3
G. W. Gribble, Naturally occurring organofluorines, The Handbook of Environmental Chemsistry, vol. 3, part N, organofluorins, 2002, 3, 121-136.
4
C. J. Thomas, Fluorinated natural products with clinical significance Current Topics in Medicinal Chemistry, 2006, 6, 1529-1543.
5
J. P. Bégué, and D. B. Delpon, Recent advances (1995–2005) in fluorinated pharmaceuticals based on natural products, J. Fluorine Chemistry, 2006,
127, 992-1012.
6
C. S. Neumann, D. G. Fujimori1 and C. T. Walsh, Halogenation strategies in natural product biosynthesis, Chemistry & Biology, 2008, 22, 99-109.
7
A. S. Eustáquio, D. O’Hagan and B. S. Moore, Engineering fluorometabolite production: Fluorinase expression in Salinispora tropica yields
fluorosalinosporamide, J. Nat. Prod., 2010, 73, 378–382.
8
K. Müller, C. Faeh, F. Diederich, Fluorine in pharmaceuticals: looking beyond intuition, Science, 2007, 317, 1881-1886.
9
L. C. Blasiak, C. L. Drennan, Structural perspective on enzymatic halogenation, Acc Chem Res. 2009, 42, 147-55.
10 C. Dong, F. Huang, H. Deng, C. Schaffrath, J. B. Spencer, D. O'Hagan1 & J. H. Naismith, Crystal structure and mechanism of a bacterial
fluorinating enzyme, Nature, 2004, 427, 561-565.
11 J. P. Bégué and D. B. Delpon, Bioorganic and medicianl chemistry of fluorine, John Wiley & Sons, 2008.
12 Xu XH, Yao GM, Li YM, Lu JH, Lin CJ, Wang X, Kong CH., 5-Fluorouracil derivatives from the sponge Phakellia fusca, J Nat Prod. 2003, 66(2),
285-288.
13 J. Amadio, C. D. Murphy, Biotransformation of fluorobiphenyl by Cunninghamella elegans, Appl Microbiol Biotechnol. 2010, 86(1), 345-351.
14 L. L. Xua, T. H. Jin-ZhongWu, Qiao-Yan Zhang, Hong Zhang, Bao-Kang Huang, K. Rahman, Lu-Ping Qin; Comparative research of chemical
constituents, antifungal and antitumor properties of ether extracts of Panax ginseng and its endophytic fungus, Phytomedicine, 2009, 16, 609–616.
15 D. B. Harper, D. O. Hagan and C. D. Murphy; Fluorinated natural products: Occurrence and biosynthesis; The Handbook of Environmental
Chemistry; 2003, 3, 141-169.
16 K. Fukuda, T. Tamura, Y. Segawa, Y. Mutaguchi and K. Inagaki, Enhanced production of the fluorinated nucleoside antibiotic nucleocidin by a rifRresistant mutant of Streptomyces calvus IFO13200, Actinomycetol., 2009, 23, 51-55.
26
Untapped plant power abounds everywhere. Almost, two_ third of the Earth’s 6.1 billion people rely on the
healing power of plants. One important source of new drugs of the pharmaceutical industry is from Nature. We need a
new way to listen to Nature, while maintaining all the advantages of science. By definition science welcomes new
evidence, new ways of thinking. It has no final truths. It is a continuous quest and exploration. Chemistry, a discipline
of science plays a vital role in the discovery and development of pharmaceuticals.
In Romeo and Juliet, William Shakspeare describes “the powerful grace that lies in herbs.” It is obvious that
plant’s powerful arsenal of bioactive substances ________ compounds that affect living cells _________ can be of
significant value in waging against human ailments. In fact the plant kingdom represents a largely unexplored reservoir
of valuable compounds to be discovered. Of the estimated 400,000_500,000 plant species around the globe, only a
small percentage has been investigated phytochemically and the fraction submitted to biological or pharmalogical
screening is even lower.
About 25% of the pharmaceuticals prescribed by doctors in the developed world have, as their origins, the
chemicals produced by flowering plants. If compounds produced by fungi and some animals are included, the figure is
above 40%. The ability of plants and some other living organisms to produce stereospecific molecules with very
complex skeleton is one aspect that makes them attractive as sources of novel molecules, since some structures are
beyond the imagination of even the most fanciful synthetic chemist.
27
J. Chem. Educ., 2007, 84, 2012-2018
Complexation between a biologically-active molecule (ligand), arriving from outside a cell, and receptor, embedded in the
membrane of this cell (schematic drawing): left) components before binding; (center) the ligand-receptor complex showing a
28
change of the receptor conformation, generating a biological message to the organism; and (right) components after binding.
Glycolysis
OH
OH
CO2
hv
H2O
OH
O
OH
O
Hexokinase
HO
OH
PO
PO
O
OH
6
OH
Pentose phosphate cycle
OH
OH
glucose 6P
OH
D-glucose
erythrose-4P
Aldolase
COOH
OHC
OH
glycine
CO2H
NH2
Cinnamic acids
3
PO
glyceraldehyde 3-P
Flavonoids
COOH
HO
HO
COOH
HS
HOOC
NH2
OH
L-serine
NH2
L-cysteine
3
3-phospho
glyceric acid
PO
COOH
OH
OH
Shikimic acid
Lignans,
Lignins
Aromatic amino acids
HOOC
OP
Alkaloids
NH2
L-valine
Phosphoenolypruvate
(PEP)
pyruvate kinase
COOH
HOOC
NH2
O
Terpenes, sterols
L-alanine
pyruvic acid
COOH
Mevalonic acid
Acetic acid
NH2
L-leucine
CoAS
Fattyacids, Lipids,
Prostaglandins,
Thromboxanes,
Leukotrienes
O
C
Acetyl-CoA
COOH
HOOC
NH2
L-aspartic acid
S
H2N
L-methionine
Krebs cycle
HOOC
COOH
O
oxaloacetic acid
H2N
H
L-Lysine
Alkaloids
NH2
COOH
COOH HOOC
HOOC
COOH
NH2
O
2-oxoglutaric acid
L-glutamic acid
NH
O
COOH
H2N
N
H
L-arginine
C OH
H2N
NH2
NH2
L-ornithine
29
Primary Metabolism
Alkaloids
Investigation of biosynthetic pathways
Eighty years ago, investigations of biosynthetic pathways progressed from purely hypothetical speculation to studies of the
regiospecificity of incorporation of isotopically labelled precursors by whole cells or partially purified enzymes. Towards the end of
the twentieth century, interdisciplinary approaches to establish many general precursor – product relationship were made which
were based on:
a) Enzymology
b) Genomics
c) Proteomics
d) X-ray crystallography of enzyme substrate complexes
e) Advanced NMR spectroscopy
f)
Advanced Mass spectroscopy
Reference:
1 E. Haslam, Editor D. Barton, Comprehensive organic chemistry, Biological Compounds, 5, 1979.
2
R. Thomas, Biogenetic speculation and biosynthetic advances, Nat. Prod. Rep., 2004, 21, 224-248.
3
R. Bentley, From miso, saké and shoyu to cosmetics: a century of science for kojic acid, Nat. Prod. Rep., 2006, 23, 1046-1062.
4
D. Shemin and R. Bentley, David Rittenberg 1906-1970, Biographical Memories, The National Academy Press, Washington D.C. 2001, 80,
1-20.
S. J. Weininger, Deuterium as a probe of the boundaries between physics, chemistry and biochemistry, 6th International Conference on the
History of Chemistry, 2009, 187-194.
S. F. Previs, S. T. Ciralo, C. A. Fernandez, M. Beylot, K. C. Agarwal, M. V. Soloviev and H. Brunengraber, Use of [6,6-2H2] glucose and of
low-enrichment [U-13C6]-glucose for sequential or simultaneous measurements of glucose turnover by gas chromatography – mass
spectrometry, Analytical Biochem., 1994, 218, 192-196.
H. Schierbeek, T. C. W. Moerdijk-poortviet, C. H. P. V. D. Akeer, F. W. J. T. Braake, T. S. Boschker and J. B. V. Goudoever, Analysis of [U13C ] glucose in human plasma using liquid chromatpgraphy/isotope ratio mass spectrometry compared with two other mass spectrometry
6
techniques, Rapid Comm. Mass Spectrom., 2009, 23, 3824-3830.
5
6
7
8
P. Adam, M. Gutlich, H. Oschkinat, A. Bacher and W. Eisenreich, Studies of the intermediary metabolism in cultured cells of the insect
Spodoptera frugiperda using 13C- or 15N-labelled tracers, BMC Biochem., 2005, 6, 1-11.
9 S. C. Morrison, D. A. Wood, P. M. Wood, Characterization of a glucose 3-dehydrogenase from the cultivated mushroom (Agaricus
bisporus), Appl. Microbiol. Biotechnol., 1999, 51, 58-64.
10 A. Lai, M. Casu and G. Saba, NMR investigation of the intramolecular distributin of deuterium in natural triacylglycerols, Mag. Res.
Chem., 1995, 33, 163-166.
11 N. Matsui, F. Chem, S. Yasuda, K. Fukushima, Conversion of guaiacyl to syringly moieties on the cinnamyl alcohol pathway during the
biosynthesis of lignin in angiosperms, Planta, 2000, 210, 831-835.
30
12 N. P. Botting, Isotope effects in the elucidation of enzyme mechanisms, Nat. Prod. Rep., 1994, 11, 337-353.
Using the Natural Molecule as a Template__________ Willow to Aspirin
In some cases it is not very suitable to use the isolated compounds from a
medicinal plant as a pharmaceutical. The plant may not have a sufficiently strong
effect, or most seriously, it might have undesirable side effects. In such cases, a
common approach, is to determine which parts of the molecule are responsible for
the desired activity (this portion of the molecule is sometimes termed the
pharmacophore) and which parts are not necessary or contribute to the undesired
effects. The natural compound is thus used as a template in attempts to synthesize
the pharmacophore, eliminate the undesired portions of the molecule, and
synthesize related compounds so that structure activity (SA) studies can be carried
out. This approach has led to the introduction of several major groups of drugs,
including probably the best-known drug in all the world, aspirin. Aspirin is made
completely synthetically but its development is based on the traditional use in
Europe of plants such as Willow and meadowsweet to treat rheumatism and
general aches and pains.
Analgesics
CH2OH
OH
HO
HO
O
(from Willow)
O
OH
CH2OH
(Salix Spp.)
COOH
COOH
OH
Salicin
OH
Aspirin
Salicylic acid
J. Nat. Prod. 67, 2141 (2004)
OCOCH3
31
Some important drugs synthesized using natural molecules as templates
Synthetic drug
Templates
Etopside, anticancer synthetic drug
O
Podophyllotoxin (Natural Prod.)
OH
O
O
O
HO
O
OH
O
O
O
O
O
O
O
H3CO
H3CO
OCH3
OCH3
From
(Podophyllum pettatum)
OH
CH3
Chloroquine Antimalerial
CH3
(Syn. drug)
N
H
OCH3
Quinine
CH3
HO
N
N
H3CO
H3CO
N
N
Physostigmine (from Physostigma venenosum)
H
Neostigmine
N
O
From
(Cinchona Spp.)
N+
N
O
N
O
For the treatment of myasthenia gravis (Syn. drug)
O
N
H
32
Asthma Drugs
OH
HO
NH
CH3
Adrenaline
(from animals)
OH
HO
Catechol-Omethyltransfera
se(COMT)
H3CO
NH
CH3
SAM
Inactive
HO
OH
HO
NH CH
CH3
Isoprenaline
(short acting)
(Synthetic)
CH3
HO
HO
OH
CH3
C
H
CH2 NH CH
CH3
Orciprenaline
long acting, less potent
(Synthetic)
HO
HO
H2C
OH
HO
Salbutamol (Synthetic)
t
NH But (Ventolin)
(Proventil)
Chem. in Britain 40 (2001)
Among the world's top 200 best selling prescription drugs
33
Anti HIV Nat. Product
Betulinic acid
(from Syzygium
claviflorm)
Nat. Prod. Report
23, 394 (2006)
H
H
H
COOH
H
COO
H
O
HO
C
EC50 1.4 M
TI
9.3
EC50 0.00035 M
(Potent anti-HIV) TI > 20,000
O
HOOC
Oleanolic acid
EC50 3.7 M
TI 12.8
H
EC50 0.00086 M
TI > 22400
(Potent anti-HIV)
H
COOH
CO
OH
O
HO
C
O
HOOC
Ursolic acid
H
COO
H
COOH
3
O
HO
C
O
C
HOO
C
O
EC50 0.31 M
TI > 155.5
O
O
EC50 2.1 M
TI > 23.6
TI = Therapeutic index
COOH
J. Nat. Prod. 63, 1619-1622 (2000)
Anti-Cancer Agent Med. Chem. 13, 1477-1499 (2013)
34
NP-derived drugs launched in USA, Europe or Japan since 1998 by year with reference to their lead compound,
classification and therapeutic area.
(Nat. Prod. Report, 22, 162-195, 2005)
S. No.
Year
Generic name
(trade name)
Orlistat
(Xenical®)
Lead
compound
Lipstatin
Classification
Disease area
Semisynthetic
NP
Antiobesity
Cefoselis
(Wincef®)
Valrubicin
(Valstar®)
Colforsin daropate
(Adele, Adehl®)
Cephalosporin
NP-derived
Antibacterial
Doxorubicin
NP-derived
Oncology
Forskolin
Semisynthetic
NP
Cardiotonic
1.
1998
2.
1998
3.
1999
4.
1999
5.
2000
Arteether
(Artemotil®)
Artemisinin
Semisynthetic
NP
Antimalarial
6.
2002
Galantamine
NP
7.
2003
Mycophenolic
acid
NP
Alzheimer’s
disease
Immunosuppression
8.
2003
Galantamine
(Reminyl®)
Mycophenolate
sodium
(Myfortic®)
Rosuvastatin
(Crestor®)
Mevastatin
NP derived
Dyslipidemia
NP = Natural Product
35
H3CO
O
O
HO
C
O
OH
Mycophenolic acid (NP)
is produced by fermentation cultures of the fungus Penicillium brevicompactum
Mycophenolate sodium
Myfortic® It has immunosuppressant action and is used during transplantation of organs
HO
COOH
OH
HO
O
O
H
O
O
H
(Opened lactone form)
(Lactone form)
Mevastatin (NP-lead)
is produced by cultures of Pencillium citrinum and is inhibitor of HMG-CoA
reductase, lowering sterol biosynthesis in mammalian cell cultures and
animals and reduces LDL
Rosuvastatin
Crestor®: is based on mevastatin used in dyslipidemia
(lowers cholestrol level, reduces the risk of heart attacks)
36
Natural Products in Crop Protection
H3CO
Clove
HO
Eugenol
Matran(R)
(50% clove oil)
Leaves
Eugenia caryophyllus
O
C
HO
Mentha piperita
(Peppermint)
O
Menthol
2-Phenethyl proponate
H
O
Citral
Cymbopogon citratus
(Lemon grass)
Bioorg. & Med. Chem. 2009, 17, 4022-4034
37
CH3
O
O
O
HO
OH
O
H3C
CH3
O
O
O
CH3
O
H
H3C
Azadirachta indica
(Meliaceae)
O
H
O
O
CH3
OH
H
H
O
H3 C
O
O
H
Azadirachtin
C
N
H
Capsicum frutesceus
Capsaicin
N
N
Nicotiana tabacum
Nicotine
38
There are more than 3,00,000 compounds described in
literature as Natural Products. In the following pages
structures of some aliphatic and aromatic compounds are
given, which provide a glimpse of structural diversity of
Natural Products.
39
Aliphatic Natural Products
H3C
(CH2)11
H3C
(CH2)10
CH3
OH
H
CH3 (CH2)12 C
(CH2)14 CH3
OH
O
CH3 (CH2)28 C
H
O
CH3 (CH2)12 C
(CH2)14 CH3
O
CH3 (CH2)26 C
OH
O
CH3 (CH2)10 C
O
O
(CH2)23 CH3
OH
Hexadecanoic acid
CH3 (CH2)8 CH
CH
CH2 OH
O
CH3 (CH2)10 CH
CH
O
C
O
CH3 (CH2)11 CH
CH
CH2 C
CH3
H
O
CH3 (CH2)6 CH2 CH
CH
CH2 C
CH3 CH2 (CH2)23 CH
CH
CH2 CH3
OH
Journal Lipid Research 46, 839 (2005)
40
O
CH2 O
HC
O
O
O
CH2 O
(CH2)14 CH3
Glycerides
(CH2)14 CH3
(CH2)14 CH3
OH
E
CH3 (CH2)12 CH CH HC
CH
CH2 OH
Sphingenine
NH2
OH
E
CH3 (CH2)12 CH CH
CH
CH
Ceramide
CH2 OH
HN C
(CH2)14 CH3
O
O
O
N+
O
P
H
O
O
O
C
(CH2)7
O
O
J. Chem. Educ. 79, 481 (2002)
Phosphatidyl choline
(Phospholipid)
41
OH
GlucO
CN
O
Linamarin
N
C
OC6H11O5
(Gluc.)
S
HO
HO
C
OH
N
OH
K O3SO
(2S)-2-Hydroxy but-3-enyl glucosinolate
Lotaustralin
GlucO
OH
N
CN
C
S
Isothiocyanate
Epilotaustralin
GlucO
CN
C
N
OH
(2S)-1-cyano 2-hydroxy-3-butene
H OH
Volkenin
NH
NC
OGulc
5
O
S
(5R)-5-Vinyl-1,3-oxazolidine-2-thione
Tetraphyllin A
Phytochemistry 31, 4129 (1992)
Planta Medica 69, 380 (2003)
J. Agric. Food Chem. 49, 471 (2001)
Aromatic Compounds
(Natural Products)
O
H
HO
C
C
C
Ferulic acid
OH
H
H3CO
HO
A
OH
B
Resveratrol
H3CO
OH
3'
HO
O
7
A
C
B
2
4'
OH
Catechin
OH
Epicatechin
3
OH
5
OH
OH
2'
HO
O
B
A
5'
6
4
OH
OCH3
OH
HO
O
B
OH
Malvin
A
O-Gluc OCH3
OGluc
J. Agric. Food Chem. 49, 1957 (2001)
Curr. Org. Chem. 2, 597 (1998)
43
O
H3CO
N
H
Capsaicin
OH
OH
HO
O
B
4'
OH
HO
2
A
3
1
O
7
A
2
B
OH
B
OH
C
3
5
HO
O
Naringenin
OH
HO
O
Luteolin
HO
O
OH
B
1
HO
A
2
3
A
OH
O
Fisetin
HO
OH
7
A
C
B
2
3
OH
5
HO
O
Quercetin
3
HO
O
Genistein
1
O
O
OH
J. Agric. Food Chem. 54, 1854 (2006)
J. Chem. Edu. 77, 993 (2000)
Chem. in. Britain, 27, (2001)
J. Nat. Prod. 63, 1035 (2001)
J. Org. Chem. 66, 7974 (2001)
44
OH
H3CO
O
Bellidifolin
B
A
HO
O
OH
OCH3
CH3
OCH3
H3CO
N
O
Glycocitrine-V
OH
HO
H2C
OH
O
OH
O
HO
HO
O
5
H
6
O
Coumarin
Betanin
N
HO
O
COO
2
OH
O
H
HOOC
15
N
COOH
H
P. Medica 63, 2 (1997)
P. Medica 72, 1132 (2006)
Chem. Pharm. Bull. 48, 65 (2000)
J. Agric. Food Chem. 49, 1971 (2001)
45
OH
OCH3
O
S
HO
HO
4
OH
N
K O3S
1
O
N
OCH3
1,4-Dimethoxy glucobrassicin
OCH3
OCH3
CH2 N
C
S
CH2 C
N
OCH3
N
N
OCH3
H
N
2'
4'
Cl
1
N
2
Epibatidine
(from frog)
H
4
O
Onychine
N
J. Agric. Food Chem. 49, 1502 (2001)
49, 1867 (2001)
Phytochem. Analysis 12, 1867 (2001)
J. Med. Cehm. 44, 2229 (2001)
46
HO
Morphine
Cocaine
H3C
O
N
H
N
O
CH3
H
C
O
HO
Sanguinarine
Magnoflorine
O
H3C
CH3
O
N+
O
N+
HO
CH3
CH3
HO
O
H3CO
(-)-Cis-Isocorypalmine N-oxide
Hydrastine
H3CO
O
+
O-
N
N
O
HO
H
OCH3
H
CH3
H
O
O
OCH3
P. Medica 67, 423 (2001)
J. Chem. Edu. 77, 993 (2000)
Nat. Prod. Rept. 13 (1987)
OCH3
OCH3
47
Colchicine
H3CO
NHCOCH3
H
H3CO
OCH3
O
OCH3
Ajmalimine
O
9
8
10
12
C
5
7
17
13
11
O
N
2
N
H
21
OH
3
19
CH3
15 20
14
H
Strictosidine
N
H
3
NH
H
H
OGluc
H
O
H3COOC
J. Nat. Prod. 64, 686 (2001)
48
The information provided above highlights the continuing role that natural products and structures
derived from or related to natural products from all sources have played and continue to play in the
development of the current therapeutic armamentarium of the physician. Inspection of the data shows
this continued important role for natural products, in spite of the current low level of natural productsbased drug discovery programs in major pharmaceutical houses. It is already clear that there is
considerable potential in compounds obtained through plowing in the landscape of natural products.
Particularly impressive are those compounds that are obtained through diverted total synthesis, i.e.,
through methodology, which was redirected from the original (and realized) goal of total synthesis, to
encompass otherwise unavailable congeners. There is strong expectation that enterprising and hearty
organic chemists will not pass up the unique head start that natural products provide in the quest for
new agents and new directions in medicinal discovery.
Organic chemists in concert with biologists and even clinicians will be enjoying as well as exploiting
the rich troves provided by nature’s small molecules. There is no doubt that a host of novel, bioactive
chemotypes await discovery from both terrestrial and marine sources. Finally, a multidisciplinary
approach to drug discovery, involving the generation of truly novel molecular diversity from natural
product sources, combined with total and combinatorial synthetic methodologies, and including the
manipulation of biosynthetic pathways (so-called combinatorial biosynthesis), provides the best
solution to the current productivity crisis facing the scientific community engaged in drug discovery and
development.
49
The facts stated above further serve to illustrate the inspiration
provided by Nature to receptive organic chemists in devising
ingenious syntheses of structural mimics to compete with Mother
Nature’s
longstanding
substrates.
Even
discounting
these
categories, the continuing and overwhelming contribution of
natural products to the expansion of the chemotherapeutic
armamentarium is clearly evident, and much of Nature’s “treasure
trove of small molecules” remains to be explored, particularly from
the marine and microbial environments.
50
1
D. J. Newman and G. M. Gragg, Natural products as sources of new drugs over the 30 years from 1981 to 2010, J. Nat. Prod., 2012, 75, 311-335.
2
G. A. Cordell and M. D. Colvard, Natural products and traditional medicine: turning on a paradigm, J. Nat. Prod., 2012, 75, 514-525.
3
D. Camp, R. A. Davis, M. Campitelli, J. Ebdon and R. J. Quinn, Drug-like propertites: guiding principles for the design of natural product libraries, J. Nat. Prod., 2012, 75, 72-81.
4
J. S. Miller, The discovery of medicines from plants: a current biological perspective, Economic Botany, 2011, 65, 396-407.
5
J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Munro and M. R. Prinsep, Marine natural products, Nat. Prod. Rep., 2012, 29, 144-222.
6
a) A. C. Abreu, A. J. McBain and M. Simões, Plants as sources of new antimicrobials and resistance modifying agents, Nat. Prod. Rep., 2012, 29, 1007-1021. b) M. Hakim, Y. Y. Broza,
O. Barash, N. Peled, M. Philips, A. Amann, and H. Haick, Volatile organic compounds of lung cancer and possible biochemical pathways, Chem. Rev., 2012, 112, 5949-5966. c) M.
Heuckendorff, C. M. Pedersen and M. Bols, Rhamnosylation: Diastereoselectivity of conformationally armed donors, J. Org. Chem., 2012, 77, 5559-5568.
7
C. Luley-Goedl and B. Nidetzky, Glycosides as compatible solutes: biosynthesis and applications, Nat. Prod. Rep., 2011, 28, 875-896.
8
A. Salatino , C. C. Fernandes-Silva , A. A. Righi and M. L. F. Salatino, Propolis research and the chemistry of plant products, Nat. Prod. Rep., 2011, 28, 925-936.
9
I. Chlubnová , B. Sylla , C. Nugier-Chauvin , R. Daniellou , L. Legentil , B. Kralová and V. Ferrières, Natural glycans and glycoconjugates as immunomodulating agents, Nat. Prod.
Rep., 2011, 28, 937-952.
10 H. Gao , R. Popescu , B. Kopp and Z. Wang, Bufadienolides and their antitumor activity, Nat. Prod. Rep., 2011, 28, 953-969
11 M. E. Maffei, J. Gertsch and G. Appendino, Plant volatiles: production, function and pharmacology, Nat. Prod. Rep., 2011, 28, 1359-1380.
12 M. S. C. Pedras, E. E. Yaya and E. Glawischnig, The phytoalexins from cultivated and wild crucifers: chemistry and biology, Nat. Prod. Rep., 2011, 28, 1381-1405.
13 M. H. Walter and D. Strack, Carotenoids and their cleavage products: Biosynthesis and functions, Nat. Prod. Rep., 2011, 28, 663-692.
14 S. Wang, X. Wu, M. Tan, J. Gong, W. Tan, B. Bian, M. Chen, Y. Wang, Fighting fire with fire: poisonous Chinese herbal medicine for cancer therapy, J. Ethnopharm., 2012, 6, 33-45.
15 M. S. C. Pedras, E. E. Yaya, Phytoalexins from Brassicaceae: News from the front, Phytochem., 2010, 71, 1191-1197.
16 R. Tsao, Chemistry and biochemistry of dietary polyphenols, Nutrie., 2010, 2, 1231-1246.
17 M. A. M. Mondol, J. H. Kim, M. Lee, F. S. Tareq, H.-S. Lee, Y.-J. Lee, and H. J. Shin, Leodomycins A – D, antimicrobial fatty acids from a Marine Bacillus sp., J. Nat. prod., 2011, 74,
1606-1612.
18 J. Clardy and C. Walsh, Lessons from natural molecules, Nature, 2004, 432, 829-837.
19 F. E. Koehn and G. T. Carter, The evolving role of natural products in drug discovery, Nature, 2005, 4, 206-220.
20 R. Slimestad, T. Fossen and I. M. Vágen, Onions, A source of unique dietary flavonoids, J. Agric. Food Chem., 2007, 55, 10067-10080.
21 R. C. Hider and X. Kong, Chemistry and biology of siderophores, Nat. Prod. Rep., 2010, 27, 637-657.
51
22 K. Yoshida, M. Mori and T. Kondo, Blue flower color development by anthocyanins: from chemical structure to cell physiology, Nat. Prod. Rep., 2009, 26, 884-915.
23
A. D. Kinghorn, L. Pan, J. N. Fletcher and H. Chai, The relevance of higher plants in lead compound discovery programs, J. Nat. Prod., 2011, 74, 1539-1555.
24
P. Williams, A. Sorribas and M.-J. R. Howes, Natural products as a source of Alzheimer’s drug leads, Nat. Prod. Rep., 2011, 28, 48-77.
25
N. Fusetani, Antifouling marine natural products, Nat. Prod. Rep., 2011, 28, 400-410.
26
K.-H. Lee, Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach, J. Nat. Prod., 2010, 73, 500-516.
27
A.
28
A. Schierling, M. Schott, K. Dettner and K. Seifert, Biosynthesis of the defensive alkaloid (z)-3-(2-methyl-1-butenyl)pyridine in Stenus similis beetles, J. Nat. Prod., 2011, 74, 22312234.
29
a) B. Meunier, Does chemistry have a future in therapeutic innovations? Angew. Chem. Int. Ed. 2012, 51, 8702-8706. b) M. A. Fischbach and C. T. Walsh, Antibiotics for emerging
pathogens, Science, 2009, 28, 1089-93.
30
G. K. Jayaprakasha, Y. Jadegoud, G. A. N. Gowda and B. S. Patil, Bioactive compounds from sour orange inhibit colon cancer cell proliferation and induce cell cycle arrest, J. Agric.
Food Chem., 2010, 58, 180-186.
31
C. Paul and G. Pohnert, Production and role of volatile halogenated compounds from marine algae, Nat. Prod. Rep., 2011, 28, 186-195.
32
N. D. Yuliana, A. Khatib, Y. H. Choi and R. Verpoorte, Metabolomics for bioactivity assessment of natural products, Phytother. Res., 2011, 25, 157-169.
33
B. O. Bachmann, Biosynthesis: is it time to retro,? Nature Chem. Biol., 2010, 6, 390-393.
34
F. E. Dayan, C. L. Cantrell, S. O. Duke, Natural products in crop protection, Bioorg. & Med. Chem., 2009, 17, 4022-4034.
35
E. Leistner and C. Drewke, Ginkgo biloba and ginkgotoxin, J. Nat. Prod., 2010, 73, 86-92.
36
D. Skropeta, Deep-sea natural products, Nat. Prod. Rep., 2008, 25, 1131-1166.
37
Y. Kariya, T. Kubota, J. Fromot and J. Kobayashi, Pyrinadine A, a novel pyridine alkaloid with an azoxy moiety from sponge Cribrochalina sp. Tetra. Lett., 2006, 47, 997-998.
38
D. G. I. Kingston, Modern natural products drug discovery and its relevance to biodiversity conservation, J. Nat. Prod., 2011, 74, 496-511.
39
M. Pucheault, Natural Products: chemical instruments to apprehend biological symphony, Org. Biomol. Chem., 2008, 6, 424-432.
40
N. Dixon, L. S. Wong, T. H. Geerlings and J. Micklefield, Cellular targets of natural products, Nat. Prod. Rep., 2007, 24, 1288.
41
David J. Newman and Gordon M. Cragg, Natural products as sources of new drugs over the last 25 Years, J. Nat. Prod. 2007, 70, 461-477.
42
Dwight D. Baker, Min Chu, Uma Oza and Vineet Rajgarhia, The value of natural products to future pharmaceutical discovery, Nat. Prod. Rep., 2007, 24, 1225–1244.
43
M. Fullbeck, E. Michalsky, M. Dunkel and R. Preissner, Natural products: Sources and databases, Nat. Prod. Rep., 2006, 23, 347-356.
44
Paul M. Dewick, Medicinal natural products, A Biosynthetic Approach 2nd Ed. 2002.
45
E. Haslam, Editor D. Barton, Comprehensive organic chemistry, Biological Compounds, 5, 1979.
Debbab, A. H. Aly, W. H. Lin, Bioactive compounds from marine bacteria and fungi, Micro. Biotech., 2010, 3, 544-583.
52
46
C.-M. Liu, G.-H. Zhang, C. Cheng and J.-M. Sun, Quercetin protects mouse brain against lead-induced neuroxicity, J. Agric. Food Chem., 2013, 61, 7630-7635.
47
F. F. Silva, J. D. F. Inacio, M. M. C. Cavalheiro and E. E. A. Amaral, Reactive oxygen species production by quercetin causes the death of Leishmania azazonensis intracellular amastigotes, J.
Nat. Prod., 2013, 76, 1505-1508.
48
A. W. Boots, L. C. Wilms, E. L. R. Swennen, J. C. S. Kleinjans, A. Bast and G. R. M. M. Haenen, In vitro and ex vivo anti-inflammatory activity of quercetin in healthy volunteers, Nutrition,
2008, 24, 703-710.
49
D. Prochazkova, I. Bousova, N. Wilhelmova, Antioxidant and prooxidant properties of flavonoids, Fitotherapia, 2011, 82, 513-523.
50
S. Y. Wang, H. Chen, M. J. Camp, M. K. Ehlenfeldt, Flavonoid constituents and their contribution to antioxidant activity in cultivars and hybrids of rabbiteye blueberry (Vaccinium ashei Reade),
Food Chem., 2012, 132, 855-864.
51
L. E. Wright, Curcuminoids block TGF- signaling in human breast cancer cells and limit osteolysis in a murine model of breast cancer bone metastasis, J. Nat. Prod., 2013, 76, 316-317.
52
A. Minass, G. S. Duffhues, J. A. Collado, E. Munoz and G. Appendino, Dissecting the pharmacophore of curumin. Which structural element is critical for which action, J. Nat. Prod., 2013, 76,
1105-1112.
53
P. V. Phan, A. Sohrabi, A. Polotsky, D. S. Hungerford, L. Lindmark and C. G. Frondoza, Ginger extract components suppress induction of chemokine expression in human synoviocytes, The
Journal of Alternative and Complementary Medicine, 2005, 11, 149-154.
54
R. Gizanna, L. Lindmark, C. G. Frondoza, Ginger-an herbal medicinal product with broad anti-inflammatory actions, J. Med. Food, 2005, 8, 125-132.
55
Y. Dai, L. Harinantenaina, P. J. Brodie, M. Goetz, Y. Shen, Karen T. Dyke, and D. G. I. Kingston, Antiproliferative homoisoflavonoids and bufatrienolides from Urginea depressa, J. Nat. Prod.,
2013, 76, 865-872.
56
L. M. Y. Banuls, E. Urban, M. Gelbcke, F. Dufransne, B. Kopp, R. Kiss and M. Zehl, Structure activity relationship analysis of bufadienolide induced in vitro growth inhibitory effects on mouse
and humann cancer cells, J. Nat. Prod., 2013, 76, 1078-1084.
57
S. C. Jonnalagadda, M. A. Corsello and C. E. Sleet, Betulin-betulinic acid natural product based analogs as anti-cancer agents, Anti-Cancer Agent. Med. Chem., 2013, 13, 1477-1499.
58
Y. Wan, S. Jiang, L.H. Lian, T. Bai, B. H. Cui, X. T. Sun, X. J. Jin, Y. L. Wu, J. X. Nan, Betulinic acid and betulin ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and
in vitro, Intern. Immunopharm., 2013, 17, 184-190.
59
R. Powell, Homoharringtonine: A pharmacognosy success story, The American Society of Pharmacognosy, The ASP Newsletter, 2012, 48(4), 1-7.
60
M. S. Butler, M. A. Blaskovich and M. A. Copper, Antibiotics in the clinical pipeline in 2013, J. Antibiot.ic., 2013, 66, 571-591.
61
A.
62
N. Masui, F. Chen, S. Yasuda, K. Fukushima, Conversion of guaiacyl to syringyl moieties on the cinnamyl alcohol pathway during the biosynthesis of lignin in angiosperms, Planta, 2000, 210,
831-835.
63
C. M. Stevens, D. M. Silver, B. Behm and R. J. Turner, OMLeT-An alternative approach to learning metabolism: glycolysis and the TCA cycle as an example, J. Chem. Edu., 2007, 84(12), 20242029.
64
R. Morphy and Z. Rankovic, Designed multiple ligands. An emerging drug discovery paradigm, J. Med. Chem., 2005, 48(21), 6523-6543.
65
C. D. Strader, The view from inside the receptor, J. Med. Chem., Guest Editorial, 1996, 39(1).
Stenbaek, P. E. Jensen, Redox regulation of chlorophyll biosynthesis, Phytochem., 2010, 71, 853-859.
53
54

similar documents