Natural products in pharmaceutical chemistry Nelson giovanny rincon silva

CONTENT
Introduction – Natural Products
Classes & Functions – Primary & Secondary Metabolites
Basics Concepts
Natural products: A continuing source of novel drug leads
2
Medicinal and Pharmaceutical Chemistry
The Role of Traditional Medicine and Plants in Drug Discovery
The Role of Marine Organisms in Drug Discovery
Other Sources (Animals
The Importance of Natural Products In Drug Discovery And Development
Generals Ideas – Conclusions

4
NATURAL PRODUCTS
N.P´s are chemical compounds or substance produced by a living organism—that are
found in nature.
N.P´s sometimes have pharmacological or biological activity that can be of therapeutic
benefit in treating diseases
P. M. Dewick. Medicinal Natural Products, A Biosynthetic Approach. Second Edition (2002). John Wiley & Sons. England
http://www.plantscience4u.com/2013/02/primary-and-secondary-metabolites.html#.VR99wvmG8o0

5
CLASSES
The broadest definition of N.P. is anything that is produced by life:
 Biotic materials (e.g. wood, silk)
 Bio-based materials (e.g. bioplastics, cornstarch)
 Bodily fluids (e.g. milk, plant exudates)
 Other natural materials (e.g. soil, coal).
N.P´s may be classified according to their:
 Biological function
 Biosynthetic pathway
 Source.

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NATURAL PRODUCTS
Within the field of O.C., the N.P´s are usually restricted to mean purified organic
compounds isolated from natural sources that are produced by the pathways:
 Primary
metabolism
 Secondary
metabolism
Edit by: Giovanny Rincon-Silva
O.C. : Organic Chemistry

7
N.P´s are often divided into two major classes:
 Primary metabolites: have an intrinsic function that is essential to the survival of the
organism that produces them.
 Secondary metabolites: have an extrinsic function that mainly affects other organisms.
Some secondary metabolites have useful medicinal properties.
Streptomycin, an important antibiotic drug produced by Streptomyces bacteria
CLASSES & FUNCTIONS

8
P.M. Components of basic metabolic pathways that are required for life.
They are associated with essential cellular functions such as:
 Nutrient assimilation
 Energy production
 Growth/development.
Primary Metabolites
Molecular building blocks of life
Re wrote: Presenter

9
S.M. Compounds that are not directly involved in the normal growth, development, or
reproduction of an organism.
Unlike P.M. absence of S.M. don’t result in immediate death, but rather the organism's
survivability, fecundity or perhaps in no significant change at all.
Humans use secondary metabolites as medicines, flavorings, and recreational drugs.
Secondary metabolites
http://myeclinik.com/tag/marijuana/

A. are produced by:
Basic Concepts - Compounds
http://thechive.com/2014/04/26/some-of-the-most-lethal-nopes-in-the-world-10-photos/venomous-poisonous-9/
Nicotiana
tabacum
Phyllobates
terribilis
10

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A. possess psychotropic (e.g. psilocin) and stimulant activities (e.g. cocaine, caffeine, nicotine), and
have been used in entheogenic rituals or as recreational drugs.
The first individual alkaloid, morphine, was isolated in 1804 from the opium poppy
(Papaver somniferum)

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Terpenoids or isoprenoids, are a large and diverse class of naturally occurring organic
chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified
in thousands of ways
Aflatoxin B1 is an aflatoxin produced by Aspergillus flavus and A. parasiticus. It is arguably the most potent
carcinogen known and is up to twice as carcinogenic as an equitoxic dose of X-rays.
Produced by certain living organisms in order to impart to them some survival advantage.
Are biosynthesized by polymerization of acetyl propionyl

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Most of the S.M. of interest to humankind fit into categories which classify secondary
metabolites based on their biosynthetic origin:
Small "small molecules“
Codeine and Morphine, present in Papaver somniferum, the opium poppy
Vincristine & Vinblastine, mitotic inhibitors found in the Rosy Periwinkle
Secondary metabolites: Categories
Cocaine
Erythroxylon coca plant Solanaceae nightshade plant
Scopolamine

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Azadirachtin, (Neem tree)
tetrahydrocannabinol, present in cannabis
Steroids (Terpenes)
Saponins (plant steroids, often glycosylated)
5α-dihydroprogesterone (5α-DHP(−)-trans-Δ9- tetrahydrocannabinol
Edit: Author

16
Glycosides (heavily modified sugar molecules):
Nojirimycin and Glucosinolates
Phenazines:
Phenazine-1-carboxylic acid (and derivatives)
Biphenyls and dibenzofurans
Beta-lactams:
Penicillin, present in Penicillium fungi (See Later)
Penicillin
Natural phenols:
Edit: Author

17
Big "small molecules", produced by large, modular, "molecular factories“
Polyketides:
Erythromycin (see before)
Lovastatin and other statins
Nystatin
Rifamycin
Fatty acid synthase products :
FR-900848
phloroglucinols
Lovastatin
Nystatin

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Nonribosomal peptides:
Ramoplanin
Teicoplanin
Gramicidin
Bacitracin
Ciclosporin
Hybrids of the above three:
Epothilone
Polyphenols
Non-"small molecules" –
DNA, RNA, ribosome, or polysaccharide "classical" biopolymers
Ribosomal peptides:
Vancomycin
Theaflavin-3-gallate, a plant derived polyphenol
Staphylococcus
aureus

19
Plants, in particular, have formed the basis of sophisticated traditional medicine systems:
2600 BCE documenting the uses of approximately 1 000 plant-derived substances.
Natural products: Historic Context
A continuing source of novel drug leads
http://laantiguamesopotamia.blogspot.com/
Commiphora species
Treatment of ailments ranging from coughs
and colds to parasitic infections and inflammation
Edit: Author
J.K. Borchardt, The beginnings of drug therapy: Ancient mesopotamian medicine, Drug News Perspect. 15 (2002) 187–192.

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Egyptian medicine dates from about 2900 BCE, but
the best known record is the "Ebers Papyrus“.
Dating from 1500 BCE, documenting over 700
drugs, mostly of plant origin
The Chinese Materia Medica has been extensively
documented over the centuries
First about 1100 BCE (containing 52 prescriptions),
followed by the Shennong Herbal
400 Drugs
K.C. Huang, The pharmacology of chinese herbs, 2nd ed. CRC Press, Boca Raton, FL, 1999.

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Documentation of the Indian Ayurvedic system dates from before 1000 BCE
(Charaka &Sushruta; Samhitas with 341 and 516 drugs respectively).
Dhanvantari (धन्वंतरी), known
as an avatar of Vishnu is the
Hindu god associated with
Ayurveda.
S. Dev, Ancient-modern concordance in ayurvedic plants: Some examples, Environ. Health Perspect. 107 (1999) 783–789.

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Ayurveda: 8 ways to diagnose illness, called Nadi (pulse), Mootra (urine), Mala (stool), Jihva
(tongue), Shabda (speech), Sparsha (touch), Druk (vision), and Aakruti (appearance)
S. Dev, Ancient-modern concordance in ayurvedic plants: Some examples, Environ. Health Perspect. 107 (1999) 783–789.

23
The Greeks and Romans contributed substantially to the rational development of the use of
herbal drugs in the ancient Western world.
Pedanius Dioscorides
(Ancient Greek: Πεδάνιος Διοσκουρίδης; c. 40 – 90 AD)
 Physician
 pharmacologist
 botanist
D.S. Fabricant, N.R. Farnsworth, The value of plants used in traditional medicine for drug discovery, Environ. Health Perspect.
109 (2001) 69–75, (supplement).
Author of De Materia Medica a encyclopedia about herbal medicine
and related medicinal substances
(A pharmacopeia)
Was widely read for more than 1,500 years.

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Aelius Galenus or Claudius G.(Greek: Κλαύδιος AD 129 – c. 200/) known as Galen of
Pergamon.
Was a prominent Greek physician, surgeon and philosopher in the Roman empire.
Arguably the most accomplished of all medical researchers of antiquity.
109 (2001) 69–75, (supplement).

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The Arabs preserved much of the Greco-Roman expertise during the Dark and Middle Ages
(5th to 12th centuries)
Abulcasis - Abu Al Qasim (936 - 1013), an surgeon at-Andalus, intellectual center of the
Caliphate of Cordova wrote "Al - Tasrif" or Vade - Mecum, 30 volumes - presents all the
knowledge of anatomy, physiology, nosology and therapy.
Edit: Author
109 (2001) 69–75, (supplement).

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In 1909 the American Chemical Society founded its ‘Division of Pharmaceutical Chemistry’;
the division was later renamed as‘Division of Chemistry of Medicinal Products.’
In 1948 the term medicinal chemistry emerged, ‘Division of Medicinal Chemistry:
Name of the field:
Medicinal chemistry Chimie thérapeutique
Wikstofforschung Chimia Farmaceutica
Farmacochemie
1973 a definition:
‘Medicinal chemistry concerns the discovery, the development, the identification and the
interpretation of the mode of action of biologically active compounds at the molecular
level. Emphasis is put on the discovery and development of drug, as indicated by the
adjective ‘medicinal.’
H. Timmerman, Medicinal and Pharmaceutical Chemistry, molecular Science and Chem, Engin. 123 (2013) 1-8

27
Edit: Author
H. Timmerman, Medicinal and Pharmaceutical Chemistry, molecular Science and Chem, Engin. 123 (2013) 1-8
The urgent need for new pharmaceuticals
for the treatment of cancer, HIV and other
infectious diseases, demands a exploration
to drug discovery and it is clear that Nature
has played, and will continue to play a vital
role in this process.

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Plant-based systems continue to play an essential role in healthcare
WHO estimated in 1985 that approximately 65% of the population of the world predominately
relied on plant-derived traditional medicines for their primary health care
The Role of Traditional Medicine and Plants
in Drug Discovery
Ammi Visnaga
Bronchodilator
Galega OfficinalisAntidiabetic drug
M. Gordon, C. David, Newman. Natural products: A continuing source of novel drug leads, Biochimica et Biophysica Acta 1830 (2013)
3670-3695.

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in Drug Discovery
Papaver somniferum
Used in the treatment of hypertension
3670-3695.

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in Drug Discovery
Natural antimalarial agents and analogues:
Cinchona species
3670-3695.
Anopheles

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Plants have a long history of use in the treatment of cancer, though many of the claims for
the efficacy of such treatment should be viewed with some skepticism
in Drug Discovery
3670-3695.
Catharanthus roseus
Treatment of leukemia
and Hodgkin's lymphoma.

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in Drug Discovery
Paclitaxel (Taxol®), the most exciting plant-derived anticancer drug discovered in recent years,
along with several key precursors (the baccatins) in the leaves of various Taxus species
3670-3695
http://home.ccr.cancer.gov/connections/2008/Vol2_No1/features3.asp
http://home.ccr.cancer.gov/connections/2008/Vol2_No1/features3.asp

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The world‘s oceans, covering more than 70% of the earth's surface, represent an enormous
resource for the discovery of potential chemotherapeutic agents.
The systematic investigation of marine environments as sources of N.B.A.A. began mid-1970s.
70’s -90´s: 3 000 new metabolites were reported from a variety of marine organisms
1003 new compounds covering just publications in 2010.
These studies have clearly demonstrated that the marine environment is a rich source of bioactive
compounds, many not found in terrestrial sources.
N.B.A.G. Novel Biologically active agents
M. Gordon, C. David, Newman. Natural products: A continuing source of novel drug leads, Biochimica et Biophysica Acta 1830 (2013) 3670-3695.

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The complex alkaloid ecteinascidin 743 isolated from the colonial tunicate Ecteinascidia
turbinata.
It has been designed in Europe and the USA under the name Yondelis® (approved 2007) by the
EMEA for the treatment of soft tissue sarcomas (STS).
3670-3695.

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Marine-derived anticancer agents are Halichondrin B, a complex polyether isolated of several
sponge sources.
Bryostatin 1 another complex macrolide originally isolated from the bryozoan, Bugula neritina
Bryozoan, Bugula neritina
Sponge
3670-3695.

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The serendipitous discovery of penicillin from the filamentous fungus, Penicillium notatum.
In 1929 - broad therapeutic use of this agent in the 1940s.
Ushered in a new era in medicine, "the Golden Age of Antibiotics", and promoted the intensive
investigation of Nature as a source of novel bioactive agents
The Role of Microorganisms in Drug Discovery.
Alexander Fleming
3670-3695.

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Microorganisms are a prolific source of structurally diverse bioactive metabolites and have
yielded some of the most important products of the pharmaceutical industry.
Antibacterial agents, such as the penicillins, Cephalosporins (Cephalosporium acremonium)
Aminoglycosides, tetracyclines and other polyketides.
Cephalosporins
Aminoglycosides
Cephalosporium
acremonium
3670-3695.

38
Immunosuppressive agents, such as the cyclosporins (from Trichoderma and
Tolypocladium species) and rapamycin (from Streptomyces species)
Trichoderma and
Tolypocladium species
Streptomyces
species
3670-3695.

39
Cholesterol lowering agents, such as mevastatin (compactin; from Penicillium
species) and lovastatin (from Aspergillus species)
And anthelmintics and antiparasitic drugs, such as
the ivermectins (from Streptomyces species)
Aspergillus species
Streptomyces species
3670-3695.

40
Antitumor Antibiotics:
Are amongst the most important of the cancer chemotherapeutic agents, which include members
of the anthracycline, the enediynes, and the staurosporines:
Mitomycin
3670-3695.

41
The epothilones isolated from myxobacteria have emerged as some of the most interesting natural
product base structures being considered as agents for clinical trials in chemotherapy.
These macrolides, with a mechanism of action similar to that of paclitaxel (Taxol®)
http://www.for1406.uni-muenchen.de/index.html
3670-3695.

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A notable discovery was the isolation of exendin-4 from the venom of the Gila monster,
Heloderma suspectum led to the development of the extenatide polypeptide, Byetta®.
.
Other Sources (Animals)
http://reptilefacts.tumblr.com/post/38234059618/u
3670-3695.
An injectable medicine used to improve glucose (blood sugar) control in type 2 diabetes

43
Epibatidine, isolated from the skin of the poisonous frog, Epipedobates tricolor, has led to
the development of a novel class of potential painkillers
http://www.dendrobase.de/html/D_epipedobates_anthonyi.html
The natural habitat is the Andean slopes of the central Ecuadorian Bolívar Province and Cotopaxi
Province, (Ecuador).
3670-3695.

44
Predatory gastropods that belong to the genus Conus are marine animals, with 700 species.
Cone snails have developed a deadly envenomation strategy that is used in prey capture and in
defense and is perceived to play an important role in its evolutionary success.
Vermivorous (worm hunters)
Molluscivorous (mollusc hunters)
Piscivorous (fish hunters)
http://darkerview.com/wordpress/?tag=snail
J. Prashanth, J. Richard, Lewis. Towarrds an integrated venomics approach for accelerated conopeptide discovery, Toxicon 60 (2012)
470-477.

45
Venom comprising numerous small, cysteine rich peptides called conotoxins or conopeptides
Along with analogues of endogenous signalling peptides and linear peptides.
Most conopeptides range between 10 and 30 amino acids in length and each cone snail species
produces venom comprising over 1000 unique peptides.
It is currently estimated that there are 50 000 different conopeptides of which less than 0.1 %
have been characterized to date
Mu-conotoxin
470-477.

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470-477.

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The high selectivity by showing conotoxins receptors and ion channels could allow use as drugs to treat
various neuropathies.
The most notable example to date is the Ziconotide drug. This compound is the synthetic form of the w-
conotoxin MVIIA, Conus magus which blocks N-type calcium channel.
The Ziconotide was evaluated as a drug to block chronic pain in patients with terminal cancer and AIDS,
and its power and effectiveness are higher than related drugs
Is a thousand times more potent than morphine and is not addictive.
https://venomstodrugs.wordpress.com/current-venom-drugs/
470-477.

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Teprotide: isolated from the venom of the pit viper, Bothrops jararaca, led to the design
and synthesis of the ACE inhibitors: treatment of hypertension.
Captopril and enalapril used in the treatment of cardiovascular disease
3670-3695.
ACE: angiotensin-converting-enzyme inhibitor

49
Dendroaspis polylepis (black mamba) is probably the most feared snake in Africa, making it a
popular icon in movies and even a “street name” for certain psychoactive illegal drugs.
(family Elapidae): Category 1 by WHO in 17 countries in sub-Saharan Africa: to species of ‘highest
medical importance’, i.e. as ‘highly venomous snakes.
http://3oneseven.com/green-mamba/http://wallpapers111.com/black-mamba-hd-wallpapers/
H. Andreas, B. Lomonte, B.Lohse, J. Fernández, J.M.Gutiérrez. Unveiling the nature of black mamba (Dendroaspis polylepis) venom through venomics
and antivenom immunoprofiling: Identification of key toxin targets for antivenom development, Journal Of Proteomics 119 (2015) 126 – 142

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Effects: Paresthesia, strange taste in the mouth, nausea, retching, vomiting, abdominal pain,
diarrhea, sweating, salivation, “gooseflesh”, and conjunctival congestion.
Neurotoxicity: eliciting effects such as
Ptosis Diplopia
Dysphagia Flaccid paralysis
Slurred speech Dyspnea due to respiratory muscle paralysis
Involuntary skeletal muscle contractions.
Associated with Hemorrhage, or necrosis.

51
Dendrotoxins are unique components of the genus Dendroaspis
Include metalloproteinase (MP), hyaluronidase (HYA), prokineticin (KTC), nerve growth factor (NGF),
vascular endothelial growth factor (VEGF), phospholipase A2 (PLA2), 5′-nucleotidase (NUCL), and
phosphodiesterase (PDE) families.
Low amount of PLA2, which is an abundant component in the majority of elapid venom

52
Mambalgins, which are members of the three-finger toxin family constitute 1.4% of the venom
proteins.
Model of mambalgins' structure.
Similar to morphine, but without side effects
II isoforms of mambalgin which have been given the names of M-1 and M-2.
Both of these isopeptides : 57 aminoacidic chain with 8 residues of cysteine.
Differ only in the residue located in the fourth position of the chain
Acid-Sensing Ion Channels (ASICs) are neuronal voltage-insensitive
cationic channels activated by extracellular protons

53
Scolopendra gigantea, also known as the Peruvian giant yellow-leg centipede or Amazonian giant
centipede, is a representatives of the genus Scolopendra with a length up to 30 cm
3670-3695.
The Red Scorpion or Blue Scorpion (Rhopalurus junceus) is an endemic species, one of 36 different
types of scorpion found on the islands of Cuba and Dominican Republic.
http://www.havanatimes.org/sp/?p=16280

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The venom of the spider called the bananeras, one of the most powerful in the world
It has medicinal properties for treating cardiac arrhythmia and cerebral ischemia.
3670-3695.
The PHKV toxin in the venom of this spider, inhibits atrial and ventricular arrhythmias
Toxin using TX3-4 experiments showed neuroprotective action, reduced hippocampal cell death
and restored the function of neurons affected by cerebral ischemia (stroke).
Phoneutria nigriventer

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The Importance of Natural Products In Drug
Discovery And Development
analyzed the sources of new drugs over the period 1981-2014, and classified these
compounds as:
N (an unmodified natural product)
NB (a natural product botanical)
ND (a modified natural product)
S (a synthetic compound with no natural product conception)
S* , S*/NM (a synthetic compoundwith a natural product pharmacophore;
/NM indicating competitive inhibition)
S/NM (a synthetic compound showing competitive inhibition of the natural product
substrate).
3670-3695.

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1073 small molecule, new chemical entities (NCEs): 66% of the “formally synthetic”.
17%: molecules containing pharmacophores derived directly from N.P´s classified as S* and S*/NM.
14% are actually modeled on a N.P. inhibitor of the molecular target of interest
(i.e. competitively inhibit) the endogenous substrate of the active site (S/NM).
Only 36% can be classified as truly synthetic (i.e., devoid of natural) in origin (S)
The Importance of Natural Products In Drug
Discovery And Development
3670-3695.

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GENERALS IDEAS – CONCLUSIONS
All humanity benefits from the discovery of new drugs, all societies should collaborate in the
preservation and evaluation of the areas of great diversity from which such structures might
emerge. This could be carried out through investments made by pharmaceutical companies to
help preserve this type of land.
From the beginning of time N.P´s have been used as medicines for
humanity, this use has become more sophisticated with the passage
of time, until the development of sciences for study such as biology
and chemistry. In fact, this has contributed to develop new subareas
of knowledge such as biochemistry and pharmacist.

58
GENERALS IDEAS – CONCLUSIONS
In the future, 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, though plant endophytes also offer an exciting
new resource.

Natural products in pharmaceutical chemistry Nelson giovanny rincon silva

Natural products in pharmaceutical chemistry Nelson giovanny rincon silva

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