natural products in pharmaceutical chemistry nelson giovanny rincon silva

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NATURAL PRODUCTS IN PHARMACEUTICAL CHEMISTRY

NELSON GIOVANNYRINCON-SILVA

CONTENT

Introduction – Natural Products

Classes & Functions – Primary & Secondary Metabolites

Basics Concepts

Natural products: A continuing source of novel drug leads

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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

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INTRODUCTION

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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

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CLASSESThe 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

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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


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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 lifeP. M. Dewick. Medicinal Natural Products, A Biosynthetic Approach. Second Edition (2002). John Wiley & Sons. England

Re wrote: Presenter

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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

P. M. Dewick. Medicinal Natural Products, A Biosynthetic Approach. Second Edition (2002). John Wiley & Sons. Englandhttp://thechive.com/2014/04/26/some-of-the-most-lethal-nopes-in-the-world-10-photos/venomous-poisonous-9/

Nicotiana tabacum

Phyllobates terribilis

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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.


Polyketides

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 poppyVincristine & Vinblastine, mitotic inhibitors found in the Rosy Periwinkle

Secondary metabolites: Categories

Alkaloids (usually a small,

heavily derivatized amino

acid):

Cocaine

Erythroxylon coca plant Solanaceae nightshade plant

Scopolamine


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Azadirachtin, (Neem tree)tetrahydrocannabinol, present in cannabisSteroids (Terpenes)Saponins (plant steroids, often glycosylated)

Terpenoids

(come from semiterpene

oligomerization):

5α-dihydroprogesterone (5α-DHP(−)-trans-Δ9- tetrahydrocannabinol

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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:

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Big "small molecules", produced by large, modular, "molecular factories“

Polyketides:Erythromycin (see before)Lovastatin and other statinsNystatinRifamycin

Fatty acid synthase products :FR-900848phloroglucinols

Lovastatin

Nystatin



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Nonribosomal peptides:

RamoplaninTeicoplaninGramicidinBacitracinCiclosporin

Hybrids of the above three:EpothilonePolyphenols

Non-"small molecules" – DNA, RNA, ribosome, or polysaccharide "classical" biopolymersRibosomal peptides:

Vancomycin

Theaflavin-3-gallate, a plant derived polyphenol


Staphylococcus aureus


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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.


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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.



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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.

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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

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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


Ammi Visnaga

Bronchodilator

Galega OfficinalisAntidiabetic drugM. 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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Papaver somniferum

Used in the treatment of hypertension

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 Role of Traditional Medicine and Plants in Drug DiscoveryNatural antimalarial agents and analogues:

Cinchona species


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



Catharanthus roseus

Treatment of leukemia and Hodgkin's lymphoma.

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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

M. Gordon, C. David, Newman. Natural products: A continuing source of novel drug leads, Biochimica et Biophysica Acta 1830 (2013) 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 enormousresource 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 agentsM. 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).



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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


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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 intensiveinvestigation of Nature as a source of novel bioactive agents

The Role of Microorganisms in Drug Discovery.

Alexander Fleming


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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


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Immunosuppressive agents, such as the cyclosporins (from Trichoderma and Tolypocladium species) and rapamycin (from Streptomyces species)


Trichoderma and Tolypocladium species

Streptomyces species


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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


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Antitumor Antibiotics:Are amongst the most important of the cancer chemotherapeutic agents, which include members of the anthracycline, the enediynes, and the staurosporines:


Mitomycin


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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


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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


An injectable medicine used to improve glucose (blood sugar) control in type 2 diabetes

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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).


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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.

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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


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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/


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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



ACE: angiotensin-converting-enzyme inhibitor

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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 DiplopiaDysphagia Flaccid paralysisSlurred speech Dyspnea due to respiratory muscle paralysisInvoluntary skeletal muscle contractions.

Associated with Hemorrhage, or necrosis.


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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


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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

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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



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.



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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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).


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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)



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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.

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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.

Thank You

natural products in pharmaceutical chemistry nelson giovanny rincon silva

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